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e3ef14d24d09ecfbc148d3175c1878c983336a30 | wikidoc | Hysteroscopy | Hysteroscopy
# Overview
Hysteroscopy is the inspection of the uterine cavity by endoscopy. It allows for the diagnosis of intrauterine pathology and serves as a method for surgical intervention (operative hysteroscopy).
# Method
The hysterocope has an optical system usually now connected to a video system, a light bearing system with fiberoptics, and a channel for delivery of a distention medium. The uterine cavity is a potential cavity, for inspection it needs to be distended. Thus during hysteroscopy either fluid (saline, sorbitol, or a dextrane solution) or CO2 gas is introduced to expand the cavity.
After cervical dilation, the hysteroscope is guided into the uterine cavity and an inspection is performed. If abnormalities are found, an operative hysteroscope also has a channel to allow specialized instruments to enter the cavity and perform surgery.
Typically hysteroscopic intervention is done under anesthesia, but a diagnostic procedure can be performed without anesthesia with instruments of smaller caliber.
# Indications
Hysteroscopy is useful in a number of uterine conditions:
- Asherman syndrome
- Endometrial polyp
- Gynecologic bleeding
- Uterine fibroids
- Uterine malformations
# Complications
The most common problem is a uterine perforation when the instrument breaches the wall of the uterus. This can lead to bleeding and to damage to other organs. Distention media also can lead to an embolus or water intoxication.
# Variations
A contact hysteroscope is a hysteroscope that does not use distention media. A resectoscope is a variation of a hysteroscope that contains an electric loop to resect a submucous leiomyoma.
de:Hysteroskopie
he:היסטרוסקופיה
nl:Hysteroscopie | Hysteroscopy
Template:Interventions infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Hysteroscopy is the inspection of the uterine cavity by endoscopy. It allows for the diagnosis of intrauterine pathology and serves as a method for surgical intervention (operative hysteroscopy).
# Method
The hysterocope has an optical system usually now connected to a video system, a light bearing system with fiberoptics, and a channel for delivery of a distention medium. The uterine cavity is a potential cavity, for inspection it needs to be distended. Thus during hysteroscopy either fluid (saline, sorbitol, or a dextrane solution) or CO2 gas is introduced to expand the cavity.
After cervical dilation, the hysteroscope is guided into the uterine cavity and an inspection is performed. If abnormalities are found, an operative hysteroscope also has a channel to allow specialized instruments to enter the cavity and perform surgery.
Typically hysteroscopic intervention is done under anesthesia, but a diagnostic procedure can be performed without anesthesia with instruments of smaller caliber.
# Indications
Hysteroscopy is useful in a number of uterine conditions:
- Asherman syndrome
- Endometrial polyp
- Gynecologic bleeding
- Uterine fibroids
- Uterine malformations
# Complications
The most common problem is a uterine perforation when the instrument breaches the wall of the uterus. This can lead to bleeding and to damage to other organs. Distention media also can lead to an embolus or water intoxication.
# Variations
A contact hysteroscope is a hysteroscope that does not use distention media. A resectoscope is a variation of a hysteroscope that contains an electric loop to resect a submucous leiomyoma.
Template:Urogenital surgical procedures
de:Hysteroskopie
he:היסטרוסקופיה
nl:Hysteroscopie
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Hysteroscopy | |
6876a5d73ab332bff96f8642021d6a33df38aff2 | wikidoc | ICF syndrome | ICF syndrome
ICF syndrome (or Immunodeficiency, Centromere instability and Facial anomalies syndrome) is a very rare autosomal recessive immune disorder.
# Genetics
ICF syndrome can be caused by a mutation in the DNA-methyltransferase-3b (Dnmt3b) gene.
# Presentation
It is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. ICF syndrome patients exhibit facial anomalies which include hypertelorism, low-set ears, epicanthal folds and macroglossia. | ICF syndrome
ICF syndrome (or Immunodeficiency, Centromere instability and Facial anomalies syndrome)[1] is a very rare autosomal recessive[2] immune disorder.
# Genetics
ICF syndrome can be caused by a mutation in the DNA-methyltransferase-3b (Dnmt3b) gene.[3]
# Presentation
It is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. ICF syndrome patients exhibit facial anomalies which include hypertelorism, low-set ears, epicanthal folds and macroglossia. | https://www.wikidoc.org/index.php/ICF_syndrome | |
b79fad2eec4d83da408e65b2e3264d86a1d925e7 | wikidoc | Iatrogenesis | Iatrogenesis
# Overview
The terms Iatrogenesis and Iatrogenic artifact refer to adverse effects or complications caused by or resulting from medical treatment or advice. In addition to harmful consequences of actions by physicians, iatrogenesis can also refer to actions by other healthcare professionals, such as psychologists, therapists, pharmacists, nurses, dentists, and others. Iatrogenisis is not restricted to conventional medicine and can also result from complementary and alternative medicine treatments.
Some iatrogenic artifacts are clearly defined and easily recognized, such as a complication following a surgical procedure. Some are less obvious and can require significant investigation to identify, such as complex drug interactions. And, some conditions have been described for which it is unknown, unproven or even controversial whether they iatrogenic or not; this has been encountered particularly with regard to various psychological and chronic pain conditions. Research in these areas is ongoing.
# History
Etymologically, the term means "brought forth by a healer" (iatros means healer in Greek); as such, in its earlier forms, it could refer to good or bad effects.
Since Hippocrates's time, the potential damaging effect of a healer's actions has been recognized. The old mandate "first do no harm" (primum non nocere) is an important clause of medical ethics, and iatrogenic illness or death caused purposefully, or by avoidable error or negligence on the healer's part became a punishable offence in many civilizations.
With the development of scientific medicine in the 20th century, it could be expected that iatrogenic illness or death would be more easily avoided. With the discovery of antiseptics, anesthesia, antibiotics, and new and better surgical techniques, iatrogenic mortality decreased enormously.
# Sources of iatrogenesis
Examples of iatrogenesis:
- medical error, poor prescription handwriting
- negligence or faulty procedures
- prescription drug interaction
- adverse effects of prescription drugs
- over-use of drugs leading to antibiotic resistance in bacteria
- nosocomial infection
- blood transfusion
## Medical error and negligence
Iatrogenic conditions do not necessarily result from medical errors, such as mistakes made in surgery, or the prescription or dispensing of the wrong therapy, such as a drug. In fact, intrinsic and sometimes adverse effects of a medical treatment are iatrogenic; for example, radiation therapy or chemotherapy, due to the needed aggressiveness of the therapeutic agents, frequent effects are hair loss, anemia, vomiting, nausea, brain damage etc. Excessive or inappropriate dependence on a therapist is a frequent example of iatrogenesis. The loss of functions resulting from the required removal of a diseased organ is also considered iatrogenesis, e.g., iatrogenic diabetes brought on by removal of all or part of the pancreas.
In other situations, actual negligence or faulty procedures are involved, such as when drug prescriptions are handwritten by the pharmacotherapist. It has been proved that poor handwriting can lead a pharmacist to dispense the wrong drug, worsening a patient's condition.
## Adverse effects
A very common iatrogenic effect is caused by drug interaction, i.e., when pharmacotherapists fail to check for all medications a patient is taking and prescribe new ones which interact agonistically or antagonistically (potentiate or decrease the intended therapeutic effect). Significant morbidity and mortality is caused because of this. Adverse reactions, such as allergic reactions to drugs, even when unexpected by pharmacotherapists, are also classified as iatrogenic.
The evolution of antibiotic resistance in bacteria is iatrogenic as well.Finland M (1979). "Emergence of antibiotic resistance in hospitals, 1935-1975". Rev. Infect. Dis. 1 (1): 4–22. PMID 45521..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} Bacteria strains resistant to antibiotics have evolved in response to the overprescription of antibiotic drugs.
## Nosocomial infection
A related term is nosocomial, which refers to an iatrogenic illness due to or acquired during hospital care, such as an infection. Sometimes, hospital staff can be unwitting transmitters of nosocomial infections (in one of such instances, many hospitals have forbidden physicians to use long ties, because they transmitted bacteria from bed to bed when the doctor swept the tie over the patients when bending over them). The most common iatrogenic illness in this realm, however, are nosocomial infections caused by unclean or inadequately sterilized hypodermic needles, surgical instruments, and the use of ungloved hands to perform medical or dental procedures. For example, a number of hepatitis B and C infections caused by dentists and surgeons on their patients have been documented. One of the most horrid cases of massive death caused in recent times by iatrogenic infection has been reported on several bush hospitals in Zaire and Sudan, where the intensive reuse of poorly sterilized syringes and needles by nurses spread the Ebola virus, probably causing hundreds of deaths.
The use of contaminated vaccines was also an important source of iatrogenesis, because many of them are manufactured with live, but attenuated viruses or bacteria, and may become contaminated. Major occurrences were the many children who died of tuberculosis by the application of contaminated BCG vaccines, as well as the victims of some defective vaccine batches of polio vaccines by Dr. Jonathan Salk.
## Psychology
In psychology, iatrogenesis can occur due to misdiagnosis (including diagnosis with a false condition as was the case of hystero-epilepsy). Conditions hypothesized to be partially or completely iatrogenic include bipolar disorder, dissociative identity disorder , fibromyalgia,somatoform disorder, chronic fatigue syndrome, posttraumatic stress disorder, substance abuse, antisocial youths and others though research is unequivocal for each condition. The degree of association of any particular condition with iatrogenesis is unclear and in some cases controversial.
## Physician's wrongdoing
Although very rare, iatrogenic illness or death can be attributed to mental, nervous, sensorial or muscular disease in physicians. This may range from the banal, such as trembling fingers in a surgeon causing slippages and errors, or long medical resident work hours causing sleep deprivation-induced errors, to extreme cases such as the sociopathic physicians and nurses who kill scores of their patients (such as the Death Angels of Lainz, the British nurse Beverley Allitt and GP Harold Shipman), American physician Richard J. Schmidt (who tried to kill his girlfriend by contaminating her with AIDS-tainted blood), and the bizarre case of German surgeon Prof. Ernst Ferdinand Sauerbruch (1875-1951), who became demented and continued to perform absurd operations on many patients, with fatal results, even after his colleagues detected the errors but were unable to stop him because of his fame and power.
Medical torture can be regarded as an extreme form of iatrogenesis, i.e., the involvement and sometimes active participation of medical professionals in acts of torture, to either to judge what victims can endure, to apply treatments that will enhance torture, or as torturers in their own right. Unfortunately, many episodes of humankind's history, such as the Nazi use of torturous human experimentation by physicians such as Josef Mengele, have also witnessed extreme iatrogenesis. Although these could be considered rare instances in medical history, unethical medical experimentation is much more common, i.e., use of involuntary subjects or the inadequate handling of informed consent in clinical trials. Horrid perpetrations were recorded even in democratic countries, such as the famous episode of involuntary syphilis inoculation in African-Americans (Tuskegee Syphilis Study), or soldiers and sailors unwillingly subjected to radioactivity (Operation Plumbbob) in the USA.
Medical action, such as assisted suicide (by physicians such as Dr. Jack Kevorkian) and medical euthanasia are also forms of doctor originated (iatrogenic) death.
A related concept is Institutional Damage but it can occur separately from the medical acts, even in a hospital.
# Cascade iatrogenesis
Cascade iatrogenesis is a series of increasingly more severe effects on the health of patients, caused by medical interventions which were applied to solve the previous one. A good example was a real case of a patient who had severe arthritis. Cortisone therapy at a high dose was instituted and was effective for a while, but prolonged use caused the first iatrogenic effect in the cascade: diabetes. Chronic diabetes increased the patient's susceptibility to infections and activated a latent pulmonary tuberculosis with hemoptysis. Cortisone treatment was suspended and substituted by ACTH therapy, which provoked adrenal insufficiency and severe osteoporosis, with painful spontaneous bone fractures (including fracture of ribs caused by an external cardiopulmonary resuscitation attempt. Generalized organ failure and infection followed, with death.
# Incidence and importance
Iatrogenesis is a major phenomenon, and a severe risk to patients.
A study carried out in 1981 more than one-third of illnesses of patients in a university hospital were iatrogenic, nearly one in ten were considered major, and in 2% of the patients, the iatrogenic disorder ended in death. Complications were most strongly associated with exposure to drugs and medications. In another study, the main factors leading to problems were inadequate patient evaluation, lack of monitoring and follow-up, and failure to perform necessary tests.
In the United State alone, recorded deaths per year (2000):
- 12,000 -- unnecessary surgery
- 7,000 -- medication errors in hospitals
- 20,000 -- other errors in hospitals
- 80,000 -- infections in hospitals
- 106,000 -- non-error, negative effects of drugs
Based on these figures, 225,000 deaths per year constitutes the third leading cause of death in the United States, after deaths from heart disease and cancer. Also, there is a wide margin between these numbers of deaths and the next leading cause of death (cerebrovascular disease).
This totals 225,000 deaths per year from iatrogenic causes.
In interpreting these numbers, note the following:
- most data were derived from studies in hospitalized patients.
- the estimates are for deaths only and do not include negative effects that are associated with disability or discomfort.
- the estimates of death due to error are lower than those in the IOM report. If higher estimates are used, the deaths due to iatrogenic causes would range from 230,000 to 284,000. | Iatrogenesis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The terms Iatrogenesis and Iatrogenic artifact refer to adverse effects or complications caused by or resulting from medical treatment or advice. In addition to harmful consequences of actions by physicians, iatrogenesis can also refer to actions by other healthcare professionals, such as psychologists, therapists, pharmacists, nurses, dentists, and others. Iatrogenisis is not restricted to conventional medicine and can also result from complementary and alternative medicine treatments.
Some iatrogenic artifacts are clearly defined and easily recognized, such as a complication following a surgical procedure. Some are less obvious and can require significant investigation to identify, such as complex drug interactions. And, some conditions have been described for which it is unknown, unproven or even controversial whether they iatrogenic or not; this has been encountered particularly with regard to various psychological and chronic pain conditions. Research in these areas is ongoing.
# History
Etymologically, the term means "brought forth by a healer" (iatros means healer in Greek); as such, in its earlier forms, it could refer to good or bad effects.
Since Hippocrates's time, the potential damaging effect of a healer's actions has been recognized. The old mandate "first do no harm" (primum non nocere) is an important clause of medical ethics, and iatrogenic illness or death caused purposefully, or by avoidable error or negligence on the healer's part became a punishable offence in many civilizations.
With the development of scientific medicine in the 20th century, it could be expected that iatrogenic illness or death would be more easily avoided. With the discovery of antiseptics, anesthesia, antibiotics, and new and better surgical techniques, iatrogenic mortality decreased enormously.
# Sources of iatrogenesis
Examples of iatrogenesis:
- medical error, poor prescription handwriting
- negligence or faulty procedures
- prescription drug interaction
- adverse effects of prescription drugs
- over-use of drugs leading to antibiotic resistance in bacteria
- nosocomial infection
- blood transfusion
## Medical error and negligence
Iatrogenic conditions do not necessarily result from medical errors, such as mistakes made in surgery, or the prescription or dispensing of the wrong therapy, such as a drug. In fact, intrinsic and sometimes adverse effects of a medical treatment are iatrogenic; for example, radiation therapy or chemotherapy, due to the needed aggressiveness of the therapeutic agents, frequent effects are hair loss, anemia, vomiting, nausea, brain damage etc. Excessive or inappropriate dependence on a therapist is a frequent example of iatrogenesis. The loss of functions resulting from the required removal of a diseased organ is also considered iatrogenesis, e.g., iatrogenic diabetes brought on by removal of all or part of the pancreas.
In other situations, actual negligence or faulty procedures are involved, such as when drug prescriptions are handwritten by the pharmacotherapist. It has been proved that poor handwriting can lead a pharmacist to dispense the wrong drug, worsening a patient's condition.
## Adverse effects
A very common iatrogenic effect is caused by drug interaction, i.e., when pharmacotherapists fail to check for all medications a patient is taking and prescribe new ones which interact agonistically or antagonistically (potentiate or decrease the intended therapeutic effect). Significant morbidity and mortality is caused because of this. Adverse reactions, such as allergic reactions to drugs, even when unexpected by pharmacotherapists, are also classified as iatrogenic.
The evolution of antibiotic resistance in bacteria is iatrogenic as well.Finland M (1979). "Emergence of antibiotic resistance in hospitals, 1935-1975". Rev. Infect. Dis. 1 (1): 4–22. PMID 45521..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} Bacteria strains resistant to antibiotics have evolved in response to the overprescription of antibiotic drugs.
## Nosocomial infection
A related term is nosocomial, which refers to an iatrogenic illness due to or acquired during hospital care, such as an infection. Sometimes, hospital staff can be unwitting transmitters of nosocomial infections (in one of such instances, many hospitals have forbidden physicians to use long ties, because they transmitted bacteria from bed to bed when the doctor swept the tie over the patients when bending over them). The most common iatrogenic illness in this realm, however, are nosocomial infections caused by unclean or inadequately sterilized hypodermic needles, surgical instruments, and the use of ungloved hands to perform medical or dental procedures. For example, a number of hepatitis B and C infections caused by dentists and surgeons on their patients have been documented. One of the most horrid cases of massive death caused in recent times by iatrogenic infection has been reported on several bush hospitals in Zaire and Sudan, where the intensive reuse of poorly sterilized syringes and needles by nurses spread the Ebola virus, probably causing hundreds of deaths.[1]
The use of contaminated vaccines was also an important source of iatrogenesis, because many of them are manufactured with live, but attenuated viruses or bacteria, and may become contaminated. Major occurrences were the many children who died of tuberculosis by the application of contaminated BCG vaccines, as well as the victims of some defective vaccine batches of polio vaccines by Dr. Jonathan Salk.
## Psychology
In psychology, iatrogenesis can occur due to misdiagnosis (including diagnosis with a false condition as was the case of hystero-epilepsy[2]). Conditions hypothesized to be partially or completely iatrogenic include bipolar disorder[3], dissociative identity disorder[4][2] , fibromyalgia[5],somatoform disorder[6], chronic fatigue syndrome[6], posttraumatic stress disorder[7], substance abuse[8], antisocial youths [9] and others [10] though research is unequivocal for each condition. The degree of association of any particular condition with iatrogenesis is unclear and in some cases controversial.
## Physician's wrongdoing
Although very rare, iatrogenic illness or death can be attributed to mental, nervous, sensorial or muscular disease in physicians. This may range from the banal, such as trembling fingers in a surgeon causing slippages and errors, or long medical resident work hours causing sleep deprivation-induced errors, to extreme cases such as the sociopathic physicians and nurses who kill scores of their patients (such as the Death Angels of Lainz, the British nurse Beverley Allitt and GP Harold Shipman), American physician Richard J. Schmidt (who tried to kill his girlfriend by contaminating her with AIDS-tainted blood), and the bizarre case of German surgeon Prof. Ernst Ferdinand Sauerbruch (1875-1951), who became demented and continued to perform absurd operations on many patients, with fatal results, even after his colleagues detected the errors but were unable to stop him because of his fame and power.[11]
Medical torture can be regarded as an extreme form of iatrogenesis, i.e., the involvement and sometimes active participation of medical professionals in acts of torture, to either to judge what victims can endure, to apply treatments that will enhance torture, or as torturers in their own right. Unfortunately, many episodes of humankind's history, such as the Nazi use of torturous human experimentation by physicians such as Josef Mengele, have also witnessed extreme iatrogenesis. Although these could be considered rare instances in medical history, unethical medical experimentation is much more common, i.e., use of involuntary subjects or the inadequate handling of informed consent in clinical trials. Horrid perpetrations were recorded even in democratic countries, such as the famous episode of involuntary syphilis inoculation in African-Americans (Tuskegee Syphilis Study), or soldiers and sailors unwillingly subjected to radioactivity (Operation Plumbbob) in the USA.
Medical action, such as assisted suicide (by physicians such as Dr. Jack Kevorkian) and medical euthanasia are also forms of doctor originated (iatrogenic) death.
A related concept is Institutional Damage but it can occur separately from the medical acts, even in a hospital.
# Cascade iatrogenesis
Cascade iatrogenesis is a series of increasingly more severe effects on the health of patients, caused by medical interventions which were applied to solve the previous one. A good example was a real case of a patient who had severe arthritis. Cortisone therapy at a high dose was instituted and was effective for a while, but prolonged use caused the first iatrogenic effect in the cascade: diabetes. Chronic diabetes increased the patient's susceptibility to infections and activated a latent pulmonary tuberculosis with hemoptysis. Cortisone treatment was suspended and substituted by ACTH therapy, which provoked adrenal insufficiency and severe osteoporosis, with painful spontaneous bone fractures (including fracture of ribs caused by an external cardiopulmonary resuscitation attempt. Generalized organ failure and infection followed, with death.
# Incidence and importance
Iatrogenesis is a major phenomenon, and a severe risk to patients.
A study carried out in 1981 more than one-third of illnesses of patients in a university hospital were iatrogenic, nearly one in ten were considered major, and in 2% of the patients, the iatrogenic disorder ended in death. Complications were most strongly associated with exposure to drugs and medications.[12] In another study, the main factors leading to problems were inadequate patient evaluation, lack of monitoring and follow-up, and failure to perform necessary tests.[13]
In the United State alone, recorded deaths per year (2000):
- 12,000 -- unnecessary surgery
- 7,000 -- medication errors in hospitals
- 20,000 -- other errors in hospitals
- 80,000 -- infections in hospitals
- 106,000 -- non-error, negative effects of drugs
Based on these figures, 225,000 deaths per year constitutes the third leading cause of death in the United States, after deaths from heart disease and cancer. Also, there is a wide margin between these numbers of deaths and the next leading cause of death (cerebrovascular disease).
This totals 225,000 deaths per year from iatrogenic causes.
In interpreting these numbers, note the following:
- most data were derived from studies in hospitalized patients.
- the estimates are for deaths only and do not include negative effects that are associated with disability or discomfort.
- the estimates of death due to error are lower than those in the IOM report. If higher estimates are used, the deaths due to iatrogenic causes would range from 230,000 to 284,000.[14] | https://www.wikidoc.org/index.php/Iatrogenesis | |
7f301c0485b96e3d2bd6ee3475fccaaeb28b1b6d | wikidoc | Idarucizumab | Idarucizumab
# 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
Idarucizumab is a humanized monoclonal antibody fragment (Fab) that is FDA approved for the treatment of patients treated with dabigatran when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding. Common adverse reactions include headache (5%) in healthy volunteers and hypokalemia, delirium, constipation, pyrexia, and pneumonia (5%) in patients.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Idarucizumab is indicated in patients treated with dabigatran when reversal of the anticoagulant effects of this drug is needed:
- For emergency surgery/urgent procedures
- In life-threatening or uncontrolled bleeding
This indication is approved under accelerated approval based on a reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers. Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study.
- For intravenous use only.
- The recommended dose of Idarucizumab is 5 g, provided as two separate vials each containing 2.5 g/50 mL idarucizumab (see Figure 1).
- There is limited data to support administration of an additional 5 g of Idarucizumab.
- Restarting Antithrombotic Therapy
- Patients being treated with dabigatran therapy have underlying disease states that predispose them to thromboembolic events. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.
- Idarucizumab is a specific reversal agent for dabigatran, with no impact on the effect of other anticoagulant or antithrombotic therapies.
- Dabigatran treatment can be initiated 24 hours after administration of Idarucizumab.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idarucizumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idarucizumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idarucizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idarucizumab in pediatric patients.
# Contraindications
None
# Warnings
Patients being treated with dabigatran therapy have underlying disease states that predispose them to thromboembolic events. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.
In a limited number of patients in the clinical program, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT)) have been observed.
If reappearance of clinically relevant bleeding together with elevated coagulation parameters is observed after administration of 5 g Idarucizumab, administration of an additional 5 g dose of Idarucizumab may be considered. Similarly, patients who require a second emergency surgery/urgent procedure and have elevated coagulation parameters may receive an additional 5 g dose of Idarucizumab.
The safety and effectiveness of repeat treatment with Idarucizumab have not been established.
There is insufficient clinical experience with Idarucizumab in patients to evaluate risk of hypersensitivity to idarucizumab. In clinical studies adverse events possibly indicative of hypersensitivity reactions where a possible relationship could not be excluded were reported. The risk of using Idarucizumab in patients with known hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or to any of the excipients needs to be weighed cautiously against the potential benefit of such an emergency treatment. If an anaphylactic reaction or other serious allergic reaction occurs, immediately discontinue administration of Idarucizumab and institute appropriate treatment.
In patients with the condition of hereditary fructose intolerance who have received parenteral administration of sorbitol, serious adverse reactions, including fatal reactions, have been reported. Reactions have included hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function.
The recommended dose of Idarucizumab contains 4 g sorbitol as an excipient. When prescribing Idarucizumab to patients with hereditary fructose intolerance consider the combined daily metabolic load of sorbitol/fructose from all sources, including Idarucizumab and other drugs containing sorbitol. The minimum amount of sorbitol at which serious adverse reactions may occur in these patients is not known.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are described in more detail elsewhere in the labeling:
- Thromboembolic Risk
- Hypersensitivity Reactions
- Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Three clinical trials in healthy volunteers have been completed, in which 224 subjects were treated with idarucizumab. In these trials during the treatment period the overall frequency of adverse events was similar between idarucizumab-treated subjects (55/224, 25%) and placebo-treated subjects (26/105, 25%). Among those subjects treated with idarucizumab, adverse reactions reported in greater than or equal to 5% of subjects was headache (12/224, 5%).
In the interim analysis of the RE-VERSE AD™ (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial, a total of 123 dabigatran-treated patients were administered idarucizumab either because they required an emergency surgery or urgent procedure, or because they presented with life-threatening or uncontrolled bleeding. Adverse reactions reported in greater than or equal to 5% of patients were: hypokalemia (9/123, 7%), delirium (9/123, 7%), constipation (8/123, 7%), pyrexia (7/123, 6%), pneumonia (7/123, 6%). Of the total, 26 patients died, 11 within the first day after idarucizumab dosing; each of these deaths could be attributed either as a complication of the index event or associated with co-morbidities.
- Thromboembolic Events
- In the interim analysis of the RE-VERSE AD trial, 5 of 123 patients reported thrombotic events, 1 patient 2 days after treatment with idarucizumab and 4 patients 7 days or more after treatment with idarucizumab. None of these patients were on antithrombotic therapy at the time of the event, and in each of these cases, the thrombotic event could be attributed to the underlying medical condition of the patient.
- Hypersensitivity
- Pyrexia, bronchospasm, hyperventilation, rash, and pruritus have been reported in clinical trials with idarucizumab.
As with all proteins there is a potential for immunogenicity with idarucizumab. Using an electro-chemiluminescence (ECL) based assay, plasma samples from 283 subjects (224 treated with idarucizumab) were tested for antibodies cross-reacting with idarucizumab. Pre-existing antibodies with cross-reactivity to idarucizumab were detected in approximately 13% (36/283) of the subjects. The majority of pre-existing antibodies were shown to have low titers. No impact on the pharmacokinetics or the reversal effect of idarucizumab or hypersensitivity reactions were observed in these subjects. Treatment-emergent possibly persisting anti-idarucizumab antibodies with low titers were observed in 4% (9/224) of the subjects treated with idarucizumab.
The epitope specificity of antibodies to idarucizumab was characterized using probe molecules. For pre-existing antibodies, 97% (35/36) had specificity for the C-terminus, a region of idarucizumab to which dabigatran does not bind. For treatment emergent possibly persisting antibodies, 56% (5/9) had specificity for the C-terminus, 22% (2/9) had specificity for the variable region, 11% (1/9) had mixed specificity and 11% (1/9) was indeterminate.
Detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to idarucizumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Idarucizumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Idarucizumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
- There are no adequate and well-controlled studies of Idarucizumab in pregnant women to inform on associated risks. Animal reproductive and development studies have not been conducted with idarucizumab. It is also not known whether Idarucizumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Idarucizumab should be given to a pregnant woman only if clearly needed.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Idarucizumab in women who are pregnant.
### Labor and Delivery
Idarucizumab has not been studied for use during labor and delivery. Safety and effectiveness of Idarucizumab during labor and delivery have not been studied in clinical trials.
### Nursing Mothers
There are no data on the effects of Idarucizumab on the breastfed child or on milk production.
It is not known whether idarucizumab is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Idarucizumab is administered to a nursing woman.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Idarucizumab and any potential adverse effects on the breastfed child from Idarucizumab or from the underlying maternal condition.
### Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
A total of 111 (90%) patients treated with idarucizumab in the case series trial were 65 years of age and older, and 74 (60%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Idarucizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Idarucizumab with respect to specific racial populations.
### Renal Impairment
Renal impairment did not impact the reversal effect of idarucizumab. No dose adjustment is required in renally impaired patients.
### Hepatic Impairment
No formal studies of Idarucizumab in patients with hepatic impairment have been conducted.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Idarucizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Idarucizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Preparation
- Ensure aseptic handling when preparing the infusion.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Once solution has been removed from the vial, administration should begin promptly or within 1 hour.
- Administration
- Do not mix with other medicinal products. Use aseptic technique when administering Idarucizumab.
- Intravenously administer the dose of 5 g (2 vials, each contains 2.5 g) as
- Two consecutive infusions (see Figure 2) or
- Bolus injection by injecting both vials consecutively one after another via syringe (see Figure 3).
- A pre-existing intravenous line may be used for administration of Idarucizumab. The line must be flushed with sterile 0.9% Sodium Chloride Injection, USP solution prior to infusion. No other infusion should be administered in parallel via the same intravenous access.
- Idarucizumab treatment can be used in conjunction with standard supportive measures, which should be considered as medically appropriate.
### Monitoring
There is limited information regarding Idarucizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Idarucizumab and IV administrations.
# Overdosage
There is limited information regarding Idarucizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran and its acylglucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin, neutralizing their anticoagulant effect.
## Structure
Idarucizumab is a humanized monoclonal antibody fragment (Fab) derived from an IgG1 isotype molecule, whose target is the direct thrombin inhibitor dabigatran. Using recombinant expression technology, idarucizumab is produced in a well characterized recombinant (mammalian) CHO cell line and is purified using standard technology. Idarucizumab is composed of a light chain of 219 amino acids and a heavy chain fragment of 225 amino acids, covalently linked together by one disulfide bond between cysteine 225 of the heavy chain fragment and cysteine 219 of the light chain, and has an estimated molecular mass of approximately 47,766 Daltons.
Idarucizumab is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution for intravenous administration. Idarucizumab is supplied in 2 single-use vials, each containing 2.5 g of idarucizumab in 50 mL formulated as a buffered, isotonic, solution containing acetic acid glacial (10.05 mg), polysorbate 20 (10 mg), sodium acetate trihydrate (147.35 mg), sorbitol (2004.20 mg), and water for injection with an osmolality of 270-330 mOsm/kg and a pH of 5.3-5.7.
## Pharmacodynamics
In healthy subjects aged 45 to 64 years, the plasma concentrations of unbound dabigatran were reduced to below the lower limit of quantification immediately after the administration of 5 g idarucizumab. Subjects’ diluted thrombin time (dTT), ECT, aPTT, thrombin time (TT), and activated clotting time (ACT) parameters returned to baseline levels (see Figure 4 and Figure 5). This reduction of dabigatran plasma concentration was observed over the entire observation period of at least 24 hours. Similar findings were also observed in elderly subjects (aged 65 to 80 years) as well as subjects with mild and moderate renal impairment.
In a limited number of patients, re-distribution of dabigatran from the periphery to plasma led to re-elevation of dTT, ECT, aPTT, and TT.
Re-dosing with 2.5 g idarucizumab in 6 healthy subjects aged 45-64 years at 2 months after first infusion revealed no differences in safety and no indication of allergic reactions.
No changes in the pharmacokinetics or pharmacodynamics of dabigatran were noted upon re-initiation 24 hours after the administration of idarucizumab.
- Thrombin Generation Parameters
- Idarucizumab alone has shown no procoagulant effect measured as endogenous thrombin potential (ETP).
- Cardiac Electrophysiology
- Clinical trials with idarucizumab in healthy subjects measured heart rate and electrocardiogram (ECG) parameters (waveform morphology, P wave duration, and PR, QRS, QT, and QTc intervals). There were no clinically relevant abnormal findings related to ECG.
- Drug Interactions
- In vitro Assessment of Drug Interactions
- In vitro data suggest that the inhibition of dabigatran by idarucizumab is not affected by coagulation factor concentrates .
- Assessment of Drug Interactions in Animal Studies
- The potential effect of the binding of idarucizumab to dabigatran in the presence of volume replacement agents (e.g., crystalloids, colloids, and retransfusion of washed red blood cells) was investigated in swine. The results of this study suggest that neutralization of dabigatran anticoagulant activity is not influenced by 50% hemodilution with routinely used volume replacement strategies.
## Pharmacokinetics
There were no obvious differences in the idarucizumab plasma concentration time profiles when idarucizumab was administered alone or after pretreatment with dabigatran. A dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine was observed.
- Distribution
- Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of a 5 g dose, the geometric mean volume of distribution at steady state (Vss) was 8.9 L (geometric coefficient of variation (gCV 24.8%)).
- Elimination
- Idarucizumab was rapidly eliminated with a total clearance of 47.0 mL/min (gCV 18.4%), an initial half-life of 47 minutes (gCV 11.4%), and a terminal half-life of 10.3 h (gCV 18.9%). After intravenous administration of 5 g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within a collection period of 6 hours and less than 1% in the following 18 hours. The remaining part of the dose is assumed to be eliminated via protein catabolism, mainly in the kidney.
- Metabolism
- Several pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve biodegradation of the antibody to smaller molecules, i.e., small peptides or amino acids which are then reabsorbed and incorporated in the general protein synthesis.
- Specific Populations
- Age, Sex, Race and Body Weight
- Age, sex, race (Caucasian vs Asian) and body weight had no clinically important effect on systemic exposure of idarucizumab based on population pharmacokinetic analyses in a healthy volunteer cohort of 201 males and 19 females.
- Renal Impairment
- Idarucizumab has been studied in 12 subjects with mild renal impairment (creatinine clearance ≥60 to <90 mL/min, by Cockcroft-Gault equation) and 6 subjects with moderate impairment (creatinine clearance ≥30 to <60 mL/min). Compared to healthy subjects, the total clearance was reduced, leading to an increase in idarucizumab’s area under the curve (AUC) by 43.5% and 83.5% in mild and moderate renal impairment, respectively.
## Nonclinical Toxicology
No carcinogenicity or genotoxicity studies have been conducted with idarucizumab. No animal studies have been performed to evaluate the potential effects of idarucizumab on fertility in males or females or on reproduction and development.
# Clinical Studies
The safety and effectiveness of Idarucizumab has been investigated in pharmacokinetic/pharmacodynamic trials with healthy volunteers and in an ongoing single cohort case series trial with dabigatran-treated patients who have life-threatening or uncontrolled bleeding, or who require emergency surgery or urgent procedure (RE-VERSE AD).
- Healthy Volunteers
- Three randomized, placebo-controlled trials in a total of 283 subjects assessed the safety, dose-response, and effect of idarucizumab on reducing unbound dabigatran and coagulation parameters. Of the 283 subjects, 224 received at least one dose of idarucizumab. These trials included 19 females and 30 subjects aged 65 years or older (median age 36 years).
- The tables below summarize the idarucizumab effect on coagulation parameters dTT, aPTT, ECT, TT, and ACT over time for 14 subjects treated in one of the healthy volunteer trials. Fourteen subjects received dabigatran 220 mg orally twice daily for three days and an additional single 220 mg dose of dabigatran on day four, two hours before receiving idarucizumab. Idarucizumab was administered as one 5 g intravenous infusion over five minutes. Table 1 shows the results of the idarucizumab treatment group and Table 2 shows the results of the placebo treatment group.
The effect of idarucizumab on reducing unbound dabigatran in healthy volunteers is summarized in Pharmacodynamics section.
- RE-VERSE AD Patient Experience
- In an ongoing single cohort case series trial, 5 g idarucizumab was administered to patients treated with dabigatran who presented with dabigatran-related life-threatening or uncontrolled bleeding (Group A) or who required emergency surgery or urgent procedures (Group B). The primary endpoint was the maximum percentage reversal of the pharmacodynamic anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, based on central laboratory determination of dTT or ECT.
- An interim analysis of the ongoing single cohort case series trial included data for 123 patients: 66 patients with serious bleeding (Group A) and 57 requiring an urgent procedure (Group B). Approximately half of the patients in each group were male. The median age was 77 years and the median creatinine clearance was 55 mL/min. Approximately 67% of patients in Group A and 63% of patients in Group B had been treated with dabigatran 110 mg BID. Results of central laboratory evaluations were available for a subset of 90 patients (51 in Group A, 39 in Group B).
- Among the 90 patients with available data, the median maximum reversal of the pharmacodynamic anticoagulant effect of dabigatran as measured by ECT or dTT in the first 4 hours after administration of 5 g idarucizumab was 100%, with most patients (>89%) achieving complete reversal. Reversal of the pharmacodynamics effects was evident immediately after administration. Results for Groups A and B were similar. In a limited number of patients, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., aPTT or ECT) have been observed. ECT measures over the 24-hour observation time are shown in Figure 6.
Activated partial thromboplastin time (aPTT) showed similar results to ECT (see Figure 7).
# How Supplied
- Idarucizumab is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution supplied as 2 single-use vials each containing 2.5 g/50 mL of idarucizumab.
- NDC number 0597-0197-05: Carton containing two 2.5 g/50 mL vials.
## Storage
- Store Idarucizumab vials in the refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Do not shake.
- Prior to use, the unopened vial may be kept at room temperature 25°C (77°F) for up to 48 hours, if stored in the original package in order to protect from light, or up to 6 hours when exposed to light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Thromboembolic Risk
- Inform patients that reversing dabigatran therapy exposes them to the thromboembolic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as the patient is sufficiently stable.
- Recurrence of Bleeding
- Inform patients to get immediate medical attention for any signs or symptoms of bleeding.
- Hypersensitivity Reactions
- Inform patients of signs and symptoms of allergic hypersensitivity reactions such as anaphylactoid reactions that may be experienced during or after injection of Idarucizumab.
- Risk of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient
- Inform patients with hereditary fructose intolerance (HFI) that Idarucizumab contains sorbitol. Parenteral administration of sorbitol in patients who have HFI has been associated with reports of hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function, and death and may occur during or after injection of Idarucizumab.
# Precautions with Alcohol
Alcohol-Idarucizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
PRAXBIND®
# Look-Alike Drug Names
There is limited information regarding Idarucizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Idarucizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]
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# Overview
Idarucizumab is a humanized monoclonal antibody fragment (Fab) that is FDA approved for the treatment of patients treated with dabigatran when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding. Common adverse reactions include headache (5%) in healthy volunteers and hypokalemia, delirium, constipation, pyrexia, and pneumonia (5%) in patients.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Idarucizumab is indicated in patients treated with dabigatran when reversal of the anticoagulant effects of this drug is needed:
- For emergency surgery/urgent procedures
- In life-threatening or uncontrolled bleeding
This indication is approved under accelerated approval based on a reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers. Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study.
- For intravenous use only.
- The recommended dose of Idarucizumab is 5 g, provided as two separate vials each containing 2.5 g/50 mL idarucizumab (see Figure 1).
- There is limited data to support administration of an additional 5 g of Idarucizumab.
- Restarting Antithrombotic Therapy
- Patients being treated with dabigatran therapy have underlying disease states that predispose them to thromboembolic events. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.
- Idarucizumab is a specific reversal agent for dabigatran, with no impact on the effect of other anticoagulant or antithrombotic therapies.
- Dabigatran treatment can be initiated 24 hours after administration of Idarucizumab.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idarucizumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idarucizumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Idarucizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Idarucizumab in pediatric patients.
# Contraindications
None
# Warnings
Patients being treated with dabigatran therapy have underlying disease states that predispose them to thromboembolic events. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.
In a limited number of patients in the clinical program, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT)) have been observed.
If reappearance of clinically relevant bleeding together with elevated coagulation parameters is observed after administration of 5 g Idarucizumab, administration of an additional 5 g dose of Idarucizumab may be considered. Similarly, patients who require a second emergency surgery/urgent procedure and have elevated coagulation parameters may receive an additional 5 g dose of Idarucizumab.
The safety and effectiveness of repeat treatment with Idarucizumab have not been established.
There is insufficient clinical experience with Idarucizumab in patients to evaluate risk of hypersensitivity to idarucizumab. In clinical studies adverse events possibly indicative of hypersensitivity reactions where a possible relationship could not be excluded were reported. The risk of using Idarucizumab in patients with known hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or to any of the excipients needs to be weighed cautiously against the potential benefit of such an emergency treatment. If an anaphylactic reaction or other serious allergic reaction occurs, immediately discontinue administration of Idarucizumab and institute appropriate treatment.
In patients with the condition of hereditary fructose intolerance who have received parenteral administration of sorbitol, serious adverse reactions, including fatal reactions, have been reported. Reactions have included hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function.
The recommended dose of Idarucizumab contains 4 g sorbitol as an excipient. When prescribing Idarucizumab to patients with hereditary fructose intolerance consider the combined daily metabolic load of sorbitol/fructose from all sources, including Idarucizumab and other drugs containing sorbitol. The minimum amount of sorbitol at which serious adverse reactions may occur in these patients is not known.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are described in more detail elsewhere in the labeling:
- Thromboembolic Risk
- Hypersensitivity Reactions
- Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Three clinical trials in healthy volunteers have been completed, in which 224 subjects were treated with idarucizumab. In these trials during the treatment period the overall frequency of adverse events was similar between idarucizumab-treated subjects (55/224, 25%) and placebo-treated subjects (26/105, 25%). Among those subjects treated with idarucizumab, adverse reactions reported in greater than or equal to 5% of subjects was headache (12/224, 5%).
In the interim analysis of the RE-VERSE AD™ (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial, a total of 123 dabigatran-treated patients were administered idarucizumab either because they required an emergency surgery or urgent procedure, or because they presented with life-threatening or uncontrolled bleeding. Adverse reactions reported in greater than or equal to 5% of patients were: hypokalemia (9/123, 7%), delirium (9/123, 7%), constipation (8/123, 7%), pyrexia (7/123, 6%), pneumonia (7/123, 6%). Of the total, 26 patients died, 11 within the first day after idarucizumab dosing; each of these deaths could be attributed either as a complication of the index event or associated with co-morbidities.
- Thromboembolic Events
- In the interim analysis of the RE-VERSE AD trial, 5 of 123 patients reported thrombotic events, 1 patient 2 days after treatment with idarucizumab and 4 patients 7 days or more after treatment with idarucizumab. None of these patients were on antithrombotic therapy at the time of the event, and in each of these cases, the thrombotic event could be attributed to the underlying medical condition of the patient.
- Hypersensitivity
- Pyrexia, bronchospasm, hyperventilation, rash, and pruritus have been reported in clinical trials with idarucizumab.
As with all proteins there is a potential for immunogenicity with idarucizumab. Using an electro-chemiluminescence (ECL) based assay, plasma samples from 283 subjects (224 treated with idarucizumab) were tested for antibodies cross-reacting with idarucizumab. Pre-existing antibodies with cross-reactivity to idarucizumab were detected in approximately 13% (36/283) of the subjects. The majority of pre-existing antibodies were shown to have low titers. No impact on the pharmacokinetics or the reversal effect of idarucizumab or hypersensitivity reactions were observed in these subjects. Treatment-emergent possibly persisting anti-idarucizumab antibodies with low titers were observed in 4% (9/224) of the subjects treated with idarucizumab.
The epitope specificity of antibodies to idarucizumab was characterized using probe molecules. For pre-existing antibodies, 97% (35/36) had specificity for the C-terminus, a region of idarucizumab to which dabigatran does not bind. For treatment emergent possibly persisting antibodies, 56% (5/9) had specificity for the C-terminus, 22% (2/9) had specificity for the variable region, 11% (1/9) had mixed specificity and 11% (1/9) was indeterminate.
Detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to idarucizumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Idarucizumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Idarucizumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
- There are no adequate and well-controlled studies of Idarucizumab in pregnant women to inform on associated risks. Animal reproductive and development studies have not been conducted with idarucizumab. It is also not known whether Idarucizumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Idarucizumab should be given to a pregnant woman only if clearly needed.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Idarucizumab in women who are pregnant.
### Labor and Delivery
Idarucizumab has not been studied for use during labor and delivery. Safety and effectiveness of Idarucizumab during labor and delivery have not been studied in clinical trials.
### Nursing Mothers
There are no data on the effects of Idarucizumab on the breastfed child or on milk production.
It is not known whether idarucizumab is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Idarucizumab is administered to a nursing woman.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Idarucizumab and any potential adverse effects on the breastfed child from Idarucizumab or from the underlying maternal condition.
### Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
A total of 111 (90%) patients treated with idarucizumab in the case series trial were 65 years of age and older, and 74 (60%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Idarucizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Idarucizumab with respect to specific racial populations.
### Renal Impairment
Renal impairment did not impact the reversal effect of idarucizumab. No dose adjustment is required in renally impaired patients.
### Hepatic Impairment
No formal studies of Idarucizumab in patients with hepatic impairment have been conducted.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Idarucizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Idarucizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Preparation
- Ensure aseptic handling when preparing the infusion.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Once solution has been removed from the vial, administration should begin promptly or within 1 hour.
- Administration
- Do not mix with other medicinal products. Use aseptic technique when administering Idarucizumab.
- Intravenously administer the dose of 5 g (2 vials, each contains 2.5 g) as
- Two consecutive infusions (see Figure 2) or
- Bolus injection by injecting both vials consecutively one after another via syringe (see Figure 3).
- A pre-existing intravenous line may be used for administration of Idarucizumab. The line must be flushed with sterile 0.9% Sodium Chloride Injection, USP solution prior to infusion. No other infusion should be administered in parallel via the same intravenous access.
- Idarucizumab treatment can be used in conjunction with standard supportive measures, which should be considered as medically appropriate.
### Monitoring
There is limited information regarding Idarucizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Idarucizumab and IV administrations.
# Overdosage
There is limited information regarding Idarucizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran and its acylglucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin, neutralizing their anticoagulant effect.
## Structure
Idarucizumab is a humanized monoclonal antibody fragment (Fab) derived from an IgG1 isotype molecule, whose target is the direct thrombin inhibitor dabigatran. Using recombinant expression technology, idarucizumab is produced in a well characterized recombinant (mammalian) CHO cell line and is purified using standard technology. Idarucizumab is composed of a light chain of 219 amino acids and a heavy chain fragment of 225 amino acids, covalently linked together by one disulfide bond between cysteine 225 of the heavy chain fragment and cysteine 219 of the light chain, and has an estimated molecular mass of approximately 47,766 Daltons.
Idarucizumab is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution for intravenous administration. Idarucizumab is supplied in 2 single-use vials, each containing 2.5 g of idarucizumab in 50 mL formulated as a buffered, isotonic, solution containing acetic acid glacial (10.05 mg), polysorbate 20 (10 mg), sodium acetate trihydrate (147.35 mg), sorbitol (2004.20 mg), and water for injection with an osmolality of 270-330 mOsm/kg and a pH of 5.3-5.7.
## Pharmacodynamics
In healthy subjects aged 45 to 64 years, the plasma concentrations of unbound dabigatran were reduced to below the lower limit of quantification immediately after the administration of 5 g idarucizumab. Subjects’ diluted thrombin time (dTT), ECT, aPTT, thrombin time (TT), and activated clotting time (ACT) parameters returned to baseline levels (see Figure 4 and Figure 5). This reduction of dabigatran plasma concentration was observed over the entire observation period of at least 24 hours. Similar findings were also observed in elderly subjects (aged 65 to 80 years) as well as subjects with mild and moderate renal impairment.
In a limited number of patients, re-distribution of dabigatran from the periphery to plasma led to re-elevation of dTT, ECT, aPTT, and TT.
Re-dosing with 2.5 g idarucizumab in 6 healthy subjects aged 45-64 years at 2 months after first infusion revealed no differences in safety and no indication of allergic reactions.
No changes in the pharmacokinetics or pharmacodynamics of dabigatran were noted upon re-initiation 24 hours after the administration of idarucizumab.
- Thrombin Generation Parameters
- Idarucizumab alone has shown no procoagulant effect measured as endogenous thrombin potential (ETP).
- Cardiac Electrophysiology
- Clinical trials with idarucizumab in healthy subjects measured heart rate and electrocardiogram (ECG) parameters (waveform morphology, P wave duration, and PR, QRS, QT, and QTc intervals). There were no clinically relevant abnormal findings related to ECG.
- Drug Interactions
- In vitro Assessment of Drug Interactions
- In vitro data suggest that the inhibition of dabigatran by idarucizumab is not affected by coagulation factor concentrates [3- or 4-factor prothrombin complex concentrates (PCCs), activated PCC, or recombinant Factor VIIa].
- Assessment of Drug Interactions in Animal Studies
- The potential effect of the binding of idarucizumab to dabigatran in the presence of volume replacement agents (e.g., crystalloids, colloids, and retransfusion of washed red blood cells) was investigated in swine. The results of this study suggest that neutralization of dabigatran anticoagulant activity is not influenced by 50% hemodilution with routinely used volume replacement strategies.
## Pharmacokinetics
There were no obvious differences in the idarucizumab plasma concentration time profiles when idarucizumab was administered alone or after pretreatment with dabigatran. A dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine was observed.
- Distribution
- Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of a 5 g dose, the geometric mean volume of distribution at steady state (Vss) was 8.9 L (geometric coefficient of variation (gCV 24.8%)).
- Elimination
- Idarucizumab was rapidly eliminated with a total clearance of 47.0 mL/min (gCV 18.4%), an initial half-life of 47 minutes (gCV 11.4%), and a terminal half-life of 10.3 h (gCV 18.9%). After intravenous administration of 5 g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within a collection period of 6 hours and less than 1% in the following 18 hours. The remaining part of the dose is assumed to be eliminated via protein catabolism, mainly in the kidney.
- Metabolism
- Several pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve biodegradation of the antibody to smaller molecules, i.e., small peptides or amino acids which are then reabsorbed and incorporated in the general protein synthesis.
- Specific Populations
- Age, Sex, Race and Body Weight
- Age, sex, race (Caucasian vs Asian) and body weight had no clinically important effect on systemic exposure of idarucizumab based on population pharmacokinetic analyses in a healthy volunteer cohort of 201 males and 19 females.
- Renal Impairment
- Idarucizumab has been studied in 12 subjects with mild renal impairment (creatinine clearance ≥60 to <90 mL/min, by Cockcroft-Gault equation) and 6 subjects with moderate impairment (creatinine clearance ≥30 to <60 mL/min). Compared to healthy subjects, the total clearance was reduced, leading to an increase in idarucizumab’s area under the curve (AUC) by 43.5% and 83.5% in mild and moderate renal impairment, respectively.
## Nonclinical Toxicology
No carcinogenicity or genotoxicity studies have been conducted with idarucizumab. No animal studies have been performed to evaluate the potential effects of idarucizumab on fertility in males or females or on reproduction and development.
# Clinical Studies
The safety and effectiveness of Idarucizumab has been investigated in pharmacokinetic/pharmacodynamic trials with healthy volunteers and in an ongoing single cohort case series trial with dabigatran-treated patients who have life-threatening or uncontrolled bleeding, or who require emergency surgery or urgent procedure (RE-VERSE AD).
- Healthy Volunteers
- Three randomized, placebo-controlled trials in a total of 283 subjects assessed the safety, dose-response, and effect of idarucizumab on reducing unbound dabigatran and coagulation parameters. Of the 283 subjects, 224 received at least one dose of idarucizumab. These trials included 19 females and 30 subjects aged 65 years or older (median age 36 years).
- The tables below summarize the idarucizumab effect on coagulation parameters dTT, aPTT, ECT, TT, and ACT over time for 14 subjects treated in one of the healthy volunteer trials. Fourteen subjects received dabigatran 220 mg orally twice daily for three days and an additional single 220 mg dose of dabigatran on day four, two hours before receiving idarucizumab. Idarucizumab was administered as one 5 g intravenous infusion over five minutes. Table 1 shows the results of the idarucizumab treatment group and Table 2 shows the results of the placebo treatment group.
The effect of idarucizumab on reducing unbound dabigatran in healthy volunteers is summarized in Pharmacodynamics section.
- RE-VERSE AD Patient Experience
- In an ongoing single cohort case series trial, 5 g idarucizumab was administered to patients treated with dabigatran who presented with dabigatran-related life-threatening or uncontrolled bleeding (Group A) or who required emergency surgery or urgent procedures (Group B). The primary endpoint was the maximum percentage reversal of the pharmacodynamic anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, based on central laboratory determination of dTT or ECT.
- An interim analysis of the ongoing single cohort case series trial included data for 123 patients: 66 patients with serious bleeding (Group A) and 57 requiring an urgent procedure (Group B). Approximately half of the patients in each group were male. The median age was 77 years and the median creatinine clearance was 55 mL/min. Approximately 67% of patients in Group A and 63% of patients in Group B had been treated with dabigatran 110 mg BID. Results of central laboratory evaluations were available for a subset of 90 patients (51 in Group A, 39 in Group B).
- Among the 90 patients with available data, the median maximum reversal of the pharmacodynamic anticoagulant effect of dabigatran as measured by ECT or dTT in the first 4 hours after administration of 5 g idarucizumab was 100%, with most patients (>89%) achieving complete reversal. Reversal of the pharmacodynamics effects was evident immediately after administration. Results for Groups A and B were similar. In a limited number of patients, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., aPTT or ECT) have been observed. ECT measures over the 24-hour observation time are shown in Figure 6.
Activated partial thromboplastin time (aPTT) showed similar results to ECT (see Figure 7).
# How Supplied
- Idarucizumab is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution supplied as 2 single-use vials each containing 2.5 g/50 mL of idarucizumab.
- NDC number 0597-0197-05: Carton containing two 2.5 g/50 mL vials.
## Storage
- Store Idarucizumab vials in the refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Do not shake.
- Prior to use, the unopened vial may be kept at room temperature 25°C (77°F) for up to 48 hours, if stored in the original package in order to protect from light, or up to 6 hours when exposed to light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Thromboembolic Risk
- Inform patients that reversing dabigatran therapy exposes them to the thromboembolic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as the patient is sufficiently stable.
- Recurrence of Bleeding
- Inform patients to get immediate medical attention for any signs or symptoms of bleeding.
- Hypersensitivity Reactions
- Inform patients of signs and symptoms of allergic hypersensitivity reactions such as anaphylactoid reactions that may be experienced during or after injection of Idarucizumab.
- Risk of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient
- Inform patients with hereditary fructose intolerance (HFI) that Idarucizumab contains sorbitol. Parenteral administration of sorbitol in patients who have HFI has been associated with reports of hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function, and death and may occur during or after injection of Idarucizumab.
# Precautions with Alcohol
Alcohol-Idarucizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
PRAXBIND®
# Look-Alike Drug Names
There is limited information regarding Idarucizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Idarucizumab | |
3ff04ebfc6ae28f7e17a5a86db25e10ec1e8d9c4 | wikidoc | Idealization | Idealization
When an individual is unable to integrate difficult feelings, specific defenses are mobilized to regulate these unbearable feelings. The defense that helps in this process is called splitting. Splitting is the tendency to view events or people as either all bad or all good. When viewing people as ‘all good’, you are said to be using the defense mechanism idealization: a mental mechanism in which the person attributes exaggeratedly positive qualities to the self or others. The counterpart of idealization is devaluation: attributing exaggerated negative qualities to the self or others.
In child development idealization and devaluation are quite normal. Being raised in a healthy environment, the child learns how to deal with reality. Being an adult and using idealization and devaluation as the only way to protect the feeling of the self is pathologic.
# Freud
The term idealization first appeared in connection with Freud|Freud’s definition of narcissism. Freud’s vision was that all human infants pass through a phase of primary narcissism in which they assume they are the centre of their universe. To obtain the parents' love the child comes to do what he thinks the parents value. Internalising these values the child forms an ego ideal. This ego ideal contains rules for good behavior and standards of excellence toward which the ego has to strive. When the child cannot bear ambivalence between the real self and the ego ideal and defences are used too often, it is called pathologic. Freud called this situation secondary narcissism, because the ego itself is idealized. Idealization of others besides the self was explained both in drive theory as well as in object-relation theory. From the viewpoint of libidinal drives, idealization of other people is a "flowing-over" of narcissistic libido onto the object; from the viewpoint of self-object relations, the object representations (like that of the caregivers) were made more beautiful than they really were.
# Kohut
An extension of Freud’s theory of narcissism came when Heinz Kohut presented the so-called "self-object transferences" of idealization and mirroring. To Kohut, idealization in childhood is a healthy mechanism. If the parents fail to provide appropriate opportunities for idealization (healthy narcissism) and mirroring (how to cope with reality), the child does not develop beyond a developmental stage in which he sees himself as grandiose but in which he also remains dependent on others to provide his self-esteem. Kohut stated that, with narcissistic patients, idealization of the self and the therapist should be allowed during therapy and then very gradually will diminish as a result of unavoidable optimal frustration.
# Kernberg
Otto Kernberg provided the most extensive discussion of idealization, both in its defensive and adaptive aspects. He conceptualised idealization as involving a denial of unwanted characteristics of an object, then enhancing the object by projecting one’s own libido or omnipotence on it. He proposed a developmental line with on one end of the continuum a normal form of idealization and on the other end a pathological form. In the latter, the individual has a problem with object constancy and sees others as all good or all bad, thus bolstering idealization and devaluation. At this stage idealization is associated with borderline pathology. At the upper pole of the continuumTemplate:Clarifyme idealization is said to be a necessary precursor for feelings of mature love. | Idealization
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
When an individual is unable to integrate difficult feelings, specific defenses are mobilized to regulate these unbearable feelings. The defense that helps in this process is called splitting. Splitting is the tendency to view events or people as either all bad or all good.[1] When viewing people as ‘all good’, you are said to be using the defense mechanism idealization: a mental mechanism in which the person attributes exaggeratedly positive qualities to the self or others. The counterpart of idealization is devaluation: attributing exaggerated negative qualities to the self or others.
In child development idealization and devaluation are quite normal. Being raised in a healthy environment, the child learns how to deal with reality. Being an adult and using idealization and devaluation as the only way to protect the feeling of the self is pathologic.
# Freud
The term idealization first appeared in connection with Freud|Freud’s definition of narcissism. Freud’s vision was that all human infants pass through a phase of primary narcissism in which they assume they are the centre of their universe. To obtain the parents' love the child comes to do what he thinks the parents value. Internalising these values the child forms an ego ideal.[2][3] This ego ideal contains rules for good behavior and standards of excellence toward which the ego has to strive. When the child cannot bear ambivalence between the real self and the ego ideal and defences are used too often, it is called pathologic. Freud called this situation secondary narcissism, because the ego itself is idealized. Idealization of others besides the self was explained both in drive theory as well as in object-relation theory. From the viewpoint of libidinal drives, idealization of other people is a "flowing-over" of narcissistic libido onto the object; from the viewpoint of self-object relations, the object representations (like that of the caregivers) were made more beautiful than they really were.[4]
# Kohut
An extension of Freud’s theory of narcissism came when Heinz Kohut presented the so-called "self-object transferences" of idealization and mirroring. To Kohut, idealization in childhood is a healthy mechanism. If the parents fail to provide appropriate opportunities for idealization (healthy narcissism) and mirroring (how to cope with reality), the child does not develop beyond a developmental stage in which he sees himself as grandiose but in which he also remains dependent on others to provide his self-esteem.[5][6] Kohut stated that, with narcissistic patients, idealization of the self and the therapist should be allowed during therapy and then very gradually will diminish as a result of unavoidable optimal frustration.[7]
# Kernberg
Otto Kernberg provided the most extensive discussion of idealization, both in its defensive and adaptive aspects. He conceptualised idealization as involving a denial of unwanted characteristics of an object, then enhancing the object by projecting one’s own libido or omnipotence on it. He proposed a developmental line with on one end of the continuum a normal form of idealization and on the other end a pathological form. In the latter, the individual has a problem with object constancy and sees others as all good or all bad, thus bolstering idealization and devaluation. At this stage idealization is associated with borderline pathology. At the upper pole of the continuumTemplate:Clarifyme idealization is said to be a necessary precursor for feelings of mature love.[8] | https://www.wikidoc.org/index.php/Idealization | |
cddb18b1cb888c05045ea603a78c15f530a5a8aa | wikidoc | Idiosyncrasy | Idiosyncrasy
Idiosyncrasy comes from Greek ιδιοσυγκρασία "a peculiar temperament", "habit of body" (idios "one's own" and sun-krasis "mixture"). It is defined as a structural or behavioral characteristic peculiar to an individual or group. The term can also be applied to symbols. Idiosyncratic symbols mean one thing for a particular person, as a blade could mean war, but to someone else, it could symbolize a knighting.
By the same principle, linguists state that words are not only arbitrary, but also largely idiosyncratic signs.
The word idiosyncratic is often used as a label to denote a group attitude or opinion that regards the own group as righteous and superior, everyone else or a selected outgroup as an evil enemy, while at the same time regarding all criticisms towards the own position as hostile attacks.
# Idiosyncrasy in medicine
## Disease
Idiosyncrasy defined the way physicians conceived diseases in the nineteenth century. They considered each disease as a unique condition, related to each patient. This understanding began to change in the 1870s, when discoveries made by researchers in Europe permitted the advent of a 'scientific medicine', a precursor to the Evidence-Based Medicine that is the standard to practice today.
## Pharmacology
In contemporary medicine (as of 2007), the term Idiosyncratic drug reaction denotes a non-immunological hypersensitivity to a substance, without connection to pharmalogical toxicity.. Idiosyncratic stresses here the fact that other individuals would react differently, or not at all, and that the reaction is an individual one based on a specific condition of the one who suffers it. Most commonly, this is caused by an enzymopathy, congenital or acquired, so that the triggering substance cannot be processed properly in the organism and causes symptoms by accumulating or blocking other substances to be processed. An idiosyncrasy causing symptoms like an allergy is also called pseudoanaphylaxis .
## Psychiatry
In psychiatry, the term means a specific and unique mental condition of a patient, often accompanied by neologisms. In psychoanalysis and behaviorism, it is used for the personal way a given individual reacts, perceives and experiences a common situation: a certain dish made of meat may cause nostalgic memories in one person and disgust in another. These reactions are called idiosyncratic.
# Idiosyncrasy in economics
In portfolio theory, risks of price changes due to the unique circumstances of a specific security, as opposed to the overall market, are described as idiosyncratic risk. This risk can be virtually eliminated from a portfolio through diversification. It is also often called unsystematic or specific risk. It means there is no compensation for risk, no matter how risky the asset is, and no matter how risk averse we are.
In econometrics, idiosyncratic error is used to describe error from panel data that both changes over time and across units (individuals, firms, cities, etc.) | Idiosyncrasy
Idiosyncrasy comes from Greek ιδιοσυγκρασία "a peculiar temperament", "habit of body" (idios "one's own" and sun-krasis "mixture"). It is defined as a structural or behavioral characteristic peculiar to an individual or group. The term can also be applied to symbols. Idiosyncratic symbols mean one thing for a particular person, as a blade could mean war, but to someone else, it could symbolize a knighting.
By the same principle, linguists state that words are not only arbitrary, but also largely idiosyncratic signs.
The word idiosyncratic is often used as a label to denote a group attitude or opinion that regards the own group as righteous and superior, everyone else or a selected outgroup as an evil enemy, while at the same time regarding all criticisms towards the own position as hostile attacks.
# Idiosyncrasy in medicine
## Disease
Idiosyncrasy defined the way physicians conceived diseases in the nineteenth century. They considered each disease as a unique condition, related to each patient. This understanding began to change in the 1870s, when discoveries made by researchers in Europe permitted the advent of a 'scientific medicine', a precursor to the Evidence-Based Medicine that is the standard to practice today.
## Pharmacology
In contemporary medicine (as of 2007), the term Idiosyncratic drug reaction denotes a non-immunological hypersensitivity to a substance, without connection to pharmalogical toxicity.[1]. Idiosyncratic stresses here the fact that other individuals would react differently, or not at all, and that the reaction is an individual one based on a specific condition of the one who suffers it. Most commonly, this is caused by an enzymopathy, congenital or acquired, so that the triggering substance cannot be processed properly in the organism and causes symptoms by accumulating or blocking other substances to be processed. An idiosyncrasy causing symptoms like an allergy is also called pseudoanaphylaxis [1].
## Psychiatry
In psychiatry, the term means a specific and unique mental condition of a patient, often accompanied by neologisms. In psychoanalysis and behaviorism, it is used for the personal way a given individual reacts, perceives and experiences a common situation: a certain dish made of meat may cause nostalgic memories in one person and disgust in another. These reactions are called idiosyncratic.
# Idiosyncrasy in economics
In portfolio theory, risks of price changes due to the unique circumstances of a specific security, as opposed to the overall market, are described as idiosyncratic risk. This risk can be virtually eliminated from a portfolio through diversification. It is also often called unsystematic or specific risk. It means there is no compensation for risk, no matter how risky the asset is, and no matter how risk averse we are.
In econometrics, idiosyncratic error is used to describe error from panel data that both changes over time and across units (individuals, firms, cities, etc.) | https://www.wikidoc.org/index.php/Idiosyncrasy | |
d6a8246e5cc6ad631dd9a34f4a67da28af7fc7f8 | wikidoc | Ilex guayusa | Ilex guayusa
Ilex guayusa, commonly known as "guayusa", is a tree of the holly genus, native to the Ecuadorian Amazon Rainforest. It is a distant relative of both Yerba Mate and Yaupon Holly (the plant used to make the "black drink"). The leaves have the highest caffeine content of any known plant.
The leaves are boiled to produce a tea; due to the high caffeine content, the same leaves are often used multiple times, sometimes for several days. Fresh leaves are used as well as dried leaves, which are dried in rolls and strung together as a wreath resembling a Hawaiian lei.
In addition to the stimulant effects, the tea is used to enhance dream recall. To achieve this effect, it is believed that the tea must be drunk consistently in the early morning, just after waking, before the sunrise. For many Ecuadorian indigenous, the morning drinking of guayusa is a social ritual.
In areas in which it grows, it is also a common admixture to the powerful entheogenic brew ayahuasca. It is added both in addition to the more common DMT containing plants as well as in the place of them. According to the Ecuadorian indigenous, it is also slightly hallucinogenic on its own, when drunk in high enough quantities.
Guayusa is sold under the brand name "Qat Tea™", but is unrelated to the stimulant plant known as qat. | Ilex guayusa
Ilex guayusa, commonly known as "guayusa", is a tree of the holly genus, native to the Ecuadorian Amazon Rainforest. It is a distant relative of both Yerba Mate and Yaupon Holly (the plant used to make the "black drink"). The leaves have the highest caffeine content of any known plant.
The leaves are boiled to produce a tea; due to the high caffeine content, the same leaves are often used multiple times, sometimes for several days. Fresh leaves are used as well as dried leaves, which are dried in rolls and strung together as a wreath resembling a Hawaiian lei.
In addition to the stimulant effects, the tea is used to enhance dream recall. To achieve this effect, it is believed that the tea must be drunk consistently in the early morning, just after waking, before the sunrise. For many Ecuadorian indigenous, the morning drinking of guayusa is a social ritual.
In areas in which it grows, it is also a common admixture to the powerful entheogenic brew ayahuasca. It is added both in addition to the more common DMT containing plants as well as in the place of them. According to the Ecuadorian indigenous, it is also slightly hallucinogenic on its own, when drunk in high enough quantities.
Guayusa is sold under the brand name "Qat Tea™", but is unrelated to the stimulant plant known as qat. | https://www.wikidoc.org/index.php/Ilex_guayusa | |
0ea39281d950c14dd27908b3b00c357ea48a1e7e | wikidoc | Ilium (bone) | Ilium (bone)
# Overview
The ilium of the pelvis is divisible into two parts, the body and the ala; the separation is indicated on the internal surface by a curved line, the arcuate line, and on the external surface by the margin of the acetabulum. The name comes from the Latin, meaning "groin" or "flank."
# Body (corpus oss. ilii)
The body enters into the formation of the acetabulum, of which it forms rather less than two-fifths.
Its external surface is partly articular, partly non-articular; the articular segment forms part of the lunate surface of the acetabulum, the non-articular portion contributes to the acetabular fossa.
The internal surface of the body is part of the wall of the lesser pelvis and gives origin to some fibers of the Obturator internus.
Below, it is continuous with the pelvic surfaces of the ischium and pubis, only a faint line indicating the place of union.
# Ala (ala oss. ilii) | Ilium (bone)
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The ilium of the pelvis is divisible into two parts, the body and the ala; the separation is indicated on the internal surface by a curved line, the arcuate line, and on the external surface by the margin of the acetabulum. The name comes from the Latin, meaning "groin" or "flank." [1]
# Body (corpus oss. ilii)
The body enters into the formation of the acetabulum, of which it forms rather less than two-fifths.
Its external surface is partly articular, partly non-articular; the articular segment forms part of the lunate surface of the acetabulum, the non-articular portion contributes to the acetabular fossa.
The internal surface of the body is part of the wall of the lesser pelvis and gives origin to some fibers of the Obturator internus.
Below, it is continuous with the pelvic surfaces of the ischium and pubis, only a faint line indicating the place of union.
# Ala (ala oss. ilii) | https://www.wikidoc.org/index.php/Ilia | |
f60f4267bdd7675fdbbbd3827b6b9f9ab4c5d7f2 | wikidoc | Iliac artery | Iliac artery
In human anatomy, iliac artery refers to several anatomical structures located in the pelvis:
- Common iliac artery - forms at terminus of the aorta.
- External iliac artery - forms when the common iliac artery bifurcates, continues as the femoral artery at the inguinal ligament.
- Internal iliac artery - forms when the common iliac artery bifurcates, supplies the perineum and sexual organs. | Iliac artery
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In human anatomy, iliac artery refers to several anatomical structures located in the pelvis:
- Common iliac artery - forms at terminus of the aorta.
- External iliac artery - forms when the common iliac artery bifurcates, continues as the femoral artery at the inguinal ligament.
- Internal iliac artery - forms when the common iliac artery bifurcates, supplies the perineum and sexual organs. | https://www.wikidoc.org/index.php/Iliac_arteries | |
a3089f7d2a865bbc966c383109b456661221434a | wikidoc | Imidacloprid | Imidacloprid
Imidacloprid (IUPAC name (EZ)-1-(6-chloro-3-pyridylmethyl)-N-nitroimidazolidin-2-ylideneamine) is an insecticide manufactured by Bayer Cropscience (part of the drug and chemical conglomerate Bayer AG). It is sold under a variety of trade names including Admire, Advantage, Gaucho, Merit, Confidor, Hachikusan, Premise, Prothor, and Winner.
Imidacloprid was first patented in the United States in U.S. Pat. No. 4,742,060, on May 3 1988, by Nihon Tokushu Noyaku Seizo K.K. of Tokyo, Japan.
In France, its use (as Gaucho) has become controversial in terms of a possible link to derangement of behavior in domesticated honeybees. See Imidacloprid effects on bee population.
# Biochemistry
A chlorinated analog of nicotine, the compound therefore belongs to the class of chloronicotinyl insecticides, and acts on the nicotinic acetylcholine receptor; the chlorination inhibits degradation by acetylcholine-esterase. Imidacloprid is notable for its relatively low toxicity to most animals other than insects due to its specificity for this type of receptor, which is found more often in insect nervous systems and zooplankton than that of other animals (exceptions exist; earthworms and a few species of fish, for example). This potentially allows for lower concentrations (e.g. 0.05-0.125 lbs/acre) to be used for insect control than other neurotoxins (particularly organophosphates) and enabling its use in applications as diverse as flea treatments for pets, control of beetle larvae in lawns, eradication or prevention of termite infestation in buildings, and other uses where animals and people may be exposed. Imidacloprid is, for example, present as a main (or the sole) active ingredient in concentrations between five and ten percent in three out of the four most widely used flea treatment and preventative topical treatments for dogs in the United States; these manufacturers claim an effective killing persistence of at least four weeks. The compound is also used for flea treatment on cats, whose livers have only limited detoxification ability compared to dogs and humans.
Imidacloprid is rated as "moderately toxic" acutely by the WHO and the EPA (class II or III, requiring a "Warning" or "Caution" label), and a "potential" ground water contaminant. It is rated as an "unlikely" carcinogen by the EPA (group E), and is not listed for endocrine, reproductive, or developmental toxicity, or as a chemical of special concern by any agencies. It is not banned, restricted, cancelled, or illegal to import in any countries. Tolerances for imidacloprid residue in food range from 0.02 ppm in eggs to 3.0 ppm in hops.
Animal toxicity is similar to that of the parent compound, nicotine; fatigue, twitching, cramps, and weakness leading to asphyxia. The oral LD50 (the dose which resulted in mortality of half of the test animals) of imidacloprid is 450 mg/kg body weight in rats and 131 mg/kg in mice; the 24-hour dermal LD50 in rats is greater than >5000 mg/kg. It is not irritating to eyes or skin in rabbits and guinea pigs (although some commercial preparations contain clay as an inert ingredient, which may be an irritant). The acute inhalation LD50 in rats was not reached at the greatest attainable concentrations, 69 mg/cubic meter of air as an aerosol, and 5,323 mg/cubic meter of air as a dust. In rats subjected to a two year feeding study, no observable effect was seen at 100 ppm. At 300 ppm females showed decreased body weight gain and males showed increased thyroid lesions, while females showed increased thyroid lesions at 900 ppm. In a one year feeding study in dogs, no observable effect was seen at 1,250 ppm, while levels up to 2,500 ppm led to hypercholesterolemia and elevated liver cytochrome p-450 measurements. Reproductive studies in rats resulted in no observable effect at 100 ppm and decreased pup weight at 250 ppm; developmental toxicity studies in rats showed no observable effect at 30 mg/kg/day and skeletal anomalies at 100 mg/kg/day, while in rabbits no observable effect was detected at 24 mg/kg/day and skeletal abnormalities at 72 mg/kg/day. Imidacloprid was negative for mutagenicity in 21 out of 23 different laboratory tests, but was positive for chromosomal changes in human lymphocytes and for genotoxicity in CHO cells. No carcinogenicity was seen in rats fed up to 1,800 ppm of imidacloprid for two years.
Imidacloprid has low vapor pressure. The chemical breaks down to inorganic molecules by both photolysis and microbial action, in the air and with a half-life of 30 days in water and 27 days in soil anaerobically. Although it is not "persistent" in the technical sense since it does degrade, it can have a half-life in soil under aerobic conditions of as long as 997 days, which is the cause of the concern over possible water contamination as it gradually leaches out of a hypothetical soil reservoir. The manufacturer maintains that, when applied according to instructions, such long-term contamination is only found as the result of "repetitive application over several years" and spread to beneficial insect populations is minimal. In the body, 96% of the chemical is eliminated within 48 hours; the most important degradation product in the body is 6-chloronicotinic acid, another nicotinic neurotoxin with similar properties. Imidacloprid has, however, been reported to degrade into toxic, persistent, 2-chloropyridine.
# Uses
The most widely used applications for imidacloprid in California are pest control in structures, turf pest control, grape growing, and head and leaf lettuce growing. Other widespread crop uses are rice, grains/cereals including corn (maize), potatoes, vegetables, sugar beets, fruit, cotton, and hops. Target insects include sucking insects (e.g. aphids, whiteflies, leafhoppers and planthoppers, thrips, scales, mealybugs, bugs, psyllids, and phylloxera), beetles (e.g. longhorn beetles, leaf beetles, Colorado potato beetles, rice water-weevils, wireworms, grubs, and flea beetles), and others (e.g. lepidopterous leafminers, some diptera, termites, locusts, and fleas).
When used for seed treatments, it is sold under the trade names Akteur, Amigo, Baytan Secur, Chinook, El Hombre, Escocet, Gaucho, Gaucho Blé, Gaucho CS, Gaucho Maícero, Gaucho MZ, Gaucho Orge, Gaucho Primo, Gaucho T, Gaucho MT, Gaucho XT, Genesis, Faibel, Ferial Blé, Férial Orge, Imprimo, Manta Plus, Monceren Extra, Monceren G, Monceren GT, Montur, Prestige, Prestige M, Raxil Secur, Seed-one, Sibutol Secur, Yunta and Zorro FS 236.
When used on citrus, coffee, cotton, fruits, grapes, potatoes, rice, soybeans, sugarcane, tobacco and vegetables as an insecticide spray, it is sold under the trade names Admire, Confidor, Connect, Evidence, Leverage, Muralla, Provado and Trimax.
It is marketed as Premise for termite control and Advantage in the US and Europe for flea control on pets. It is also sold under the trade names Merit, Admire, Confidor and Winner, as well as Hachikusan (in Japan).
# Proper use of Advantage
When using Advantage flea control on animals, make sure to use a soap-free shampoo. The company's question hotline states that it is necessary to use a pet soap-free shampoo, otherwise the poison will be removed. However, Bayer's website claims the product remains effective even after shampooing.
## A systemic insecticide
Imidacloprid is taken up by plant roots and diffuses in the plant vascular system, where insects ingest it by sucking the plant fluids. The products Confidor and Admire are meant for application via irrigation, application to the soil, or on foliage, while Gaucho is intended for use as a seed dressing, applied to the seed before sowing.
Seed applied insecticides are often used to deal with numerous insects as they are easy to use and comparable in cost to most traditional insecticides used at sowing time. Some also indicate that it might be better for the environment because less chemical is required than for broadcast or banded applications, or at least because less chemical is sprayed in the air. However, some note that the use of seed-applied insecticides at each season implies the chemical is used whether there is need to fight insects or not.
Imacloprid is receiving increased attention as a possible factor in Colony Collapse Disorder, a mysterious condition that causes sudden death of honey bee populations. Mass die-offs of bees threaten pollination of food crops in the USA and Europe. | Imidacloprid
Imidacloprid (IUPAC name (EZ)-1-(6-chloro-3-pyridylmethyl)-N-nitroimidazolidin-2-ylideneamine) is an insecticide manufactured by Bayer Cropscience (part of the drug and chemical conglomerate Bayer AG). It is sold under a variety of trade names including Admire, Advantage, Gaucho, Merit, Confidor, Hachikusan, Premise, Prothor, and Winner.
Imidacloprid was first patented in the United States in U.S. Pat. No. 4,742,060, on May 3 1988, by Nihon Tokushu Noyaku Seizo K.K. of Tokyo, Japan.
In France, its use (as Gaucho) has become controversial in terms of a possible link to derangement of behavior in domesticated honeybees. See Imidacloprid effects on bee population.
# Biochemistry
A chlorinated analog of nicotine, the compound therefore belongs to the class of chloronicotinyl insecticides, and acts on the nicotinic acetylcholine receptor; the chlorination inhibits degradation by acetylcholine-esterase. Imidacloprid is notable for its relatively low toxicity to most animals other than insects due to its specificity for this type of receptor, which is found more often in insect nervous systems and zooplankton than that of other animals (exceptions exist; earthworms and a few species of fish, for example). This potentially allows for lower concentrations (e.g. 0.05-0.125 lbs/acre) to be used for insect control than other neurotoxins (particularly organophosphates) and enabling its use in applications as diverse as flea treatments for pets, control of beetle larvae in lawns, eradication or prevention of termite infestation in buildings, and other uses where animals and people may be exposed. Imidacloprid is, for example, present as a main (or the sole) active ingredient in concentrations between five and ten percent in three out of the four most widely used flea treatment and preventative topical treatments for dogs in the United States; these manufacturers claim an effective killing persistence of at least four weeks. The compound is also used for flea treatment on cats, whose livers have only limited detoxification ability compared to dogs and humans.
Imidacloprid is rated as "moderately toxic" acutely by the WHO and the EPA (class II or III, requiring a "Warning" or "Caution" label), and a "potential" ground water contaminant. It is rated as an "unlikely" carcinogen by the EPA (group E), and is not listed for endocrine, reproductive, or developmental toxicity, or as a chemical of special concern by any agencies. It is not banned, restricted, cancelled, or illegal to import in any countries. Tolerances for imidacloprid residue in food range from 0.02 ppm in eggs to 3.0 ppm in hops.
Animal toxicity is similar to that of the parent compound, nicotine; fatigue, twitching, cramps, and weakness leading to asphyxia. The oral LD50 (the dose which resulted in mortality of half of the test animals) of imidacloprid is 450 mg/kg body weight in rats and 131 mg/kg in mice; the 24-hour dermal LD50 in rats is greater than >5000 mg/kg. It is not irritating to eyes or skin in rabbits and guinea pigs (although some commercial preparations contain clay as an inert ingredient, which may be an irritant). The acute inhalation LD50 in rats was not reached at the greatest attainable concentrations, 69 mg/cubic meter of air as an aerosol, and 5,323 mg/cubic meter of air as a dust. In rats subjected to a two year feeding study, no observable effect was seen at 100 ppm. At 300 ppm females showed decreased body weight gain and males showed increased thyroid lesions, while females showed increased thyroid lesions at 900 ppm. In a one year feeding study in dogs, no observable effect was seen at 1,250 ppm, while levels up to 2,500 ppm led to hypercholesterolemia and elevated liver cytochrome p-450 measurements. Reproductive studies in rats resulted in no observable effect at 100 ppm and decreased pup weight at 250 ppm; developmental toxicity studies in rats showed no observable effect at 30 mg/kg/day and skeletal anomalies at 100 mg/kg/day, while in rabbits no observable effect was detected at 24 mg/kg/day and skeletal abnormalities at 72 mg/kg/day. Imidacloprid was negative for mutagenicity in 21 out of 23 different laboratory tests, but was positive for chromosomal changes in human lymphocytes and for genotoxicity in CHO cells. No carcinogenicity was seen in rats fed up to 1,800 ppm of imidacloprid for two years. [1]
Imidacloprid has low vapor pressure. The chemical breaks down to inorganic molecules by both photolysis and microbial action, in the air and with a half-life of 30 days in water and 27 days in soil anaerobically. Although it is not "persistent" in the technical sense since it does degrade, it can have a half-life in soil under aerobic conditions of as long as 997 days, which is the cause of the concern over possible water contamination as it gradually leaches out of a hypothetical soil reservoir. The manufacturer maintains that, when applied according to instructions, such long-term contamination is only found as the result of "repetitive application over several years" and spread to beneficial insect populations is minimal. In the body, 96% of the chemical is eliminated within 48 hours; the most important degradation product in the body is 6-chloronicotinic acid, another nicotinic neurotoxin with similar properties. Imidacloprid has, however, been reported to degrade into toxic, persistent, 2-chloropyridine.
# Uses
The most widely used applications for imidacloprid in California are pest control in structures, turf pest control, grape growing, and head and leaf lettuce growing. Other widespread crop uses are rice, grains/cereals including corn (maize), potatoes, vegetables, sugar beets, fruit, cotton, and hops. Target insects include sucking insects (e.g. aphids, whiteflies, leafhoppers and planthoppers, thrips, scales, mealybugs, bugs, psyllids, and phylloxera), beetles (e.g. longhorn beetles, leaf beetles, Colorado potato beetles, rice water-weevils, wireworms, grubs, and flea beetles), and others (e.g. lepidopterous leafminers, some diptera, termites, locusts, and fleas).
When used for seed treatments, it is sold under the trade names Akteur, Amigo, Baytan Secur, Chinook, El Hombre, Escocet, Gaucho, Gaucho Blé, Gaucho CS, Gaucho Maícero, Gaucho MZ, Gaucho Orge, Gaucho Primo, Gaucho T, Gaucho MT, Gaucho XT, Genesis, Faibel, Ferial Blé, Férial Orge, Imprimo, Manta Plus, Monceren Extra, Monceren G, Monceren GT, Montur, Prestige, Prestige M, Raxil Secur, Seed-one, Sibutol Secur, Yunta and Zorro FS 236.
When used on citrus, coffee, cotton, fruits, grapes, potatoes, rice, soybeans, sugarcane, tobacco and vegetables as an insecticide spray, it is sold under the trade names Admire, Confidor, Connect, Evidence, Leverage, Muralla, Provado and Trimax.
It is marketed as Premise for termite control and Advantage in the US and Europe for flea control on pets. It is also sold under the trade names Merit, Admire, Confidor and Winner, as well as Hachikusan (in Japan).
# Proper use of Advantage
When using Advantage flea control on animals, make sure to use a soap-free shampoo. The company's question hotline states that it is necessary to use a pet soap-free shampoo, otherwise the poison will be removed. However, Bayer's website claims the product remains effective even after shampooing[1].
## A systemic insecticide
Imidacloprid is taken up by plant roots and diffuses in the plant vascular system, where insects ingest it by sucking the plant fluids. The products Confidor and Admire are meant for application via irrigation, application to the soil, or on foliage, while Gaucho is intended for use as a seed dressing, applied to the seed before sowing.
Seed applied insecticides are often used to deal with numerous insects as they are easy to use and comparable in cost to most traditional insecticides used at sowing time. Some also indicate that it might be better for the environment because less chemical is required than for broadcast or banded applications, or at least because less chemical is sprayed in the air. However, some note that the use of seed-applied insecticides at each season implies the chemical is used whether there is need to fight insects or not.
Imacloprid is receiving increased attention as a possible factor in Colony Collapse Disorder, a mysterious condition that causes sudden death of honey bee populations. Mass die-offs of bees threaten pollination of food crops in the USA and Europe. | https://www.wikidoc.org/index.php/Imidacloprid | |
0938498fa7fb25ce7563c1248b2c2d0ebf8056fb | wikidoc | Imiglucerase | Imiglucerase
# 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
Imiglucerase is a Enzyme that is FDA approved for the treatment of Type 1 Gaucher disease. Common adverse reactions include nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, tachycardia,hypersensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Cerezyme® (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions:
- anemia
- thrombocytopenia
- bone disease
- hepatomegaly or splenomegaly
### Dosage
- Cerezyme® (imiglucerase for injection) is administered by intravenous infusion over 1-2 hours. Dosage should be individualized to each patient. Initial dosages range from 2.5 U/kg of body weight 3 times a week to 60 U/kg once every 2 weeks. 60 U/kg every 2 weeks is the dosage for which the most data are available. Disease severity may dictate that treatment be initiated at a relatively high dose or relatively frequent administration. Dosage adjustments should be made on an individual basis and may increase or decrease, based on achievement of therapeutic goals as assessed by routine comprehensive evaluations of the patient’s clinical manifestations.
- Cerezyme® should be stored at 2-8°C (36-46°F). After reconstitution, Cerezyme should be inspected visually before use. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution. The diluted solution may be filtered through an in-line low protein-binding 0.2 μm filter during administration. Any vials exhibiting opaque particles or discoloration should not be used. DO NOT USE Cerezyme after the expiration date on the vial.
- On the day of use, after the correct amount of Cerezyme to be administered to the patient has been determined, the appropriate number of vials are each reconstituted with Sterile Water for Injection, USP. The final concentrations and administration volumes are provided in the following table:
- A nominal 5.0 mL for the 200 unit vial (10.0 mL for the 400 unit vial) is withdrawn from each vial. The appropriate amount of Cerezyme for each patient is diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 – 200 mL. Cerezyme is administered by intravenous infusion over 1-2 hours. Aseptic techniques should be used when diluting the dose. Since Cerezyme does not contain any preservative, after reconstitution, vials should be promptly diluted and not stored for subsequent use. Cerezyme, after reconstitution, has been shown to be stable for up to 12 hours when stored at room temperature (25°C) and at 2-8°C. Cerezyme, when diluted, has been shown to be stable for up to 24 hours when stored at 2-8°C.
- Relatively low toxicity, combined with the extended time course of response, allows small dosage adjustments to be made occasionally to avoid discarding partially used bottles. Thus, the dosage administered in individual infusions may be slightly increased or decreased to utilize fully each vial as long as the monthly administered dosage remains substantially unaltered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Imiglucerase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Imiglucerase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Cerezyme® (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions:
- anemia
- thrombocytopenia
- bone disease
- hepatomegaly or splenomegaly
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Imiglucerase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Imiglucerase in pediatric patients.
# Contraindications
- There are no known contraindications to the use of Cerezyme® (imiglucerase for injection). Treatment with Cerezyme should be carefully re-evaluated if there is significant clinical evidence of hypersensitivity to the product.
# Warnings
- Approximately 15% of patients treated and tested to date have developed IgG antibody to Cerezyme® (imiglucerase for injection) during the first year of therapy. Patients who developed IgG antibody did so largely within 6 months of treatment and rarely developed antibodies to Cerezyme after 12 months of therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity.
- Patients with antibody to Cerezyme have a higher risk of hypersensitivity reaction. Conversely, not all patients with symptoms of hypersensitivity have detectable IgG antibody. It is suggested that patients be monitored periodically for IgG antibody formation during the first year of treatment.
- Treatment with Cerezyme should be approached with caution in patients who have exhibited symptoms of hypersensitivity to the product.
- Anaphylactoid reaction has been reported in less than 1% of the patient population. Further treatment with imiglucerase should be conducted with caution. Most patients have successfully continued therapy after a reduction in rate of infusion and pretreatment with antihistamines and/or corticosteroids.
### Precautions
- In less than 1% of the patient population, pulmonary hypertension and pneumonia have also been observed during treatment with Cerezyme® (imiglucerase for injection). Pulmonary hypertension and pneumonia are known complications of Gaucher disease and have been observed both in patients receiving and not receiving Cerezyme. No causal relationship with Cerezyme has been established. Patients with respiratory symptoms in the absence of fever should be evaluated for the presence of pulmonary hypertension.
- Therapy with Cerezyme should be directed by physicians knowledgeable in the management of patients with Gaucher disease.
- Caution may be advisable in administration of Cerezyme to patients previously treated with Ceredase® (alglucerase injection) and who have developed antibody to Ceredase® or who have exhibited symptoms of hypersensitivity to Ceredase®.
# Adverse Reactions
## Clinical Trials Experience
- Since the approval of Cerezyme® (imiglucerase for injection) in May 1994, Genzyme has maintained a worldwide post-marketing database of spontaneously reported adverse events and adverse events discussed in the medical literature. The percentage of events for each reported adverse reaction term has been calculated using the number of patients from these sources as the denominator for total patient exposure to Cerezyme since 1994. Actual patient exposure is difficult to obtain due to the voluntary nature of the database and the continuous accrual and loss of patients over that span of time. The actual number of patients exposed to Cerezyme since 1994 is likely to be greater than estimated from these voluntary sources and, therefore, the percentages calculated for the frequencies of adverse reactions are most likely greater than the actual incidences.
- Experience in patients treated with Cerezyme® has revealed that approximately 13.8% of patients experienced adverse events which were judged to be related to Cerezyme administration and which occurred with an increase in frequency. Some of the adverse events were related to the route of administration. These include discomfort, pruritus, burning, swelling or sterile abscess at the site of venipuncture. Each of these events was found to occur in < 1% of the total patient population.
- Symptoms suggestive of hypersensitivity have been noted in approximately 6.6% of patients. Onset of such symptoms has occurred during or shortly after infusions; these symptoms include pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension. Anaphylactoid reaction has also been reported. Each of these events was found to occur in < 1.5% of the total patient population. Pre-treatment with antihistamines and/or corticosteroids and reduced rate of infusion have allowed continued use of Cerezyme in most patients.
- Additional adverse reactions that have been reported in approximately 6.5% of patients treated with Cerezyme include: nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia. Each of these events was found to occur in < 1.5% of the total patient population.
- Incidence rates cannot be calculated from the spontaneously reported adverse events in the post-marketing database. From this database, the most commonly reported adverse events in children (defined as ages 2 – 12 years) included dyspnea, fever, nausea, flushing, vomiting, and coughing, whereas in adolescents (>12 – 16 years) and in adults (>16 years) the most commonly reported events included headache, pruritis, and rash.
- In addition to the adverse reactions that have been observed in patients treated with Cerezyme, transient peripheral edema has been reported for this therapeutic class of drug.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Imiglucerase in the drug label.
# Drug Interactions
There is limited information regarding Imiglucerase Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Cerezyme® (imiglucerase for injection). It is also not known whether Cerezyme can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Cerezyme should not be administered during pregnancy except when the indication and need are clear and the potential benefit is judged by the physician to substantially justify the risk.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Imiglucerase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Imiglucerase 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 Cerezyme® (imiglucerase for injection) is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of Cerezyme® (imiglucerase for injection) have been established in patients between 2 and 16 years of age. Use of Cerezyme in this age group is supported by evidence from adequate and well-controlled studies of Cerezyme and Ceredase® (alglucerase injection) in adults and pediatric patients, with additional data obtained from the medical literature and from long-term postmarketing experience. Cerezyme has been administered to patients younger than 2 years of age, however the safety and effectiveness in patients younger than 2 have not been established.
### Geriatic Use
There is no FDA guidance on the use of Imiglucerase with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Imiglucerase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Imiglucerase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Imiglucerase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Imiglucerase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Imiglucerase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Imiglucerase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- It is suggested that patients be monitored periodically for IgG antibody formation during the first year of treatment.
# IV Compatibility
There is limited information regarding IV Compatibility of Imiglucerase in the drug label.
# Overdosage
- Experience with doses up to 240 U/kg every 2 weeks have been reported. At that dose there have been no reports of obvious toxicity.
# Pharmacology
## Mechanism of Action
- Gaucher disease is characterized by a deficiency of β-glucocerebrosidase activity, resulting in accumulation of glucocerebroside in tissue macrophages which become engorged and are typically found in the liver, spleen, and bone marrow and occasionally in lung, kidney, and intestine. Secondary hematologic sequelae include severe anemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly, skeletal complications, including osteonecrosis and osteopenia with secondary pathological fractures. Cerezyme® (imiglucerase for injection) catalyzes the hydrolysis of glucocerebroside to glucose and ceramide. In clinical trials, Cerezyme improved anemia and thrombocytopenia, reduced spleen and liver size, and decreased cachexia to a degree similar to that observed with Ceredase® (alglucerase injection).
## Structure
- Cerezyme® (imiglucerase for injection) is an analogue of the human enzyme β-glucocerebrosidase, produced by recombinant DNA technology. β-Glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme which catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide.
- Cerezyme® is produced by recombinant DNA technology using mammalian cell culture (Chinese hamster ovary). Purified imiglucerase is a monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites (Mr = 60,430). Imiglucerase differs from placental glucocerebrosidase by one amino acid at position 495, where histidine is substituted for arginine. The oligosaccharide chains at the glycosylation sites have been modified to terminate in mannose sugars. The modified carbohydrate structures on imiglucerase are somewhat different from those on placental glucocerebrosidase. These mannose-terminated oligosaccharide chains of imiglucerase are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease.
- Cerezyme® is supplied as a sterile, non-pyrogenic, white to off-white lyophilized product. The quantitative composition of the lyophilized drug is provided in the following table:
- An enzyme unit (U) is defined as the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (pNP-Glc) per minute at 37°C. The product is stored at 2-8°C (36-46°F). After reconstitution with Sterile Water for Injection, USP, the imiglucerase concentration is 40 U/mL (see DOSAGE AND ADMINISTRATION for final concentrations and volumes). Reconstituted solutions have a pH of approximately 6.1.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Imiglucerase in the drug label.
## Pharmacokinetics
- During one-hour intravenous infusions of four doses (7.5, 15, 30, 60 U/kg) of Cerezyme® (imiglucerase for injection), steady-state enzymatic activity was achieved by 30 minutes. Following infusion, plasma enzymatic activity declined rapidly with a half-life ranging from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 mL/min/kg (mean ± S.D., 14.5 ± 4.0 mL/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 L/kg (0.12 ± 0.02 L/kg). These variables do not appear to be influenced by dose or duration of infusion. However, only one or two patients were studied at each dose level and infusion rate. The pharmacokinetics of Cerezyme do not appear to be different from placental-derived alglucerase (Ceredase®).
- In patients who developed IgG antibody to Cerezyme, an apparent effect on serum enzyme levels resulted in diminished volume of distribution and clearance and increased elimination half-life compared to patients without antibody
## Nonclinical Toxicology
- Studies have not been conducted in either animals or humans to assess the potential effects of Cerezyme® (imiglucerase for injection) on carcinogenesis, mutagenesis, or impairment of fertility.
# Clinical Studies
There is limited information regarding Clinical Studies of Imiglucerase in the drug label.
# How Supplied
- Cerezyme® (imiglucerase for injection) is supplied as a sterile, non-pyrogenic, lyophilized product. It is available as follows:
## Storage
- Store at 2-8°C (36-46°F).
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 200 U
NDC 58468-1983-1
Cerezyme®
imiglucerase for injection
200 Units
For Intravenous infusion only
genzyme
### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 400 U
NDC 58468-4663-1
Cerezyme®
imiglucerase for injection
400 Units
For Intravenous infusion only
genzyme
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Imiglucerase in the drug label.
# Precautions with Alcohol
- Alcohol-Imiglucerase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cerezyme®
# Look-Alike Drug Names
There is limited information regarding Imiglucerase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Imiglucerase
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
Imiglucerase is a Enzyme that is FDA approved for the treatment of Type 1 Gaucher disease. Common adverse reactions include nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, tachycardia,hypersensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Cerezyme® (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions:
- anemia
- thrombocytopenia
- bone disease
- hepatomegaly or splenomegaly
### Dosage
- Cerezyme® (imiglucerase for injection) is administered by intravenous infusion over 1-2 hours. Dosage should be individualized to each patient. Initial dosages range from 2.5 U/kg of body weight 3 times a week to 60 U/kg once every 2 weeks. 60 U/kg every 2 weeks is the dosage for which the most data are available. Disease severity may dictate that treatment be initiated at a relatively high dose or relatively frequent administration. Dosage adjustments should be made on an individual basis and may increase or decrease, based on achievement of therapeutic goals as assessed by routine comprehensive evaluations of the patient’s clinical manifestations.
- Cerezyme® should be stored at 2-8°C (36-46°F). After reconstitution, Cerezyme should be inspected visually before use. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution. The diluted solution may be filtered through an in-line low protein-binding 0.2 μm filter during administration. Any vials exhibiting opaque particles or discoloration should not be used. DO NOT USE Cerezyme after the expiration date on the vial.
- On the day of use, after the correct amount of Cerezyme to be administered to the patient has been determined, the appropriate number of vials are each reconstituted with Sterile Water for Injection, USP. The final concentrations and administration volumes are provided in the following table:
- A nominal 5.0 mL for the 200 unit vial (10.0 mL for the 400 unit vial) is withdrawn from each vial. The appropriate amount of Cerezyme for each patient is diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 – 200 mL. Cerezyme is administered by intravenous infusion over 1-2 hours. Aseptic techniques should be used when diluting the dose. Since Cerezyme does not contain any preservative, after reconstitution, vials should be promptly diluted and not stored for subsequent use. Cerezyme, after reconstitution, has been shown to be stable for up to 12 hours when stored at room temperature (25°C) and at 2-8°C. Cerezyme, when diluted, has been shown to be stable for up to 24 hours when stored at 2-8°C.
- Relatively low toxicity, combined with the extended time course of response, allows small dosage adjustments to be made occasionally to avoid discarding partially used bottles. Thus, the dosage administered in individual infusions may be slightly increased or decreased to utilize fully each vial as long as the monthly administered dosage remains substantially unaltered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Imiglucerase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Imiglucerase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Cerezyme® (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions:
- anemia
- thrombocytopenia
- bone disease
- hepatomegaly or splenomegaly
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Imiglucerase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Imiglucerase in pediatric patients.
# Contraindications
- There are no known contraindications to the use of Cerezyme® (imiglucerase for injection). Treatment with Cerezyme should be carefully re-evaluated if there is significant clinical evidence of hypersensitivity to the product.
# Warnings
- Approximately 15% of patients treated and tested to date have developed IgG antibody to Cerezyme® (imiglucerase for injection) during the first year of therapy. Patients who developed IgG antibody did so largely within 6 months of treatment and rarely developed antibodies to Cerezyme after 12 months of therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity.
- Patients with antibody to Cerezyme have a higher risk of hypersensitivity reaction. Conversely, not all patients with symptoms of hypersensitivity have detectable IgG antibody. It is suggested that patients be monitored periodically for IgG antibody formation during the first year of treatment.
- Treatment with Cerezyme should be approached with caution in patients who have exhibited symptoms of hypersensitivity to the product.
- Anaphylactoid reaction has been reported in less than 1% of the patient population. Further treatment with imiglucerase should be conducted with caution. Most patients have successfully continued therapy after a reduction in rate of infusion and pretreatment with antihistamines and/or corticosteroids.
### Precautions
- In less than 1% of the patient population, pulmonary hypertension and pneumonia have also been observed during treatment with Cerezyme® (imiglucerase for injection). Pulmonary hypertension and pneumonia are known complications of Gaucher disease and have been observed both in patients receiving and not receiving Cerezyme. No causal relationship with Cerezyme has been established. Patients with respiratory symptoms in the absence of fever should be evaluated for the presence of pulmonary hypertension.
- Therapy with Cerezyme should be directed by physicians knowledgeable in the management of patients with Gaucher disease.
- Caution may be advisable in administration of Cerezyme to patients previously treated with Ceredase® (alglucerase injection) and who have developed antibody to Ceredase® or who have exhibited symptoms of hypersensitivity to Ceredase®.
# Adverse Reactions
## Clinical Trials Experience
- Since the approval of Cerezyme® (imiglucerase for injection) in May 1994, Genzyme has maintained a worldwide post-marketing database of spontaneously reported adverse events and adverse events discussed in the medical literature. The percentage of events for each reported adverse reaction term has been calculated using the number of patients from these sources as the denominator for total patient exposure to Cerezyme since 1994. Actual patient exposure is difficult to obtain due to the voluntary nature of the database and the continuous accrual and loss of patients over that span of time. The actual number of patients exposed to Cerezyme since 1994 is likely to be greater than estimated from these voluntary sources and, therefore, the percentages calculated for the frequencies of adverse reactions are most likely greater than the actual incidences.
- Experience in patients treated with Cerezyme® has revealed that approximately 13.8% of patients experienced adverse events which were judged to be related to Cerezyme administration and which occurred with an increase in frequency. Some of the adverse events were related to the route of administration. These include discomfort, pruritus, burning, swelling or sterile abscess at the site of venipuncture. Each of these events was found to occur in < 1% of the total patient population.
- Symptoms suggestive of hypersensitivity have been noted in approximately 6.6% of patients. Onset of such symptoms has occurred during or shortly after infusions; these symptoms include pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension. Anaphylactoid reaction has also been reported. Each of these events was found to occur in < 1.5% of the total patient population. Pre-treatment with antihistamines and/or corticosteroids and reduced rate of infusion have allowed continued use of Cerezyme in most patients.
- Additional adverse reactions that have been reported in approximately 6.5% of patients treated with Cerezyme include: nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia. Each of these events was found to occur in < 1.5% of the total patient population.
- Incidence rates cannot be calculated from the spontaneously reported adverse events in the post-marketing database. From this database, the most commonly reported adverse events in children (defined as ages 2 – 12 years) included dyspnea, fever, nausea, flushing, vomiting, and coughing, whereas in adolescents (>12 – 16 years) and in adults (>16 years) the most commonly reported events included headache, pruritis, and rash.
- In addition to the adverse reactions that have been observed in patients treated with Cerezyme, transient peripheral edema has been reported for this therapeutic class of drug.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Imiglucerase in the drug label.
# Drug Interactions
There is limited information regarding Imiglucerase Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Cerezyme® (imiglucerase for injection). It is also not known whether Cerezyme can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Cerezyme should not be administered during pregnancy except when the indication and need are clear and the potential benefit is judged by the physician to substantially justify the risk.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Imiglucerase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Imiglucerase 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 Cerezyme® (imiglucerase for injection) is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of Cerezyme® (imiglucerase for injection) have been established in patients between 2 and 16 years of age. Use of Cerezyme in this age group is supported by evidence from adequate and well-controlled studies of Cerezyme and Ceredase® (alglucerase injection) in adults and pediatric patients, with additional data obtained from the medical literature and from long-term postmarketing experience. Cerezyme has been administered to patients younger than 2 years of age, however the safety and effectiveness in patients younger than 2 have not been established.
### Geriatic Use
There is no FDA guidance on the use of Imiglucerase with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Imiglucerase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Imiglucerase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Imiglucerase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Imiglucerase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Imiglucerase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Imiglucerase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- It is suggested that patients be monitored periodically for IgG antibody formation during the first year of treatment.
# IV Compatibility
There is limited information regarding IV Compatibility of Imiglucerase in the drug label.
# Overdosage
- Experience with doses up to 240 U/kg every 2 weeks have been reported. At that dose there have been no reports of obvious toxicity.
# Pharmacology
## Mechanism of Action
- Gaucher disease is characterized by a deficiency of β-glucocerebrosidase activity, resulting in accumulation of glucocerebroside in tissue macrophages which become engorged and are typically found in the liver, spleen, and bone marrow and occasionally in lung, kidney, and intestine. Secondary hematologic sequelae include severe anemia and thrombocytopenia in addition to the characteristic progressive hepatosplenomegaly, skeletal complications, including osteonecrosis and osteopenia with secondary pathological fractures. Cerezyme® (imiglucerase for injection) catalyzes the hydrolysis of glucocerebroside to glucose and ceramide. In clinical trials, Cerezyme improved anemia and thrombocytopenia, reduced spleen and liver size, and decreased cachexia to a degree similar to that observed with Ceredase® (alglucerase injection).
## Structure
- Cerezyme® (imiglucerase for injection) is an analogue of the human enzyme β-glucocerebrosidase, produced by recombinant DNA technology. β-Glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme which catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide.
- Cerezyme® is produced by recombinant DNA technology using mammalian cell culture (Chinese hamster ovary). Purified imiglucerase is a monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites (Mr = 60,430). Imiglucerase differs from placental glucocerebrosidase by one amino acid at position 495, where histidine is substituted for arginine. The oligosaccharide chains at the glycosylation sites have been modified to terminate in mannose sugars. The modified carbohydrate structures on imiglucerase are somewhat different from those on placental glucocerebrosidase. These mannose-terminated oligosaccharide chains of imiglucerase are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease.
- Cerezyme® is supplied as a sterile, non-pyrogenic, white to off-white lyophilized product. The quantitative composition of the lyophilized drug is provided in the following table:
- An enzyme unit (U) is defined as the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (pNP-Glc) per minute at 37°C. The product is stored at 2-8°C (36-46°F). After reconstitution with Sterile Water for Injection, USP, the imiglucerase concentration is 40 U/mL (see DOSAGE AND ADMINISTRATION for final concentrations and volumes). Reconstituted solutions have a pH of approximately 6.1.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Imiglucerase in the drug label.
## Pharmacokinetics
- During one-hour intravenous infusions of four doses (7.5, 15, 30, 60 U/kg) of Cerezyme® (imiglucerase for injection), steady-state enzymatic activity was achieved by 30 minutes. Following infusion, plasma enzymatic activity declined rapidly with a half-life ranging from 3.6 to 10.4 minutes. Plasma clearance ranged from 9.8 to 20.3 mL/min/kg (mean ± S.D., 14.5 ± 4.0 mL/min/kg). The volume of distribution corrected for weight ranged from 0.09 to 0.15 L/kg (0.12 ± 0.02 L/kg). These variables do not appear to be influenced by dose or duration of infusion. However, only one or two patients were studied at each dose level and infusion rate. The pharmacokinetics of Cerezyme do not appear to be different from placental-derived alglucerase (Ceredase®).
- In patients who developed IgG antibody to Cerezyme, an apparent effect on serum enzyme levels resulted in diminished volume of distribution and clearance and increased elimination half-life compared to patients without antibody
## Nonclinical Toxicology
- Studies have not been conducted in either animals or humans to assess the potential effects of Cerezyme® (imiglucerase for injection) on carcinogenesis, mutagenesis, or impairment of fertility.
# Clinical Studies
There is limited information regarding Clinical Studies of Imiglucerase in the drug label.
# How Supplied
- Cerezyme® (imiglucerase for injection) is supplied as a sterile, non-pyrogenic, lyophilized product. It is available as follows:
## Storage
- Store at 2-8°C (36-46°F).
# Images
## Drug Images
## Package and Label Display Panel
### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 200 U
NDC 58468-1983-1
Cerezyme®
imiglucerase for injection
200 Units
For Intravenous infusion only
genzyme
### PACKAGE LABEL - PRINCIPAL DISPLAY PANEL – 400 U
NDC 58468-4663-1
Cerezyme®
imiglucerase for injection
400 Units
For Intravenous infusion only
genzyme
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Imiglucerase in the drug label.
# Precautions with Alcohol
- Alcohol-Imiglucerase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cerezyme®[1]
# Look-Alike Drug Names
There is limited information regarding Imiglucerase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Imiglucerase | |
4540e847d27166e9db7a036d98a78c47c32d3811 | wikidoc | Western blot | Western blot
# Overview
The western blot (alternately, immunoblot) is a method to detect a specific protein in a given sample of tissue homogenate or extract. It uses gel electrophoresis to separate native or denatured proteins by the length of the polypeptide (denaturing conditions) (Figure 1) or by the 3-D structure of the protein (native/ non-denaturing conditions). The proteins are then transferred to a membrane (typically nitrocellulose or PVDF), where they are probed (detected) using antibodies specific to the target protein. There are now many reagent companies that specialise in providing antibodies (both monoclonal and polyclonal antibodies) against many thousands of different proteins. Commercial antibodies can be expensive, though the unbound antibody can be reused between experiments. This method is used in the fields of molecular biology, biochemistry, immunogenetics and other molecular biology disciplines.
Other related techniques include using antibodies to detect proteins in tissues and cells by immunostaining and enzyme-linked immunosorbent assay (ELISA).
The method originated from the laboratory of George Stark at Stanford. The name western blot was given to the technique by W. Neal Burnette and is a play on the name Southern blot, a technique for DNA detection developed earlier by Edwin Southern. Detection of RNA is termed northern blotting.
# Steps in a western blot
## Tissue preparation
Samples may be taken from whole tissue or from cell culture. In most cases, solid tissues are first broken down mechanically using a blender (for larger sample volumes), using a homogenizer (smaller volumes), or by sonication. Cells may also be broken open by one of the above mechanical methods. However, it should be noted that bacteria, virus or environmental samples can be the source of protein and thus western blotting is not restricted to cellular studies only.
Assorted detergents, salts, and buffers may be employed to encourage lysis of cells and to solubilize proteins. Protease and phosphatase inhibitors are often added to prevent the digestion of the sample by its own enzymes.
A combination of biochemical and mechanical techniques – including various types of filtration and centrifugation – can be used to separate different cell compartments and organelles.
## Gel electrophoresis
The proteins of the sample are separated using gel electrophoresis. Separation of proteins may be by isoelectric point (pI), molecular weight, electric charge, or a combination of these factors. The nature of the separation depends on the treatment of the sample and the nature of the gel.
By far the most common type of gel electrophoresis employs polyacrylamide gels and buffers loaded with sodium dodecyl sulfate (SDS). SDS-PAGE (SDS polyacrylamide gel electrophoresis) maintains polypeptides in a denatured state once they have been treated with strong reducing agents to remove secondary and tertiary structure (e.g. S-S disulfide bonds to SH and SH) and thus allows separation of proteins by their molecular weight. Sampled proteins become covered in the negatively charged SDS and move to the positively charged electrode through the acrylamide mesh of the gel. Smaller proteins migrate faster through this mesh and the proteins are thus separated according to size (usually measured in kilo Ryans, kR). The concentration of acrylamide determines the resolution of the gel - the greater the acrylamide concentration the better the resolution of lower molecular weight proteins. The lower the acrylamide concentration the better the resolution of higher molecular weight proteins. Proteins travel only in one dimension along the gel for most blots.
Samples are loaded into wells in the gel. One lane is usually reserved for a marker or ladder, a commercially available mixture of proteins having defined molecular weights, typically stained so as to form visible, coloured bands. An example of a ladder is the GE Full Range Molecular weight ladder (Figure 1). When voltage is applied along the gel, proteins migrate into it at different speeds. These different rates of advancement (different electrophoretic mobilities) separate into bands within each lane.
It is also possible to use a two-dimensional (2-D) gel which spreads the proteins from a single sample out in two dimensions. Proteins are separated according to isoelectric point (pH at which they have neutral net charge) in the first dimension, and according to their molecular weight in the second dimension.
## Transfer
In order to make the proteins accessible to antibody detection, they are moved from within the gel onto a membrane made of nitrocellulose or PVDF. The membrane is placed on top of the gel, and a stack of tissue papers placed on top of that. The entire stack is placed in a buffer solution which moves up the paper by capillary action, bringing the proteins with it. Another method for transferring the proteins is called electroblotting and uses an electric current to pull proteins from the gel into the PVDF or nitrocellulose membrane. The proteins move from within the gel onto the membrane while maintaining the organization they had within the gel. As a result of this "blotting" process, the proteins are exposed on a thin surface layer for detection (see below). Both varieties of membrane are chosen for their non-specific protein binding properties (i.e. binds all proteins equally well). Protein binding is based upon hydrophobic interactions, as well as charged interactions between the membrane and protein. Nitrocellulose membranes are cheaper than PVDF, but are far more fragile and do not stand up well to repeated probings.
The uniformity and overall effectiveness of transfer of protein from the gel to the membrane can be checked by staining the membrane with Coomassie or Ponceau S dyes. Coomassie is the more sensitive of the two, although Ponceau S's water solubility makes it easier to subsequently destain and probe the membrane as described below.
## Blotting
Since the membrane has been chosen for its ability to bind protein, and both antibodies and the target are proteins, steps must be taken to prevent interactions between the membrane and the antibody used for detection of the target protein. Blocking of non-specific binding is achieved by placing the membrane in a dilute solution of protein - typically Bovine serum albumin (BSA) or non-fat dry milk (both are inexpensive), with a minute percentage of detergent such as Tween 20. The protein in the dilute solution attaches to the membrane in all places where the target proteins have not attached. Thus, when the antibody is added, there is no room on the membrane for it to attach other than on the binding sites of the specific target protein. This reduces "noise" in the final product of the Western blot, leading to clearer results, and eliminates false positives.
## Detection
During the detection process the membrane is "probed" for the protein of interest with a modified antibody which is linked to a reporter enzyme, which when exposed to an appropriate substrate drives a colorimetric reaction and produces a colour. For a variety of reasons, this traditionally takes place in a two-step process, although there are now one-step detection methods available for certain applications.
### Two step
- Primary antibody
Antibodies are generated when a host species or immune cell culture is exposed to the protein of interest (or a part thereof). Normally, this is part of the immune response, whereas here they are harvested and used as sensitive and specific detection tools that bind the protein directly.
After blocking, a dilute solution of primary antibody (generally between 0.5 and 5 micrograms/ml) is incubated with the membrane under gentle agitation. Typically, the solution is comprised of buffered saline solution with a small percentage of detergent, and sometimes with powdered milk or BSA. The antibody solution and the membrane can be sealed and incubated together for anywhere from 30 minutes to overnight. It can also be incubated at different temperatures, with warmer temperatures being associated with more binding, both specific (to the target protein, the "signal") and non-specific ("noise").
- Secondary antibody
After rinsing the membrane to remove unbound primary antibody, the membrane is exposed to another antibody, directed at a species-specific portion of the primary antibody. This is known as a secondary antibody, and due to its targeting properties, tends to be referred to as "anti-mouse," "anti-goat," etc. Antibodies come from animal sources (or animal sourced hybridoma cultures); an anti-mouse secondary will bind to just about any mouse-sourced primary antibody. This allows some cost savings by allowing an entire lab to share a single source of mass-produced antibody, and provides far more consistent results. The secondary antibody is usually linked to biotin or to a reporter enzyme such as alkaline phosphatase or horseradish peroxidase. This means that several secondary antibodies will bind to one primary antibody and enhances the signal.
Most commonly, a horseradish peroxidase-linked secondary is used in conjunction with a chemiluminescent agent, and the reaction product produces luminescence in proportion to the amount of protein. A sensitive sheet of photographic film is placed against the membrane, and exposure to the light from the reaction creates an image of the antibodies bound to the blot.
As with the ELISPOT and ELISA procedures, the enzyme can be provided with a substrate molecule that will be converted by the enzyme to a colored reaction product that will be visible on the membrane (see the figure below with blue bands).
A third alternative is to use a radioactive label rather than an enzyme coupled to the secondary antibody, such as labeling an antibody-binding protein like Staphylococcus Protein A with a radioactive isotope of iodine. Since other methods are safer, quicker and cheaper this method is now rarely used.
### One step
Historically, the probing process was performed in two steps because of the relative ease of producing primary and secondary antibodies in separate processes. This gives researchers and corporations huge advantages in terms of flexibility, and adds an amplification step to the detection process. Given the advent of high-throughput protein analysis and lower limits of detection, however, there has been interest in developing one-step probing systems that would allow the process to occur faster and with less consumables. This requires a probe antibody which both recognizes the protein of interest and contains a detectable label, probes which are often available for known protein tags. The primary probe is incubated with the membrane in a manner similar to that for the primary antibody in a two-step process, and then is ready for direct detection after a series of wash steps.
## Analysis
After the unbound probes are washed away, the western blot is ready for detection of the probes that are labeled and bound to the protein of interest. In practical terms, not all westerns reveal protein only at one band in a membrane. Size approximations are taken by comparing the stained bands to that of the marker or ladder loaded during electrophoresis. The process is repeated for a structural protein, such as actin or tubulin, that should not change between samples. The amount of target protein is indexed to the structural protein to control between groups. This practice ensures correction for the amount of total protein on the membrane in case of errors or incomplete transfers.
### Colorimetric detection
The colorimetric detection method depends on incubation of the western blot with a substrate that reacts with the reporter enzyme (such as peroxidase) that is bound to the secondary antibody. This converts the soluble dye into an insoluble form of a different color that precipitates next to the enzyme and thereby stains the nitrocellulose membrane. Development of the blot is then stopped by washing away the soluble dye. Protein levels are evaluated through densitometry (how intense the stain is) or spectrophotometry.
### Chemiluminescence
Chemiluminescent detection methods depend on incubation of the western blot with a substrate that will luminesce when exposed to the reporter on the secondary antibody. The light is then detected by photographic film, and more recently by CCD cameras which captures a digital image of the western blot. The image is analysed by densitometry, which evaluates the relative amount of protein staining and quantifies the results in terms of optical density. Newer software allows further data analysis such as molecular weight analysis if appropriate standards are used. So-called "enhanced chemiluminescent" (ECL) detection is considered to be among the most sensitive detection methods for blotting analysis.
### Radioactive detection
Radioactive labels do not require enzyme substrates, but rather allow the placement of medical X-ray film directly against the western blot which develops as it is exposed to the label and creates dark regions which correspond to the protein bands of interest (see image to the right). The importance of radioactive detections methods is declining, because it is very expensive, health and safety risks are high and ECL provides a useful alternative.
### Fluorescent detection
The fluorescently labeled probe is excited by light and the emission of the excitation is then detected by a photosensor such as CCD camera equipped with appropriate emission filters which captures a digital image of the western blot and allows further data analysis such as molecular weight analysis and a quantitative western blot analysis. Fluorescence is considered to be among the most sensitive detection methods for blotting analysis.
## Secondary probing
One major difference between nitrocellulose and PVDF membranes relates to the ability of each to support "stripping" antibodies off and reusing the membrane for subsequent antibody probes. While there are well-established protocols available for stripping nitrocellulose membranes, the sturdier PVDF allows for easier stripping, and for more reuse before background noise limits experiments. Another difference is that, unlike nitrocellulose, PVDF must be soaked in 95% ethanol, isopropanol or methanol before use. PVDF membranes also tend to be thicker and more resistant to damage during use.
# 2-D Gel Electrophoresis
2-dimensional SDS-PAGE uses the principles and techniques outlined above. 2-D SDS-PAGE, as the name suggests, involves the migration of polypeptides in 2 dimensions. For example, in the first dimension polypeptides are separated according to isoelectric point, while in the second dimension polypeptides are separated according to their molecular weight. The isoelectric point of a given protein is determined by the relative number of positively (e.g. lysine and arginine) and negatively (e.g. glutamate and aspartate) amino acids, with negatively charged amino acids contributing to a high isoelectric point and positively charged amino acids contributing to a low isoelectric point. Samples could also be separated first under nonreducing conditions using SDS-PAGE and under reducing conditions in the second dimension, which breaks apart disulfide bonds that hold subunits together. SDS-PAGE might also be coupled with urea-PAGE for a 2-dimensional gel.
In principle, this method allows for the separation of all cellular proteins on a single large gel. A major advantage of this method is that it often distinguishes between different isoforms of a particular protein - e.g. a protein that has been phosphorylated (by addition of a negatively charged group). Proteins that have been separated can be cut out of the gel and then analysed by mass spectrometry, which identifies the protein.
Please refer to reference articles for examples of the application of 2-D SDS PAGE.
# Medical diagnostic applications
- The confirmatory HIV test employs a western blot to detect anti-HIV antibody in a human serum sample. Proteins from known HIV-infected cells are separated and blotted on a membrane as above. Then, the serum to be tested is applied in the primary antibody incubation step; free antibody is washed away, and a secondary anti-human antibody linked to an enzyme signal is added. The stained bands then indicate the proteins to which the patient's serum contains antibody.
- A western blot is also used as the definitive test for Bovine spongiform encephalopathy (BSE, commonly referred to as 'mad cow disease').
- Some forms of Lyme disease testing employ western blotting.
# Protocols
Dr. Mark Barton Frank Lab protocol | Western blot
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The western blot (alternately, immunoblot) is a method to detect a specific protein in a given sample of tissue homogenate or extract. It uses gel electrophoresis to separate native or denatured proteins by the length of the polypeptide (denaturing conditions) (Figure 1) or by the 3-D structure of the protein (native/ non-denaturing conditions). The proteins are then transferred to a membrane (typically nitrocellulose or PVDF), where they are probed (detected) using antibodies specific to the target protein. There are now many reagent companies that specialise in providing antibodies (both monoclonal and polyclonal antibodies) against many thousands of different proteins. Commercial antibodies can be expensive, though the unbound antibody can be reused between experiments. This method is used in the fields of molecular biology, biochemistry, immunogenetics and other molecular biology disciplines.
Other related techniques include using antibodies to detect proteins in tissues and cells by immunostaining and enzyme-linked immunosorbent assay (ELISA).
The method originated from the laboratory of George Stark at Stanford. The name western blot was given to the technique by W. Neal Burnette[1] and is a play on the name Southern blot, a technique for DNA detection developed earlier by Edwin Southern. Detection of RNA is termed northern blotting.
# Steps in a western blot
## Tissue preparation
Samples may be taken from whole tissue or from cell culture. In most cases, solid tissues are first broken down mechanically using a blender (for larger sample volumes), using a homogenizer (smaller volumes), or by sonication. Cells may also be broken open by one of the above mechanical methods. However, it should be noted that bacteria, virus or environmental samples can be the source of protein and thus western blotting is not restricted to cellular studies only.
Assorted detergents, salts, and buffers may be employed to encourage lysis of cells and to solubilize proteins. Protease and phosphatase inhibitors are often added to prevent the digestion of the sample by its own enzymes.
A combination of biochemical and mechanical techniques – including various types of filtration and centrifugation – can be used to separate different cell compartments and organelles.
## Gel electrophoresis
The proteins of the sample are separated using gel electrophoresis. Separation of proteins may be by isoelectric point (pI), molecular weight, electric charge, or a combination of these factors. The nature of the separation depends on the treatment of the sample and the nature of the gel.
By far the most common type of gel electrophoresis employs polyacrylamide gels and buffers loaded with sodium dodecyl sulfate (SDS). SDS-PAGE (SDS polyacrylamide gel electrophoresis) maintains polypeptides in a denatured state once they have been treated with strong reducing agents to remove secondary and tertiary structure (e.g. S-S disulfide bonds to SH and SH) and thus allows separation of proteins by their molecular weight. Sampled proteins become covered in the negatively charged SDS and move to the positively charged electrode through the acrylamide mesh of the gel. Smaller proteins migrate faster through this mesh and the proteins are thus separated according to size (usually measured in kilo Ryans, kR). The concentration of acrylamide determines the resolution of the gel - the greater the acrylamide concentration the better the resolution of lower molecular weight proteins. The lower the acrylamide concentration the better the resolution of higher molecular weight proteins. Proteins travel only in one dimension along the gel for most blots.
Samples are loaded into wells in the gel. One lane is usually reserved for a marker or ladder, a commercially available mixture of proteins having defined molecular weights, typically stained so as to form visible, coloured bands. An example of a ladder is the GE Full Range Molecular weight ladder (Figure 1). When voltage is applied along the gel, proteins migrate into it at different speeds. These different rates of advancement (different electrophoretic mobilities) separate into bands within each lane.
It is also possible to use a two-dimensional (2-D) gel which spreads the proteins from a single sample out in two dimensions. Proteins are separated according to isoelectric point (pH at which they have neutral net charge) in the first dimension, and according to their molecular weight in the second dimension.
## Transfer
In order to make the proteins accessible to antibody detection, they are moved from within the gel onto a membrane made of nitrocellulose or PVDF. The membrane is placed on top of the gel, and a stack of tissue papers placed on top of that. The entire stack is placed in a buffer solution which moves up the paper by capillary action, bringing the proteins with it. Another method for transferring the proteins is called electroblotting and uses an electric current to pull proteins from the gel into the PVDF or nitrocellulose membrane. The proteins move from within the gel onto the membrane while maintaining the organization they had within the gel. As a result of this "blotting" process, the proteins are exposed on a thin surface layer for detection (see below). Both varieties of membrane are chosen for their non-specific protein binding properties (i.e. binds all proteins equally well). Protein binding is based upon hydrophobic interactions, as well as charged interactions between the membrane and protein. Nitrocellulose membranes are cheaper than PVDF, but are far more fragile and do not stand up well to repeated probings.
The uniformity and overall effectiveness of transfer of protein from the gel to the membrane can be checked by staining the membrane with Coomassie or Ponceau S dyes. Coomassie is the more sensitive of the two, although Ponceau S's water solubility makes it easier to subsequently destain and probe the membrane as described below.
## Blotting
Since the membrane has been chosen for its ability to bind protein, and both antibodies and the target are proteins, steps must be taken to prevent interactions between the membrane and the antibody used for detection of the target protein. Blocking of non-specific binding is achieved by placing the membrane in a dilute solution of protein - typically Bovine serum albumin (BSA) or non-fat dry milk (both are inexpensive), with a minute percentage of detergent such as Tween 20. The protein in the dilute solution attaches to the membrane in all places where the target proteins have not attached. Thus, when the antibody is added, there is no room on the membrane for it to attach other than on the binding sites of the specific target protein. This reduces "noise" in the final product of the Western blot, leading to clearer results, and eliminates false positives.
## Detection
During the detection process the membrane is "probed" for the protein of interest with a modified antibody which is linked to a reporter enzyme, which when exposed to an appropriate substrate drives a colorimetric reaction and produces a colour. For a variety of reasons, this traditionally takes place in a two-step process, although there are now one-step detection methods available for certain applications.
### Two step
- Primary antibody
Antibodies are generated when a host species or immune cell culture is exposed to the protein of interest (or a part thereof). Normally, this is part of the immune response, whereas here they are harvested and used as sensitive and specific detection tools that bind the protein directly.
After blocking, a dilute solution of primary antibody (generally between 0.5 and 5 micrograms/ml) is incubated with the membrane under gentle agitation. Typically, the solution is comprised of buffered saline solution with a small percentage of detergent, and sometimes with powdered milk or BSA. The antibody solution and the membrane can be sealed and incubated together for anywhere from 30 minutes to overnight. It can also be incubated at different temperatures, with warmer temperatures being associated with more binding, both specific (to the target protein, the "signal") and non-specific ("noise").
- Secondary antibody
After rinsing the membrane to remove unbound primary antibody, the membrane is exposed to another antibody, directed at a species-specific portion of the primary antibody. This is known as a secondary antibody, and due to its targeting properties, tends to be referred to as "anti-mouse," "anti-goat," etc. Antibodies come from animal sources (or animal sourced hybridoma cultures); an anti-mouse secondary will bind to just about any mouse-sourced primary antibody. This allows some cost savings by allowing an entire lab to share a single source of mass-produced antibody, and provides far more consistent results. The secondary antibody is usually linked to biotin or to a reporter enzyme such as alkaline phosphatase or horseradish peroxidase. This means that several secondary antibodies will bind to one primary antibody and enhances the signal.
Most commonly, a horseradish peroxidase-linked secondary is used in conjunction with a chemiluminescent agent, and the reaction product produces luminescence in proportion to the amount of protein. A sensitive sheet of photographic film is placed against the membrane, and exposure to the light from the reaction creates an image of the antibodies bound to the blot.
As with the ELISPOT and ELISA procedures, the enzyme can be provided with a substrate molecule that will be converted by the enzyme to a colored reaction product that will be visible on the membrane (see the figure below with blue bands).
A third alternative is to use a radioactive label rather than an enzyme coupled to the secondary antibody, such as labeling an antibody-binding protein like Staphylococcus Protein A with a radioactive isotope of iodine. Since other methods are safer, quicker and cheaper this method is now rarely used.
### One step
Historically, the probing process was performed in two steps because of the relative ease of producing primary and secondary antibodies in separate processes. This gives researchers and corporations huge advantages in terms of flexibility, and adds an amplification step to the detection process. Given the advent of high-throughput protein analysis and lower limits of detection, however, there has been interest in developing one-step probing systems that would allow the process to occur faster and with less consumables. This requires a probe antibody which both recognizes the protein of interest and contains a detectable label, probes which are often available for known protein tags. The primary probe is incubated with the membrane in a manner similar to that for the primary antibody in a two-step process, and then is ready for direct detection after a series of wash steps.
## Analysis
After the unbound probes are washed away, the western blot is ready for detection of the probes that are labeled and bound to the protein of interest. In practical terms, not all westerns reveal protein only at one band in a membrane. Size approximations are taken by comparing the stained bands to that of the marker or ladder loaded during electrophoresis. The process is repeated for a structural protein, such as actin or tubulin, that should not change between samples. The amount of target protein is indexed to the structural protein to control between groups. This practice ensures correction for the amount of total protein on the membrane in case of errors or incomplete transfers.
### Colorimetric detection
The colorimetric detection method depends on incubation of the western blot with a substrate that reacts with the reporter enzyme (such as peroxidase) that is bound to the secondary antibody. This converts the soluble dye into an insoluble form of a different color that precipitates next to the enzyme and thereby stains the nitrocellulose membrane. Development of the blot is then stopped by washing away the soluble dye. Protein levels are evaluated through densitometry (how intense the stain is) or spectrophotometry.
### Chemiluminescence
Chemiluminescent detection methods depend on incubation of the western blot with a substrate that will luminesce when exposed to the reporter on the secondary antibody. The light is then detected by photographic film, and more recently by CCD cameras which captures a digital image of the western blot. The image is analysed by densitometry, which evaluates the relative amount of protein staining and quantifies the results in terms of optical density. Newer software allows further data analysis such as molecular weight analysis if appropriate standards are used. So-called "enhanced chemiluminescent" (ECL) detection is considered to be among the most sensitive detection methods for blotting analysis.
### Radioactive detection
Radioactive labels do not require enzyme substrates, but rather allow the placement of medical X-ray film directly against the western blot which develops as it is exposed to the label and creates dark regions which correspond to the protein bands of interest (see image to the right). The importance of radioactive detections methods is declining[citation needed], because it is very expensive, health and safety risks are high and ECL provides a useful alternative.
### Fluorescent detection
The fluorescently labeled probe is excited by light and the emission of the excitation is then detected by a photosensor such as CCD camera equipped with appropriate emission filters which captures a digital image of the western blot and allows further data analysis such as molecular weight analysis and a quantitative western blot analysis. Fluorescence is considered to be among the most sensitive detection methods for blotting analysis.
## Secondary probing
One major difference between nitrocellulose and PVDF membranes relates to the ability of each to support "stripping" antibodies off and reusing the membrane for subsequent antibody probes. While there are well-established protocols available for stripping nitrocellulose membranes, the sturdier PVDF allows for easier stripping, and for more reuse before background noise limits experiments. Another difference is that, unlike nitrocellulose, PVDF must be soaked in 95% ethanol, isopropanol or methanol before use. PVDF membranes also tend to be thicker and more resistant to damage during use.
# 2-D Gel Electrophoresis
2-dimensional SDS-PAGE uses the principles and techniques outlined above. 2-D SDS-PAGE, as the name suggests, involves the migration of polypeptides in 2 dimensions. For example, in the first dimension polypeptides are separated according to isoelectric point, while in the second dimension polypeptides are separated according to their molecular weight. The isoelectric point of a given protein is determined by the relative number of positively (e.g. lysine and arginine) and negatively (e.g. glutamate and aspartate) amino acids, with negatively charged amino acids contributing to a high isoelectric point and positively charged amino acids contributing to a low isoelectric point. Samples could also be separated first under nonreducing conditions using SDS-PAGE and under reducing conditions in the second dimension, which breaks apart disulfide bonds that hold subunits together. SDS-PAGE might also be coupled with urea-PAGE for a 2-dimensional gel.
In principle, this method allows for the separation of all cellular proteins on a single large gel. A major advantage of this method is that it often distinguishes between different isoforms of a particular protein - e.g. a protein that has been phosphorylated (by addition of a negatively charged group). Proteins that have been separated can be cut out of the gel and then analysed by mass spectrometry, which identifies the protein.
Please refer to reference articles for examples of the application of 2-D SDS PAGE.
# Medical diagnostic applications
- The confirmatory HIV test employs a western blot to detect anti-HIV antibody in a human serum sample. Proteins from known HIV-infected cells are separated and blotted on a membrane as above. Then, the serum to be tested is applied in the primary antibody incubation step; free antibody is washed away, and a secondary anti-human antibody linked to an enzyme signal is added. The stained bands then indicate the proteins to which the patient's serum contains antibody.
- A western blot is also used as the definitive test for Bovine spongiform encephalopathy (BSE, commonly referred to as 'mad cow disease').
- Some forms of Lyme disease testing employ western blotting.
# Protocols
Dr. Mark Barton Frank Lab protocol | https://www.wikidoc.org/index.php/Immunoblot | |
f1a776940d25ec571a95d020e1b71618e64983d8 | wikidoc | Implantation | Implantation
# Overview
Implantation is a phenomenon in prenatal development, i.e. early in pregnancy. It is the event where the embryo, at this stage a blastocyst, adheres to the wall of uterus. It is by this adhesion the fetus receives the oxygen and the nutrients from the mother to be able to grow.
# The implantation window
There are many parameters that have to be in order for a successful implantation to take place. Actually, it is only in a specific period of time that implantation is possible, creating an "implantation window". A reason for these limits in time to enable implantation is, that if a process occurs not in the right time, then it is an omen of that something is wrong. And when there is a risk that something is wrong, the body rather performs miscarriage than wasting energy on a malformed fetus.
The implantation window is started by preparations in the endometrium of the uterus, both structurally and in the composition of its secretions.
# Adaption of uterus
To enable implantation, the uterus goes through changes in order to be able to receive the embryo.
## Predecidualization
Predecidualization is a preparation of the endometrium of the uterus, prior to implantation, to facilitate it.
The endometrium increases in thickness, becomes more vascularized and its glands grow to be tortuous and boosted in their secretions. These changes reach their maximum about 7 days after ovulation.
Furthermore, the surface of the endometrium produces a kind of rounded cells, which cover the whole area toward the uterine cavity. This happens about 9 to 10 days after ovulation . These cells are called decidual cells, which emphasises that the whole layer of them is shed off in every menstruation if no pregnancy occurs, just as leaves of deciduous trees. The uterine glands, on the other hand, decrease in activity and degenerate already 8 to 9 days after ovulation in absence of pregnancy.
The stromal cells originate from the stromal cells that are always present in the endometrium. However, the decidual cells make up a new layer, the decidua. The rest of the endometrium, in addition, expresses differences between the luminal and the basal sides. The luminal cells form the zona compacta of the endometrium, in contrast to the basalolateral zona spongiosa, which consists of the rather spongy stromal cells.
## Decidualization
Decidualization succeeds predecidualization if pregnancy occurs. This is an expansion of it, further developing the uterine glands, the zona compacta and the epithelium of decidual cells lining it. The decidual cells become filled with lipids and glycogen and take the polyhedral shape characteristic for decidual cells.
### Trigger
It is likely that the blastocyst itself makes the main contribution to this additional growing and sustaining of the decidua. An indication of this is that decidualization occurs at a higher degree in conception cycles than in nonconception cycles. Furthermore, similar changes are observed when giving stimuli mimicing the natural invasion of the embryo.
### Parts of decidua
The decidua can be organised into separate sections, although they have the same composition;
This is the part of the decidua which is located basalolateral to the embryo ofter implantation.
Decidua capsularis grows over the embryo on the luminal side, enclosing it into the endometrium. It surrounds the embryo together with decidua basalis.
All other decidua on the uterine surface belongs to decidua parietalis.
## Decidua throughout pregnancy
After implantation the decidua remains, at least the first trimester. However, its most prominent time is during the early stages of pregnancy, meanwhile as implantation. Its function as a surrounding tissue is replaced by the definitive placenta. However, some elements of the decidualization remain throughout pregnancy.
The compacta and spongiosa layers are still observable beneath the decidua in pregnancy. The glands of the spongiosa layer continue to secrete during the first trimester, when they degenerate. However, before that disappearance, some glands secrete unequally much. This phenomenon of hypersecretion is called the Arias-Stella phenomenon, after the pathologist Javier Arias-Stella.
## Pinopodes
Pinopodes are small, finger-like protrusions from the endometrium. They appear between day 19 and day 21 of gestational age. This corresponds to a fertilization age of approximately 5 to 7 days, which corresponds well with the time of implantation. They only persist for 2 to 3 days. The development of them is enhanced by progesterone but inhibited by estrogens.
### Function in implantation
Pinopodes endocytose uterine fluid and macromolecules in it. By doing so, the volume of the uterus decreases, taking the walls closer to the embryoblast floating in it. Thus, the period of active pinocytes might also limit the implantation window.
### Function during implantation
Pinopodes continue to absorb fluid, and removes most of ut during the early stages of implantation.
# Adaption of secretions
Not only the lining of the uterus transforms. In addition, the secretion from its epithelial glands changes. This change is induced by increased levels of progesterone from the corpus luteum. The target of the secretions is the embryoblast, and has several functions on it.
## Nourishment
The embryoblast spends approximately 72 hours in the uterine cavity before implanting. In that time, it cannot receive nourishment directly from the blood of the mother, and must rely on secreted nutrients into the uterine cavity, e.g. iron and fat-soluble vitamins.
## Growth and implantation
In addition to nourishment, the endometrium secretes several steroid-dependent proteins, important for growth and implantation. Cholesterol and steroids are also secreted. Implantation is further facilitated by synthesis of matrix substances, adhesion molecues and surface receptors for the matrix substances.
# Mechanism
Implantation occurs approximately 7 days after fertilisation, and is initiated when the blastocyst comes into contact with the uterine wall.
## Zona hatching
To be able to perform implantation, the blastocyst first needs to get rid of its zona pellucida. This process can be called "hatching".
### Factors
Lytic factors in the uterine cavity, as well as factors from the blastocyst itself are essential for this process. Mechanisms in the latter are indicated by that the zona pellucida remains intact if an unfertilized egg is placed in the uterus under the same conditions. A substance probably involved is plasmin. Plasminogen, the plasmin precursor, is found in the uterine cavity, and blastocyst factors contribute to its conversion to active plasmin. This hypothesis is supported by lytic effects in vitro by plasmin. Furthermore, plasmin inhibitors also inhibit the entire zona hatching in rat experiments.
## Apposition
The very first, albeit loose, connection between the blastocyst and the endometrium is called the apposition.
### Location
On the endometrium, the apposition is usually made where there is a small crypt in it, perhaps because it increases the area of contact with the rather spherical blastocyst.
On the blastocyst, on the other hand, it occurs at a location where there has been enough lysis of the zona pellucida to have created a rupture to enable direct contact between the underlying trophoblast and the decidua of the endometrium. However, ultimately, the inner cell mass, inside the trophoblast layer, is aligned closest to the decidua. Nevertheless, the apposition on the blastocyst is not dependent on if it is on the same side of the blastocyst as the inner cell mass. Rather, the inner cell mass rotates inside the trophoblast to align to the apposition. In short, the entire surface of the blastocyst has a potential to form the apposition to the decidua.
## Adhesion
Adhesion is a much stronger attachment to the endometrium than the loose apposition.
The trophoblasts adhere by penetrating the endometrium, with protrusions of trophoblast cells.
### Communication
There is massive communication between the blastocyst and the endometrium at this stage. The blastocyst signals to the endometrium to adapt further to its precense, e.g. by changes in the cytoskeleton of decidual cells. This, in turn, dislodges the decidual cells from their connection to the underlying basal lamina, which enables the blastocyst to perform the succeeding invasion.
This communication is conveyed by receptor-ligand-interactions, both integrin-matrix and proteoglycan ones.
Integrins are cell-membrane-spanning receptors with the ability to react with extracellular matrix-proteins, e.g. collagen, laminin, fibronectin and vitronectin.
In this case, integrins are found on the surface of the trophoblast-cells of the blastocyst, as well as on the decidual cells on the uterine wall. The integrins on the trophoblast reacts with collagen, laminin and fibronectin surrounding decidual cells. It is probably fibronectin that guides the blastocyst inbetween the decidual cells down to the basal lamina.
On the other hand, integrins are also found on the decidual cells, reacting with matrix proteins around decidual cells, also in this case fibronectin for instance. Experimentally, implantation is blocked when small peptides with sequences similar to fibronectin is present, because they occupy the integrins of the decidua, making them unable to attach to blastocyst fibronectins.
However, the integrins are only present on the decidua for a limited period of time, more specifically between day 20 to 24 of gestational age, contributing to the implantation window-phenomenon.
Another ligand-receptor system involved in adhesion is proteoglycan receptors, found on the surface of the decidua of the uterus. Their counterparts, the proteoglycans, are found around the trophoblast cells of the blastocyst. This ligand-receptor system also is present just at the implantation window.
## Invasion
Invasion is an even further establishment of the blastocyst in the endometrium.
### Syncytiotrophoblasts
The protrusions of trophoblast cells that adhere into the endometrium continue to proliferate and penetrate into the endometrium. These penetrating cells differentiate to become a new type of cells, syncytiotrophoblast. The prefix syn- refers to that the boundaries between these cells disappears, forming a single mass of a multitude of cell nuclei. The rest of the trophoblasts, surrounding the inner cell mass, are hereafter called cytotrophoblasts.
Invasion continues with the syncytiotrophoblasts reaching the basal membrane beneath the decidual cells, penetrating it and further invading into the uterine stroma. Finally, the whole embryo is embedded in the endometrium. Eventually, the syncytiotrophoblasts come into contact with maternal blood and form chorionic villi. This is the initiation of forming the placenta.
### Secretions
The blastocyst secretes factors for a multitude of purposes during invasion. It secretes several autocrine factors, targeting itself and stimulating it to further invade the endometrium. Furthermore, secretions loosen decidual cells from each other, prevent the embryo from being rejected by the mother, trigger the final decidualization and prevent menstruation.
Human chorionic gonadotropin is an autocrine growth factor for the blastocyst. Insulin-like growth factor type 2, on the other hand, stimulates the invasiveness of it.
The syncytiotrophoblasts dislodges decidual cells in their way, both by degradation of cell adhesion molecules linking the decidual cells together as well as degradation of the extracellular matrix between them.
Cell adhesion molecules are degraded by syncytiotrophoblast secretion of Tumor necrosis factor-alpha. This inhibits the expression of cadherins and beta-catenin. Cadherins is a cell adhesion molecule and beta-catenin helps anchoring it to the cell membrane. Inhibited expression of these molecules thus loosens the connection between decidual cells, permitting the syncytotrophoblasts and the whole embryo with them to invade into the endometrium.
The extracellular matrix is degraded by serine endopeptidases and metalloproteinases. Examples of such metalloproteinases are collagenases, gelatinases and stromelysins. These collagenases digest Type-I collagen, Type-II collagen, Type-III collagen, Type-VII collagen and Type-X collagen. The gelatinases exist in two forms; one digesting Type-IV collagen and one digesting gelatin.
The embryo differs from the cells of the mother, and would be rejected as a parasite by the immune system of the mother if it didn't secrete immunosuppresive agents. Such agents are Platelet-activating factor, human chorionic gonadotropin, early pregnancy factor, immunosuppressive factor, Prostaglandin E2, Interleukin 1-alpha, Interleukin 6, interferon-alpha, leukemia inhibitory factor and Colony-Stimulating Factor.
Factors from the blastocyst also trigger the final formation of decidual cells into their proper form. In contrast, some decidual cells in the proximity of the blastocyst degenerate, providing nutrients for it.
Human chorionic gonadotropin (hCG) not only acts as an immunosuppressive, but also "notifies" the mother's body that she is pregnant, preventing menstruation by sustaining the function of the corpus luteum.
Other factors secreted by the blastocyst are;
- ovum factor
- Embryo-derived histamine-releasing factor
- Tissue plasminogen activator as well as its inhibitors
- Estradiol
- β1-integrins
- Fibroblast growth factor
- Transforming growth factor alpha
- inhibin | Implantation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Implantation is a phenomenon in prenatal development, i.e. early in pregnancy. It is the event where the embryo, at this stage a blastocyst, adheres to the wall of uterus. It is by this adhesion the fetus receives the oxygen and the nutrients from the mother to be able to grow.
# The implantation window
There are many parameters that have to be in order for a successful implantation to take place. Actually, it is only in a specific period of time that implantation is possible[1], creating an "implantation window". A reason for these limits in time to enable implantation is, that if a process occurs not in the right time, then it is an omen of that something is wrong. And when there is a risk that something is wrong, the body rather performs miscarriage than wasting energy on a malformed fetus.
The implantation window is started by preparations in the endometrium of the uterus, both structurally and in the composition of its secretions.
# Adaption of uterus
To enable implantation, the uterus goes through changes in order to be able to receive the embryo.
## Predecidualization
Predecidualization is a preparation of the endometrium of the uterus, prior to implantation, to facilitate it.
The endometrium increases in thickness, becomes more vascularized and its glands grow to be tortuous and boosted in their secretions. These changes reach their maximum about 7 days after ovulation.
Furthermore, the surface of the endometrium produces a kind of rounded cells, which cover the whole area toward the uterine cavity. This happens about 9 to 10 days after ovulation [1]. These cells are called decidual cells, which emphasises that the whole layer of them is shed off in every menstruation if no pregnancy occurs, just as leaves of deciduous trees. The uterine glands, on the other hand, decrease in activity and degenerate already 8 to 9 days[1] after ovulation in absence of pregnancy.
The stromal cells originate from the stromal cells that are always present in the endometrium. However, the decidual cells make up a new layer, the decidua. The rest of the endometrium, in addition, expresses differences between the luminal and the basal sides. The luminal cells form the zona compacta of the endometrium, in contrast to the basalolateral zona spongiosa, which consists of the rather spongy stromal cells[1].
## Decidualization
Decidualization succeeds predecidualization if pregnancy occurs. This is an expansion of it, further developing the uterine glands, the zona compacta and the epithelium of decidual cells lining it. The decidual cells become filled with lipids and glycogen and take the polyhedral shape characteristic for decidual cells.
### Trigger
It is likely that the blastocyst itself makes the main contribution to this additional growing and sustaining of the decidua. An indication of this is that decidualization occurs at a higher degree in conception cycles than in nonconception cycles[1]. Furthermore, similar changes are observed when giving stimuli mimicing the natural invasion of the embryo[1].
### Parts of decidua
The decidua can be organised into separate sections, although they have the same composition;
This is the part of the decidua which is located basalolateral to the embryo ofter implantation.
Decidua capsularis grows over the embryo on the luminal side, enclosing it into the endometrium. It surrounds the embryo together with decidua basalis.
All other decidua on the uterine surface belongs to decidua parietalis.
## Decidua throughout pregnancy
After implantation the decidua remains, at least the first trimester[1]. However, its most prominent time is during the early stages of pregnancy, meanwhile as implantation. Its function as a surrounding tissue is replaced by the definitive placenta. However, some elements of the decidualization remain throughout pregnancy[1].
The compacta and spongiosa layers are still observable beneath the decidua in pregnancy. The glands of the spongiosa layer continue to secrete during the first trimester, when they degenerate. However, before that disappearance, some glands secrete unequally much. This phenomenon of hypersecretion is called the Arias-Stella phenomenon[1], after the pathologist Javier Arias-Stella.
## Pinopodes
Pinopodes are small, finger-like protrusions from the endometrium. They appear between day 19 and day 21[1] of gestational age. This corresponds to a fertilization age of approximately 5 to 7 days, which corresponds well with the time of implantation. They only persist for 2 to 3 days[1]. The development of them is enhanced by progesterone but inhibited by estrogens.
### Function in implantation
Pinopodes endocytose uterine fluid and macromolecules in it. By doing so, the volume of the uterus decreases, taking the walls closer to the embryoblast floating in it. Thus, the period of active pinocytes might also limit the implantation window[1].
### Function during implantation
Pinopodes continue to absorb fluid, and removes most of ut during the early stages of implantation.
# Adaption of secretions
Not only the lining of the uterus transforms. In addition, the secretion from its epithelial glands changes. This change is induced by increased levels of progesterone from the corpus luteum. The target of the secretions is the embryoblast, and has several functions on it.
## Nourishment
The embryoblast spends approximately 72[1] hours in the uterine cavity before implanting. In that time, it cannot receive nourishment directly from the blood of the mother, and must rely on secreted nutrients into the uterine cavity, e.g. iron[1] and fat-soluble vitamins[1].
## Growth and implantation
In addition to nourishment, the endometrium secretes several steroid-dependent proteins[1], important for growth and implantation. Cholesterol[1] and steroids[1] are also secreted. Implantation is further facilitated by synthesis of matrix substances, adhesion molecues and surface receptors for the matrix substances.
# Mechanism
Implantation occurs approximately 7 days after fertilisation, and is initiated when the blastocyst comes into contact with the uterine wall.
## Zona hatching
To be able to perform implantation, the blastocyst first needs to get rid of its zona pellucida. This process can be called "hatching".
### Factors
Lytic factors in the uterine cavity, as well as factors from the blastocyst itself are essential for this process. Mechanisms in the latter are indicated by that the zona pellucida remains intact if an unfertilized egg is placed in the uterus under the same conditions[1]. A substance probably involved is plasmin. Plasminogen, the plasmin precursor, is found in the uterine cavity, and blastocyst factors contribute to its conversion to active plasmin. This hypothesis is supported by lytic effects in vitro by plasmin[1]. Furthermore, plasmin inhibitors also inhibit the entire zona hatching in rat experiments[1].
## Apposition
The very first, albeit loose, connection between the blastocyst and the endometrium is called the apposition[1].
### Location
On the endometrium, the apposition is usually made where there is a small crypt in it, perhaps because it increases the area of contact with the rather spherical blastocyst.
On the blastocyst, on the other hand, it occurs at a location where there has been enough lysis of the zona pellucida to have created a rupture to enable direct contact between the underlying trophoblast and the decidua of the endometrium[1]. However, ultimately, the inner cell mass, inside the trophoblast layer, is aligned closest to the decidua. Nevertheless, the apposition on the blastocyst is not dependent on if it is on the same side of the blastocyst as the inner cell mass. Rather, the inner cell mass rotates inside the trophoblast to align to the apposition[1]. In short, the entire surface of the blastocyst has a potential to form the apposition to the decidua.
## Adhesion
Adhesion is a much stronger attachment to the endometrium than the loose apposition.
The trophoblasts adhere by penetrating the endometrium, with protrusions of trophoblast cells.
### Communication
There is massive communication between the blastocyst and the endometrium at this stage. The blastocyst signals to the endometrium to adapt further to its precense, e.g. by changes in the cytoskeleton of decidual cells. This, in turn, dislodges the decidual cells from their connection to the underlying basal lamina, which enables the blastocyst to perform the succeeding invasion[1].
This communication is conveyed by receptor-ligand-interactions, both integrin-matrix and proteoglycan ones.
Integrins are cell-membrane-spanning receptors with the ability to react with extracellular matrix-proteins, e.g. collagen, laminin, fibronectin and vitronectin.
In this case, integrins are found on the surface of the trophoblast-cells of the blastocyst, as well as on the decidual cells on the uterine wall. The integrins on the trophoblast reacts with collagen, laminin and fibronectin surrounding decidual cells. It is probably fibronectin that guides the blastocyst inbetween the decidual cells down to the basal lamina[1].
On the other hand, integrins are also found on the decidual cells, reacting with matrix proteins around decidual cells, also in this case fibronectin for instance. Experimentally, implantation is blocked when small peptides with sequences similar to fibronectin is present, because they occupy the integrins of the decidua, making them unable to attach to blastocyst fibronectins[1].
However, the integrins are only present on the decidua for a limited period of time, more specifically between day 20 to 24 of gestational age, contributing to the implantation window-phenomenon.
Another ligand-receptor system involved in adhesion is proteoglycan receptors, found on the surface of the decidua of the uterus. Their counterparts, the proteoglycans, are found around the trophoblast cells of the blastocyst. This ligand-receptor system also is present just at the implantation window[1].
## Invasion
Invasion is an even further establishment of the blastocyst in the endometrium.
### Syncytiotrophoblasts
The protrusions of trophoblast cells that adhere into the endometrium continue to proliferate and penetrate into the endometrium. These penetrating cells differentiate to become a new type of cells, syncytiotrophoblast. The prefix syn- refers to that the boundaries between these cells disappears, forming a single mass of a multitude of cell nuclei. The rest of the trophoblasts, surrounding the inner cell mass, are hereafter called cytotrophoblasts.
Invasion continues with the syncytiotrophoblasts reaching the basal membrane beneath the decidual cells, penetrating it and further invading into the uterine stroma. Finally, the whole embryo is embedded in the endometrium. Eventually, the syncytiotrophoblasts come into contact with maternal blood and form chorionic villi. This is the initiation of forming the placenta.
### Secretions
The blastocyst secretes factors for a multitude of purposes during invasion. It secretes several autocrine factors, targeting itself and stimulating it to further invade the endometrium[1]. Furthermore, secretions loosen decidual cells from each other, prevent the embryo from being rejected by the mother, trigger the final decidualization and prevent menstruation.
Human chorionic gonadotropin is an autocrine growth factor for the blastocyst[1]. Insulin-like growth factor type 2[1], on the other hand, stimulates the invasiveness of it.
The syncytiotrophoblasts dislodges decidual cells in their way, both by degradation of cell adhesion molecules linking the decidual cells together as well as degradation of the extracellular matrix between them.
Cell adhesion molecules are degraded by syncytiotrophoblast secretion of Tumor necrosis factor-alpha. This inhibits the expression of cadherins and beta-catenin[1]. Cadherins is a cell adhesion molecule and beta-catenin helps anchoring it to the cell membrane. Inhibited expression of these molecules thus loosens the connection between decidual cells, permitting the syncytotrophoblasts and the whole embryo with them to invade into the endometrium.
The extracellular matrix is degraded by serine endopeptidases and metalloproteinases. Examples of such metalloproteinases are collagenases, gelatinases and stromelysins[1]. These collagenases digest Type-I collagen, Type-II collagen, Type-III collagen, Type-VII collagen and Type-X collagen[1]. The gelatinases exist in two forms; one digesting Type-IV collagen and one digesting gelatin[1].
The embryo differs from the cells of the mother, and would be rejected as a parasite by the immune system of the mother if it didn't secrete immunosuppresive agents. Such agents are Platelet-activating factor, human chorionic gonadotropin, early pregnancy factor, immunosuppressive factor, Prostaglandin E2, Interleukin 1-alpha, Interleukin 6, interferon-alpha, leukemia inhibitory factor and Colony-Stimulating Factor.
Factors from the blastocyst also trigger the final formation of decidual cells into their proper form. In contrast, some decidual cells in the proximity of the blastocyst degenerate, providing nutrients for it[1].
Human chorionic gonadotropin (hCG) not only acts as an immunosuppressive[1], but also "notifies" the mother's body that she is pregnant, preventing menstruation by sustaining the function of the corpus luteum.
Other factors secreted by the blastocyst are;
- ovum factor
- Embryo-derived histamine-releasing factor
- Tissue plasminogen activator as well as its inhibitors
- Estradiol
- β1-integrins
- Fibroblast growth factor
- Transforming growth factor alpha
- inhibin | https://www.wikidoc.org/index.php/Implantation | |
4e7ae03c8eb34ab467786c749e9aa86f503d677c | wikidoc | Incineration | Incineration
Incineration is a waste treatment technology that involves the combustion of organic materials and/or substances. Incineration and other high temperature waste treatment systems are described as "thermal treatment". Incineration of waste materials converts the waste into incinerator bottom ash, flue gases, particulates, and heat, which can in turn be used to generate electric power. The flue gases are cleaned of pollutants before they are dispersed in the atmosphere.
Incineration with energy recovery is one of several waste-to-energy (WtE) technologies such as gasification, pyrolysis and anaerobic digestion. Incineration may also be implemented without energy and materials recovery.
In several countries there are still expert and local community concerns about the environmental impact of incinerators (see The argument against incineration).
In some countries, incinerators built just a few decades ago often did not include a materials separation to remove hazardous, bulky or recyclable materials before combustion. These facilities tended to risk the health of the plant workers and the local environment due to inadequate levels of gas cleaning and combustion process control. Most of these facilities did not generate electricity.
Incinerators reduce the volume of the original waste by 95-96 %, depending upon composition and degree of recovery of materials such as metals from the ash for recycling. This means that while incineration does not completely replace landfilling, it reduces the necessary volume for disposal significantly.
Incineration has particularly strong benefits for the treatment of certain waste types in niche areas such as clinical wastes and certain hazardous wastes where pathogens and toxins can be destroyed by high temperatures. Examples include chemical multi-product plants with diverse toxic or very toxic wastewater streams, which cannot be routed to a conventional wastewater treatment plant.
Waste combustion is particularly popular in countries such as Japan where land is a scarce resource. Denmark and Sweden have been leaders in using the energy generated from incineration for more than a century, in localised combined heat and power facilities supporting district heating schemes. In 2005, waste incineration produced 4.8 % of the electricity consumption and 13.7 % of the total domestic heat consumption in Denmark. A number of other European Countries rely heavily on incineration for handling municipal waste, in particular Luxemburg, The Netherlands, Germany and France.
# Technology
## Types of incinerators
An incinerator is a furnace for burning waste. Modern incinerators include pollution mitigation equipment such as flue gas cleaning. There are various types of incinerator plant design: moving grate, fixed grate, rotary-kiln, fluidised bed.
### Moving grate
The typical incineration plant for municipal solid waste is a moving grate incinerator. The moving grate enables the movement of waste through the combustion chamber to be optimised to allow a more efficient and complete combustion. A single moving grate boiler can handle up to 35 tonnes of waste per hour, and can operate 8,000 hours per year with only one scheduled stop for inspection and maintenance of about one months duration. Moving grate incinerators are sometimes referred to as Municipal Solid Waste Incinerators (MSWIs).
The waste is introduced by a waste crane through the "throat" at one end of the grate, from where it moves down over the descending grate to the ash pit in the other end. Here the ash is removed through a water lock.
Part of the combustion air (primary combustion air) is supplied through the grate from below. This air flow also has the purpose of cooling the grate itself. Cooling is important for the mechanical strength of the grate, and many moving grates are also water cooled internally.
Secondary combustion air is supplied into the boiler at high speed through nozzles over the grate. It facilitates complete combustion of the flue gases by introducing turbulence for better mixing and by ensuring a surplus of oxygen. In multiple/stepped hearth incinerators, the secondary combustion air is introduced in a separate chamber downstream the primary combustion chamber.
According to the European Waste Incineration Directive, incineration plants must be designed to ensure that the flue gases reach a temperature of at least 850 °C for 2 seconds in order to ensure proper breakdown of organic toxins. In order to comply with this at all times, it is required to install backup auxiliary burners (often fueled by oil), which are fired into the boiler in case the heating value of the waste becomes too low to reach this temperature alone.
The flue gases are then cooled in the superheaters, where the heat is transferred to steam, heating the steam to typically 400 °C at a pressure of 40 bar for the electricity generation in the turbine. At this point, the flue gas has a temperature of around 200 °C, and is passed to the flue gas cleaning system.
At least in Scandinavia scheduled maintenance is always performed during summer, where the demand for district heating is low. Often incineration plants consist of several separate 'boiler lines' (boilers and flue gas treatment plants), so that waste receival can continue at one boiler line while the others are subject to revision.
### Fixed grate
The older and simpler kind of incinerator was a brick-lined cell with a fixed metal grate over a lower ash pit, with one opening in the top or side for loading and another opening in the side for removing incombustible solids called clinkers. Many small incinerators formerly found in apartment houses have now been replaced by waste compactors.
### Rotary-kiln
The rotary-kiln incinerator used by municipalities and by large industrial plants.
This design of incinerators have 2 chambers a primary chamber and secondary chamber. The primary chamber in a rotary kiln incinerator consist of an inclined refractory lined cylindrical tube. Movement of the cylinder on its axis facilitates movement of waste. In the primary chamber, there is conversion of solid fraction to gases, through volatilization, destructive distillation and partial combustion reactions. The secondary chamber is necessary to complete gas phase combustion reactions
The clinkers spill out at the end of the cylinder. A tall flue gas stack, fan, or steam jet supplies the needed draft. Ash drops through the grate, but many particles are carried along with the hot gases. The particles and any combustible gases may be combusted in an "afterburner". A diagram of a rotary-kiln incinerator can be found here.
### Fluidized bed
A strong airflow is forced through a sandbed. The air seeps through the sand until a point is reached where the sand particles separate to let the air through and mixing and churning occurs, thus a fluidised bed is created and fuel and waste can now be introduced.
The sand with the pre-treated waste and/or fuel is kept suspended on pumped air currents and takes on a fluid-like character. The bed is thereby violently mixed and agitated keeping small inert particles and air in a fluid-like state. This allows all of the mass of waste, fuel and sand to be fully circulated through the furnace.
### Specialized incineration
Furniture factory sawdust incinerators need much attention as these have to handle resin powder and many flammable substances. Controlled combustion, burn back prevention systems are very essential as dust when suspended resembles the fire catch phenomenon of any liquid petroleum gas.
## Use of heat
The heat produced by an incinerator can be used to generate steam which may then be used to drive a turbine in order to produce electricity. The typical amount of net energy that can be produced per ton municipal waste is about 0.67 MWh of electricity and 2 MJ of district heating. Thus, incinerating about 600 tonnes per day of waste will produce about 17 MW of electrical power and 1200 MJ district heating each day.
## Pollution
Incineration has a number of outputs such as the ash and the emission to the atmosphere of flue gas. Before the flue gas cleaning system, the flue gases may contain significant amounts of particulate matter, heavy metals, dioxins, furans, sulfur dioxide, and hydrochloric acid.
In a study from 1994, Delaware Solid Waste Authority found that, for same amount of produced energy, incineration plants emitted fewer particles, hydrocarbons and less SO2, HCl, CO and NOx than coal-fired power plants, but more than natural gas fired power plants.
According to Germany's Ministry of the Environment, waste incinerators reduce the amount of some atmospheric pollutants by substituting power produced by coal-fired plants with power from waste-fired plants.
## Gaseous emissions
### Dioxin and furans
The most publicized concerns from environmentalists about the incineration of municipal solid wastes (MSW) involve the fear that it produces significant amounts of dioxin and furan emissions. Dioxins and furans are considered by many to be serious health hazards. Older generation incinerators that were not equipped with adequate gas cleaning technologies were indeed significant sources of dioxin emissions. Today, however, due to advances in emission control designs and stringent new governmental regulations, incinerators emit virtually no dioxins. In 2005, The Ministry of the Environment of Germany, where there were 66 incinerators at that time, estimated that "...whereas in 1990 one third of all dioxin emissions in Germany came from incineration plants, for the year 2000 the figure was less than 1 %. Chimneys and tiled stoves in private households alone discharge approximately twenty times more dioxin into the environment than incineration plants.". According to the U.S. EPA, incineration plants are no longer significant sources of dioxins and furans. In 1987, before the governmental regulations required the use of emission controls, there was a total of 10,000 grams of dioxin emissions from U.S. incinerators. Today, the total emissions from the 87 plants are only 10 grams yearly, a reduction of 99.9 %. Backyard barrel burning of household and garden wastes, still allowed in some rural areas, generates 580 grams of dioxins yearly.
Studies conducted by EPA demonstrate that the emissions from just one family using a burn barrel produces more emissions than an incineration plant disposing of 200 tonnes of waste per day.
Generally the breakdown of dioxin requires exposure of the molecule to a sufficiently high temperature so as to trigger thermal breakdown of the molecular bonds holding it together. When burning of plastics outdoors in a burn barrel or garbage pit such temperatures are not reached, causing high dioxin emissions as mentioned above. While the plastic does burn in an open-air fire, the dioxins remain after combustion and float off into the atmosphere.
Modern municipal incinerator designs include a high temperature zone, where the flue gas is ensured to sustain a temperature above 850 oC for at least 2 seconds befores it is cooled down. They are equipped with auxiliary heaters to ensure this at all times. These are often fueled by oil, and normally only active for a very small fraction of the time. A side effect controlling dioxin is the potential for generation of reactive oxides (NOx) in the flue gas, which must be removed with SCR or SNCR (see below).
For very small municipal incinerators, the required temperature for thermal breakdown of dioxin may be reached using a high-temperature electrical heating element, plus an SCR stage.
### CO2
As for other complete combustion processes, nearly all of the carbon content in the waste is emitted as CO2 to the atmosphere. MSW contain approximately the same mass fraction of carbon as CO2 itself (27%), so incineration of one tonne of MSW produce approximately 1 tonne of CO2.
In the event that the waste was landfilled, one tonne of MSW would produce approximately 62 m³ methane via the anaerobic decomposition of the biodegradable part of the waste. This amount of methane has more than twice the global warming potential than the one tonne of CO2, which would have been produced by incineration. In some countries, large amounts of landfill gas are collected, but still the global warming potential of the landfill gas emitted to atmosphere in the US in 1999 was approximately 32 % higher than the amount of CO2 that would have been emitted by incineration.
In addition, nearly all biodegradable waste has biological origin. This material has been formed by plants using atmospheric CO2 typically within the last growing season. If these plants are regrown the CO2 emitted from their combustion will be taken out from the atmosphere once more.
Such considerations are the main reason why several countries administrate incineration of the biodegradable part of waste as renewable energy. The rest - mainly plastics and other oil and gas derived products - is generally treated as non-renewables.
Different results for the CO2 footprint of incineration can be reached with different assumptions. Local conditions (such as limited local district heating demand, no fossil fuel generated electricity to replace or high levels of aluminum in the waste stream) can decrease the CO2 benefits of incineration.
The methology and other assumptions may also influence the results significantly. For example the methane emissions from landfills occurring at a later date may be neglected or given less weight, or biodegradable waste may not be considered CO2 neutral. A recent study by Eunomia Research and Consulting on potential waste treatment technologies in London demonstrated that by applying several of these (according to the authors) unusual assumptions the average existing incineration plants performed poorly for CO2 balance compared to the theoretical potential of other emerging waste treatment technologies..
### Other emissions
Other gaseous toxins in the flue gas from incinerator furnaces include sulfur dioxide, hydrochloric acid, heavy metals and fine particles.
The steam content in the flue may produce visible fume from the stack, which can be perceived as a visual pollution. It may be avoided by decreasing the steam content by flue gas condensation, or by increasing the flue gas exit temperature well above its dew point. Flue gas condensation allows the latent heat of vaporization of the water to be recovered, subsequently increasing the thermal efficiency of the plant.
### Flue gas cleaning
The quantity of pollutants in the flue gas from incineration plants is reduced by several processes.
Particulate is collected by particle filtration, most often electrostatic precipitators (ESP) and/or baghouse filters. The latter are generally very efficient for collecting fine particles. In an investigation by the Ministry of the Environment of Denmark in 2006, the average particulate emissions per energy content of incinerated waste from 16 Danish incinerators were below 2.02 g/GJ (grams per energy content of the incinerated waste). Detailed measurements of fine particles with sizes below 2.5 micrometres (PM2.5) were performed on three of the incinerators: One incinerator equipped with an ESP for particle filtration emitted 5.3 g/GJ fine particles, while two incinerators equipped with baghouse filters emitted 0.002 and 0.013 g/GJ PM2.5.
Acid gas scrubbers are used to remove hydrochloric acid, nitric acid, hydrofluoric acid, mercury, lead and other heavy metals. Basic scrubbers remove sulfur dioxide, forming gypsum by reaction with lime.
Waste water from scrubbers must subsequently pass through a waste water treatment plant.
Sulfur dioxide may also be removed by dry desulfurisation by injection limestone slurry into the flue gas before the particle filtration.
NOx is either reduced by catalytic reduction with ammonia in a catalytic converter (selective catalytic reduction, SCR) or by a high temperature reaction with ammonia in the furnace (selective non-catalytic reduction, SNCR).
Heavy metals are often adsorbed on injected active carbon powder, which is collected by the particle filtration.
## Solid outputs
Incineration produces fly ash and bottom ash just as is the case when coal is combusted. The total amount of ash produced by municipal solid waste incineration ranges from 4-10 % by volume and 15-20 % by weight of the original quantity of waste, and the fly ash amounts to about 10-20 % of the total ash. The fly ash, by far, constitutes more of a potential health hazard than does the bottom ash because the fly ash often contain high concentrations of heavy metals such as lead, cadmium, copper and zinc as well as small amounts of dioxins and furans. The bottom ash seldom contain significant levels of heavy metals. While fly ash is always regarded as hazardous waste, bottom ash is generally considered safe for regular landfill after a certain level of testing defined by the local legislation. Ash, which is considered hazardous, may generally only be disposed of in landfills which are carefully designed to prevent pollutants in the ash from leaching into underground aquifers - or after chemical treatment to reduce its leaching characteristics. In testing over the past decade, no ash from an incineration plant in the USA has ever been determined to be a hazardous waste. At present although some historic samples tested by the incinerator operators' group would meet the being ecotoxic criteria at present the EA say "we have agreed" to regard incinerator bottom ash as "non-hazardous" until the testing programme is complete.
## Other pollution issues
Odour pollution can be a problem with old-style incinerators, but odours and dust are extremely well controlled in newer incineration plants. They receive and store the waste in an enclosed area with a negative pressure with the airflow being routed through the boiler which prevents unpleasant odours from escaping into the atmosphere. However, not all plants are implemented this way, resulting in inconveniences in the locality.
An issue that affects community relationships is the increased road traffic of waste collection vehicles to transport municipal waste to the incinerator. Due to this reason, most incinerators are located in industrial areas.
# The debate over incineration
Use of incinerators for waste management is controversial. The debate over incinerators typically involves business interests (representing both waste generators and incinerator firms), government regulators, environmental activists and local citizens who must weigh the economic appeal of local industrial activity with their concerns over health and environmental risk.
People and organizations professionally involved in this issue include the U.S. Environmental Protection Agency and a great many local and national air quality regulatory agencies worldwide.
## The argument for incineration
- The concerns over the health effects of dioxin and furan emissions have been significantly lessened by advances in emission control designs and very stringent new governmental regulations that have resulted in large reductions in the amount of dioxins and furans emissions.
- Incineration plants generate electricity and heat that can substitute power plants powered by other fuels at the regional electric and district heating grid, and steam supply for industrial customers.
- The bottom ash residue remaining after combustion has been shown to be a non-hazardous solid waste that can be safely landfilled or recycled as construction aggregate.
- In densely populated areas, finding space for additional landfills is becoming increasingly difficult.
- Fine particles can be efficiently removed from the flue gases with baghouse filters. Even though approximately 40 % of the incinerated waste in Denmark was incinerated at plants with no baghouse filters, estimates based on measurements by the Danish Environmental Research Institute showed that incinerators were only responsible for approximately 0.3 % of the total domestic emissions of particulate smaller than 2.5 micrometres (PM2.5) to the atmosphere in 2006.
- Incineration of municipal solid waste avoids the release of methane. Every ton of MSW incinerated, prevents about one ton of carbon dioxide equivalents from being released to the atmosphere.
- Incineration of medical waste and sewage sludge produces an end product ash that is sterile and non-hazardous.
## The argument against incineration
- The highly toxic fly ash must be safely disposed of. This usually involves additional waste miles and the need for specialist toxic waste landfill elsewhere, sometimes with concerns for local residents.
- There are still concerns by many about the health effects of dioxin and furan emissions into the atmosphere from old incinerators; especially during start up and shut down events, or where filter bypass events are required.
- Incinerators emit varying levels of heavy metals such as vanadium, manganese, chromium, nickel, arsenic, mercury, lead, and cadmium, which can be toxic at very minute levels.
- Incinerator Bottom Ash (IBA) has high levels of heavy metals with ecotoxicity concerns if not reused properly. Some people have the opinion that IBA reuse is still in its infancy and is still not considered to be a mature or desirable product, despite additional engineering treatments.
- Alternative technologies are available or in development such as Mechanical Biological Treatment, Anaerobic Digestion (MBT/AD), Autoclaving or Mechanical Heat Treatment (MHT) using steam or Plasma arc gasification PGP, or combinations.
- Building and operating an incinerator requires long contract periods to recover initial investment costs, causing a long term lock-in. Incinerator lifetimes normally range from 25-30 years.
- Incinerators produce fine particles in the furnace. Even with modern particle filtering of the flue gases, a fraction of these are emitted to the atmosphere. As an example, the baghouse filters in an incineration plant planned for erection in the UK, are only specified to capture 65-70 % (in weight) particulate smaller than 2.5 micrometres (PM2.5), if the significant filtration in the filter cake is not accounted for. PM2.5 is not separately regulated in the European Waste Incineration Directive, even though they are suspected to be linked to infant mortality in the UK, and PM2.5 emissions from local incinerators to be a significant PM2.5 source here.
- Local communities are often opposed to the idea of locating incinerators in their vicinity. (The Not In My Back Yard phenomenon). Studies in Andover, Massachusetts linked 10 % property devaluations with close incinerator proximity .
- Prevention, waste minimisation, reuse and recycling of waste should all be preferred to incineration according to the waste hierarchy. Supporters of zero waste consider incinerators and other waste treatment technologies as barriers to recycling and separation beyond particular levels, and that waste resources are sacrificed for energy producion.
- A recent Eunomia report found that incinerators under some circumstances and assumptions can be seen as contributing to climate change, and are less energy efficient than emerging technologies for treating residual mixed waste.
- Some incinerators are architecturally monstrous and ugly. In many countries they require a visually intrusive chimney stack.
- Disposal of sewage sludge or hospital waste is more safely and completely undertaken by Plasma arc gasification when compared to Russian incinerators in the 1990s, due to hotter temperatures, lesser residues and the rudimentary flue gas cleaning on these incinerators.
# Trends in incinerator use
The history of municipal solid waste (MSW) incineration is linked intimately to the history of landfills and other waste treatment technology. The merits of incineration are inevitably judged in relation to the alternatives available. Since the 1970s, recycling and other prevention measures have changed the context for such judgements. Since the 1990s alternative waste treatment technologies have been maturing and becoming viable.
Incineration is a key process in the treatment of hazardous wastes and clinical wastes. It is often imperative that medical waste be subjected to the high temperatures of incineration to destroy pathogens and toxic contamination it contains.
## Incineration in North America
The first full-scale waste-to-energy facility in the U.S. was the Arnold O. Chantland Resource Recovery Plant, built in 1975 located in Ames, Iowa. This plant is still in operation and produces refuse-derived fuel that is sent to local power plants for fuel. The first commercially-successful incineration plant in the U.S. was built in Saugus, Massachusetts in October 1975 by Wheelabrator Technologies, and is still in operation today.
Several older generation incinerators have been closed; of the 186 MSW incinerators in 1990, only 89 remained by 2007, and of the 6200 medical waste incinerators in 1988, only 115 remained in 2003.
Between 1996 and 2007, no new incinerators were built. The main reasons for lack of activity have been:
- Economics. With the increase in the number of large inexpensive regional landfills and, up until recently, the relatively low price of electricity, incinerators were not able to compete for the 'fuel', i.e., waste. By contrast, a number of Canadian cities are working toward installation of incinerators.
- Tax Policies. Tax credits for plants producing electricity from waste were rescinded in the 1990s. In Europe, some of the electricity generated from waste is deemed to be from a 'Renewable Energy Source (RES)'. A new law granting tax credits for such plants was implemented in the U.S. in 2004.
Despite these problems, there has been renewed interest in waste-to-energy in the U.S., Canada, and the UK. Projects to add capacity to existing plants are underway, and municipalities are once again evaluating the option of building incinerators rather than continue landfilling municipal wastes.
## Incineration in Europe
In Europe, with the ban on landfilling untreated waste, scores of incinerators have been built in the last decade, with more under construction. Recently, a number of municipal governments have begun the process of contracting for the construction and operation of incinerators. In Europe, some of the electricity generated from waste is deemed to be from a 'Renewable Energy Source (RES)' and is thus eligible for tax credits if privately operated.
## Incineration in the United Kingdom
The technology employed in the UK waste management industry has been greatly lagging behind that of Europe due to the wide availablility of landfills. The Landfill Directive set down by the European Union led to the Government of the United Kingdom imposing waste legislation including the landfill tax and Landfill Allowance Trading Scheme. This legislation is designed to reduce the release of greenhouse gases produced by landfills through the use of alternative methods of waste treatment. It is the UK Government's position that incineration will play an increasingly large role in the treatment of municipal waste and supply of energy in the UK.
## Small incinerator units
Small scale incinerators exist for special purposes. For example, the small scale incinerators are aimed for hygienically safe destruction of medical waste in developing countries. Simple, mobile incinerators are becoming more widely used in developing countries where the threat of avian influenza is high. Small incinerators can be quickly deployed to remote areas where an outbreak has occurred to dispose of infected animals quickly and without the risk of cross contamination.
# Incinerators
- Allington Incinerator
- Isle of Man Incinerator
- Kirklees Incinerator
- List of incinerators in the UK
- SELCHP
- Sheffield Incinerator | Incineration
Incineration is a waste treatment technology that involves the combustion of organic materials and/or substances.[1] Incineration and other high temperature waste treatment systems are described as "thermal treatment". Incineration of waste materials converts the waste into incinerator bottom ash, flue gases, particulates, and heat, which can in turn be used to generate electric power. The flue gases are cleaned of pollutants before they are dispersed in the atmosphere.
Incineration with energy recovery is one of several waste-to-energy (WtE) technologies such as gasification, pyrolysis and anaerobic digestion. Incineration may also be implemented without energy and materials recovery.
In several countries there are still expert and local community concerns about the environmental impact of incinerators (see The argument against incineration).
In some countries, incinerators built just a few decades ago often did not include a materials separation to remove hazardous, bulky or recyclable materials before combustion. These facilities tended to risk the health of the plant workers and the local environment due to inadequate levels of gas cleaning and combustion process control. Most of these facilities did not generate electricity.
Incinerators reduce the volume of the original waste by 95-96 %, depending upon composition and degree of recovery of materials such as metals from the ash for recycling.[2] This means that while incineration does not completely replace landfilling, it reduces the necessary volume for disposal significantly.
Incineration has particularly strong benefits for the treatment of certain waste types in niche areas such as clinical wastes and certain hazardous wastes where pathogens and toxins can be destroyed by high temperatures. Examples include chemical multi-product plants with diverse toxic or very toxic wastewater streams, which cannot be routed to a conventional wastewater treatment plant.
Waste combustion is particularly popular in countries such as Japan where land is a scarce resource. Denmark and Sweden have been leaders in using the energy generated from incineration for more than a century, in localised combined heat and power facilities supporting district heating schemes.[3] In 2005, waste incineration produced 4.8 % of the electricity consumption and 13.7 % of the total domestic heat consumption in Denmark.[4] A number of other European Countries rely heavily on incineration for handling municipal waste, in particular Luxemburg, The Netherlands, Germany and France.
[2]
# Technology
## Types of incinerators
An incinerator is a furnace for burning waste. Modern incinerators include pollution mitigation equipment such as flue gas cleaning. There are various types of incinerator plant design: moving grate, fixed grate, rotary-kiln, fluidised bed.
### Moving grate
The typical incineration plant for municipal solid waste is a moving grate incinerator. The moving grate enables the movement of waste through the combustion chamber to be optimised to allow a more efficient and complete combustion. A single moving grate boiler can handle up to 35 tonnes of waste per hour, and can operate 8,000 hours per year with only one scheduled stop for inspection and maintenance of about one months duration[5]. Moving grate incinerators are sometimes referred to as Municipal Solid Waste Incinerators (MSWIs).
The waste is introduced by a waste crane through the "throat" at one end of the grate, from where it moves down over the descending grate to the ash pit in the other end. Here the ash is removed through a water lock.
Part of the combustion air (primary combustion air) is supplied through the grate from below. This air flow also has the purpose of cooling the grate itself. Cooling is important for the mechanical strength of the grate, and many moving grates are also water cooled internally.
Secondary combustion air is supplied into the boiler at high speed through nozzles over the grate. It facilitates complete combustion of the flue gases by introducing turbulence for better mixing and by ensuring a surplus of oxygen. In multiple/stepped hearth incinerators, the secondary combustion air is introduced in a separate chamber downstream the primary combustion chamber.
According to the European Waste Incineration Directive, incineration plants must be designed to ensure that the flue gases reach a temperature of at least 850 °C for 2 seconds in order to ensure proper breakdown of organic toxins. In order to comply with this at all times, it is required to install backup auxiliary burners (often fueled by oil), which are fired into the boiler in case the heating value of the waste becomes too low to reach this temperature alone.
The flue gases are then cooled in the superheaters, where the heat is transferred to steam, heating the steam to typically 400 °C at a pressure of 40 bar for the electricity generation in the turbine. At this point, the flue gas has a temperature of around 200 °C, and is passed to the flue gas cleaning system.
At least in Scandinavia scheduled maintenance is always performed during summer, where the demand for district heating is low. Often incineration plants consist of several separate 'boiler lines' (boilers and flue gas treatment plants), so that waste receival can continue at one boiler line while the others are subject to revision.
### Fixed grate
The older and simpler kind of incinerator was a brick-lined cell with a fixed metal grate over a lower ash pit, with one opening in the top or side for loading and another opening in the side for removing incombustible solids called clinkers. Many small incinerators formerly found in apartment houses have now been replaced by waste compactors.
### Rotary-kiln
The rotary-kiln incinerator[6] used by municipalities and by large industrial plants.
This design of incinerators have 2 chambers a primary chamber and secondary chamber. The primary chamber in a rotary kiln incinerator consist of an inclined refractory lined cylindrical tube. Movement of the cylinder on its axis facilitates movement of waste. In the primary chamber, there is conversion of solid fraction to gases, through volatilization, destructive distillation and partial combustion reactions. The secondary chamber is necessary to complete gas phase combustion reactions
The clinkers spill out at the end of the cylinder. A tall flue gas stack, fan, or steam jet supplies the needed draft. Ash drops through the grate, but many particles are carried along with the hot gases. The particles and any combustible gases may be combusted in an "afterburner".[7] A diagram of a rotary-kiln incinerator can be found here.
### Fluidized bed
A strong airflow is forced through a sandbed. The air seeps through the sand until a point is reached where the sand particles separate to let the air through and mixing and churning occurs, thus a fluidised bed is created and fuel and waste can now be introduced.
The sand with the pre-treated waste and/or fuel is kept suspended on pumped air currents and takes on a fluid-like character. The bed is thereby violently mixed and agitated keeping small inert particles and air in a fluid-like state. This allows all of the mass of waste, fuel and sand to be fully circulated through the furnace.
### Specialized incineration
Furniture factory sawdust incinerators need much attention as these have to handle resin powder and many flammable substances. Controlled combustion, burn back prevention systems are very essential as dust when suspended resembles the fire catch phenomenon of any liquid petroleum gas.
## Use of heat
The heat produced by an incinerator can be used to generate steam which may then be used to drive a turbine in order to produce electricity. The typical amount of net energy that can be produced per ton municipal waste is about 0.67 MWh of electricity and 2 MJ of district heating[2]. Thus, incinerating about 600 tonnes per day of waste will produce about 17 MW of electrical power and 1200 MJ district heating each day.
## Pollution
Incineration has a number of outputs such as the ash and the emission to the atmosphere of flue gas. Before the flue gas cleaning system, the flue gases may contain significant amounts of particulate matter, heavy metals, dioxins, furans, sulfur dioxide, and hydrochloric acid.
In a study[8] from 1994, Delaware Solid Waste Authority found that, for same amount of produced energy, incineration plants emitted fewer particles, hydrocarbons and less SO2, HCl, CO and NOx than coal-fired power plants, but more than natural gas fired power plants.
According to Germany's Ministry of the Environment, waste incinerators reduce the amount of some atmospheric pollutants by substituting power produced by coal-fired plants with power from waste-fired plants[9].
## Gaseous emissions
### Dioxin and furans
The most publicized concerns from environmentalists about the incineration of municipal solid wastes (MSW) involve the fear that it produces significant amounts of dioxin and furan emissions.[10] Dioxins and furans are considered by many to be serious health hazards. Older generation incinerators that were not equipped with adequate gas cleaning technologies were indeed significant sources of dioxin emissions. Today, however, due to advances in emission control designs and stringent new governmental regulations, incinerators emit virtually no dioxins. In 2005, The Ministry of the Environment of Germany, where there were 66 incinerators at that time, estimated that "...whereas in 1990 one third of all dioxin emissions in Germany came from incineration plants, for the year 2000 the figure was less than 1 %. Chimneys and tiled stoves in private households alone discharge approximately twenty times more dioxin into the environment than incineration plants."[9]. According to the U.S. EPA, incineration plants are no longer significant sources of dioxins and furans. In 1987, before the governmental regulations required the use of emission controls, there was a total of 10,000 grams of dioxin emissions from U.S. incinerators. Today, the total emissions from the 87 plants are only 10 grams yearly, a reduction of 99.9 %. Backyard barrel burning of household and garden wastes, still allowed in some rural areas, generates 580 grams of dioxins yearly.
Studies conducted by EPA[11] demonstrate that the emissions from just one family using a burn barrel produces more emissions than an incineration plant disposing of 200 tonnes of waste per day.
Generally the breakdown of dioxin requires exposure of the molecule to a sufficiently high temperature so as to trigger thermal breakdown of the molecular bonds holding it together. When burning of plastics outdoors in a burn barrel or garbage pit such temperatures are not reached, causing high dioxin emissions as mentioned above. While the plastic does burn in an open-air fire, the dioxins remain after combustion and float off into the atmosphere.
Modern municipal incinerator designs include a high temperature zone, where the flue gas is ensured to sustain a temperature above 850 oC for at least 2 seconds befores it is cooled down. They are equipped with auxiliary heaters to ensure this at all times. These are often fueled by oil, and normally only active for a very small fraction of the time. A side effect controlling dioxin is the potential for generation of reactive oxides (NOx) in the flue gas, which must be removed with SCR or SNCR (see below).
For very small municipal incinerators, the required temperature for thermal breakdown of dioxin may be reached using a high-temperature electrical heating element, plus an SCR stage.
### CO2
As for other complete combustion processes, nearly all of the carbon content in the waste is emitted as CO2 to the atmosphere. MSW contain approximately the same mass fraction of carbon as CO2 itself (27%), so incineration of one tonne of MSW produce approximately 1 tonne of CO2.
In the event that the waste was landfilled, one tonne of MSW would produce approximately 62 m³ methane via the anaerobic decomposition of the biodegradable part of the waste. This amount of methane has more than twice the global warming potential than the one tonne of CO2, which would have been produced by incineration. In some countries, large amounts of landfill gas are collected, but still the global warming potential of the landfill gas emitted to atmosphere in the US in 1999 was approximately 32 % higher than the amount of CO2 that would have been emitted by incineration.[12]
In addition, nearly all biodegradable waste has biological origin. This material has been formed by plants using atmospheric CO2 typically within the last growing season. If these plants are regrown the CO2 emitted from their combustion will be taken out from the atmosphere once more.
Such considerations are the main reason why several countries administrate incineration of the biodegradable part of waste as renewable energy[13]. The rest - mainly plastics and other oil and gas derived products - is generally treated as non-renewables.
Different results for the CO2 footprint of incineration can be reached with different assumptions. Local conditions (such as limited local district heating demand, no fossil fuel generated electricity to replace or high levels of aluminum in the waste stream) can decrease the CO2 benefits of incineration.
The methology and other assumptions may also influence the results significantly. For example the methane emissions from landfills occurring at a later date may be neglected or given less weight, or biodegradable waste may not be considered CO2 neutral. A recent study by Eunomia Research and Consulting on potential waste treatment technologies in London demonstrated that by applying several of these (according to the authors) unusual assumptions the average existing incineration plants performed poorly for CO2 balance compared to the theoretical potential of other emerging waste treatment technologies.[14].
### Other emissions
Other gaseous toxins in the flue gas from incinerator furnaces include sulfur dioxide, hydrochloric acid, heavy metals and fine particles.
The steam content in the flue may produce visible fume from the stack, which can be perceived as a visual pollution. It may be avoided by decreasing the steam content by flue gas condensation, or by increasing the flue gas exit temperature well above its dew point. Flue gas condensation allows the latent heat of vaporization of the water to be recovered, subsequently increasing the thermal efficiency of the plant.
### Flue gas cleaning
The quantity of pollutants in the flue gas from incineration plants is reduced by several processes.
Particulate is collected by particle filtration, most often electrostatic precipitators (ESP) and/or baghouse filters. The latter are generally very efficient for collecting fine particles. In an investigation by the Ministry of the Environment of Denmark in 2006, the average particulate emissions per energy content of incinerated waste from 16 Danish incinerators were below 2.02 g/GJ (grams per energy content of the incinerated waste). Detailed measurements of fine particles with sizes below 2.5 micrometres (PM2.5) were performed on three of the incinerators: One incinerator equipped with an ESP for particle filtration emitted 5.3 g/GJ fine particles, while two incinerators equipped with baghouse filters emitted 0.002 and 0.013 g/GJ PM2.5.[15]
Acid gas scrubbers are used to remove hydrochloric acid, nitric acid, hydrofluoric acid, mercury, lead and other heavy metals. Basic scrubbers remove sulfur dioxide, forming gypsum by reaction with lime.[16]
Waste water from scrubbers must subsequently pass through a waste water treatment plant.
Sulfur dioxide may also be removed by dry desulfurisation by injection limestone slurry into the flue gas before the particle filtration.
NOx is either reduced by catalytic reduction with ammonia in a catalytic converter (selective catalytic reduction, SCR) or by a high temperature reaction with ammonia in the furnace (selective non-catalytic reduction, SNCR).
Heavy metals are often adsorbed on injected active carbon powder, which is collected by the particle filtration.
## Solid outputs
Incineration produces fly ash and bottom ash just as is the case when coal is combusted. The total amount of ash produced by municipal solid waste incineration ranges from 4-10 % by volume and 15-20 % by weight of the original quantity of waste[2][17], and the fly ash amounts to about 10-20 % of the total ash[citation needed]. The fly ash, by far, constitutes more of a potential health hazard than does the bottom ash because the fly ash often contain high concentrations of heavy metals such as lead, cadmium, copper and zinc as well as small amounts of dioxins and furans[18]. The bottom ash seldom contain significant levels of heavy metals. While fly ash is always regarded as hazardous waste, bottom ash is generally considered safe for regular landfill after a certain level of testing defined by the local legislation. Ash, which is considered hazardous, may generally only be disposed of in landfills which are carefully designed to prevent pollutants in the ash from leaching into underground aquifers - or after chemical treatment to reduce its leaching characteristics[19]. In testing over the past decade, no ash from an incineration plant in the USA has ever been determined to be a hazardous waste[citation needed]. At present although some historic samples tested by the incinerator operators' group would meet the being ecotoxic criteria at present the EA say "we have agreed" to regard incinerator bottom ash as "non-hazardous" until the testing programme is complete[citation needed].
## Other pollution issues
Odour pollution can be a problem with old-style incinerators, but odours and dust are extremely well controlled in newer incineration plants. They receive and store the waste in an enclosed area with a negative pressure with the airflow being routed through the boiler which prevents unpleasant odours from escaping into the atmosphere. However, not all plants are implemented this way, resulting in inconveniences in the locality.
An issue that affects community relationships is the increased road traffic of waste collection vehicles to transport municipal waste to the incinerator. Due to this reason, most incinerators are located in industrial areas.
# The debate over incineration
Use of incinerators for waste management is controversial. The debate over incinerators typically involves business interests (representing both waste generators and incinerator firms), government regulators, environmental activists and local citizens who must weigh the economic appeal of local industrial activity with their concerns over health and environmental risk.
People and organizations professionally involved in this issue include the U.S. Environmental Protection Agency and a great many local and national air quality regulatory agencies worldwide.
## The argument for incineration
- The concerns over the health effects of dioxin and furan emissions have been significantly lessened by advances in emission control designs and very stringent new governmental regulations that have resulted in large reductions in the amount of dioxins and furans emissions.[9]
- Incineration plants generate electricity and heat that can substitute power plants powered by other fuels at the regional electric and district heating grid, and steam supply for industrial customers.
- The bottom ash residue remaining after combustion has been shown to be a non-hazardous solid waste that can be safely landfilled or recycled as construction aggregate.[19]
- In densely populated areas, finding space for additional landfills is becoming increasingly difficult[citation needed].
- Fine particles can be efficiently removed from the flue gases with baghouse filters. Even though approximately 40 % of the incinerated waste in Denmark was incinerated at plants with no baghouse filters, estimates based on measurements by the Danish Environmental Research Institute showed that incinerators were only responsible for approximately 0.3 % of the total domestic emissions of particulate smaller than 2.5 micrometres (PM2.5) to the atmosphere in 2006.[15]
- Incineration of municipal solid waste avoids the release of methane. Every ton of MSW incinerated, prevents about one ton of carbon dioxide equivalents from being released to the atmosphere.[12]
- Incineration of medical waste and sewage sludge produces an end product ash that is sterile and non-hazardous[citation needed].
## The argument against incineration
- The highly toxic fly ash must be safely disposed of. This usually involves additional waste miles and the need for specialist toxic waste landfill elsewhere, sometimes with concerns for local residents.[citation needed]
- There are still concerns by many about the health effects of dioxin and furan emissions into the atmosphere from old incinerators; especially during start up and shut down events, or where filter bypass events are required.
- Incinerators emit varying levels of heavy metals such as vanadium, manganese, chromium, nickel, arsenic, mercury, lead, and cadmium, which can be toxic at very minute levels.
- Incinerator Bottom Ash (IBA) has high levels of heavy metals with ecotoxicity concerns if not reused properly. Some people have the opinion that IBA reuse is still in its infancy and is still not considered to be a mature or desirable product, despite additional engineering treatments.[citation needed]
- Alternative technologies are available or in development such as Mechanical Biological Treatment, Anaerobic Digestion (MBT/AD), Autoclaving or Mechanical Heat Treatment (MHT) using steam or Plasma arc gasification PGP, or combinations.
- Building and operating an incinerator requires long contract periods to recover initial investment costs, causing a long term lock-in. Incinerator lifetimes normally range from 25-30 years.
- Incinerators produce fine particles in the furnace. Even with modern particle filtering of the flue gases, a fraction of these are emitted to the atmosphere. As an example, the baghouse filters in an incineration plant planned for erection in the UK, are only specified to capture 65-70 % (in weight) particulate smaller than 2.5 micrometres (PM2.5), if the significant filtration in the filter cake is not accounted for.[20] PM2.5 is not separately regulated in the European Waste Incineration Directive, even though they are suspected to be linked to infant mortality in the UK,[21] and PM2.5 emissions from local incinerators to be a significant PM2.5 source here.[22][23]
- Local communities are often opposed to the idea of locating incinerators in their vicinity. (The Not In My Back Yard phenomenon). Studies in Andover, Massachusetts linked 10 % property devaluations with close incinerator proximity [24].
- Prevention, waste minimisation, reuse and recycling of waste should all be preferred to incineration according to the waste hierarchy. Supporters of zero waste consider incinerators and other waste treatment technologies as barriers to recycling and separation beyond particular levels, and that waste resources are sacrificed for energy producion.[25][26][27]
- A recent Eunomia report found that incinerators under some circumstances and assumptions can be seen as contributing to climate change, and are less energy efficient than emerging technologies for treating residual mixed waste.[28]
- Some incinerators are architecturally monstrous and ugly. In many countries they require a visually intrusive chimney stack.
- Disposal of sewage sludge or hospital waste is more safely and completely undertaken by Plasma arc gasification when compared to Russian incinerators in the 1990s, due to hotter temperatures, lesser residues and the rudimentary flue gas cleaning on these incinerators.[29]
# Trends in incinerator use
The history of municipal solid waste (MSW) incineration is linked intimately to the history of landfills and other waste treatment technology. The merits of incineration are inevitably judged in relation to the alternatives available. Since the 1970s, recycling and other prevention measures have changed the context for such judgements. Since the 1990s alternative waste treatment technologies have been maturing and becoming viable.
Incineration is a key process in the treatment of hazardous wastes and clinical wastes. It is often imperative that medical waste be subjected to the high temperatures of incineration to destroy pathogens and toxic contamination it contains.
## Incineration in North America
The first full-scale waste-to-energy facility in the U.S. was the Arnold O. Chantland Resource Recovery Plant, built in 1975 located in Ames, Iowa. This plant is still in operation and produces refuse-derived fuel that is sent to local power plants for fuel.[30] The first commercially-successful incineration plant in the U.S. was built in Saugus, Massachusetts in October 1975 by Wheelabrator Technologies, and is still in operation today.[17]
Several older generation incinerators have been closed; of the 186 MSW incinerators in 1990, only 89 remained by 2007, and of the 6200 medical waste incinerators in 1988, only 115 remained in 2003.[31]
Between 1996 and 2007, no new incinerators were built. The main reasons for lack of activity have been:
- Economics. With the increase in the number of large inexpensive regional landfills and, up until recently, the relatively low price of electricity, incinerators were not able to compete for the 'fuel', i.e., waste. By contrast, a number of Canadian cities are working toward installation of incinerators.
- Tax Policies. Tax credits for plants producing electricity from waste were rescinded in the 1990s. In Europe, some of the electricity generated from waste is deemed to be from a 'Renewable Energy Source (RES)'. A new law granting tax credits for such plants was implemented in the U.S. in 2004.[citation needed]
Despite these problems, there has been renewed interest in waste-to-energy in the U.S., Canada, and the UK. Projects to add capacity to existing plants are underway, and municipalities are once again evaluating the option of building incinerators rather than continue landfilling municipal wastes.
## Incineration in Europe
In Europe, with the ban on landfilling untreated waste, scores of incinerators have been built in the last decade, with more under construction. Recently, a number of municipal governments have begun the process of contracting for the construction and operation of incinerators. In Europe, some of the electricity generated from waste is deemed to be from a 'Renewable Energy Source (RES)' and is thus eligible for tax credits if privately operated.
## Incineration in the United Kingdom
The technology employed in the UK waste management industry has been greatly lagging behind that of Europe due to the wide availablility of landfills. The Landfill Directive set down by the European Union led to the Government of the United Kingdom imposing waste legislation including the landfill tax and Landfill Allowance Trading Scheme. This legislation is designed to reduce the release of greenhouse gases produced by landfills through the use of alternative methods of waste treatment. It is the UK Government's position that incineration will play an increasingly large role in the treatment of municipal waste and supply of energy in the UK.
## Small incinerator units
Small scale incinerators exist for special purposes. For example, the small scale [32] incinerators are aimed for hygienically safe destruction of medical waste in developing countries. Simple, mobile incinerators are becoming more widely used in developing countries where the threat of avian influenza is high[citation needed]. Small incinerators can be quickly deployed to remote areas where an outbreak has occurred to dispose of infected animals quickly and without the risk of cross contamination[citation needed].
# Incinerators
- Allington Incinerator
- Isle of Man Incinerator
- Kirklees Incinerator
- List of incinerators in the UK
- SELCHP
- Sheffield Incinerator | https://www.wikidoc.org/index.php/Incineration | |
1a914885b2df2051e343bf1fbd307b0d0adf1784 | wikidoc | Perspiration | Perspiration
# Overview
Perspiration (also called sweating or sometimes transpiration) is the production and evaporation of a fluid, consisting primarily of water as well as a smaller amount of sodium chloride (the main constituent of table salt), that is excreted by the sweat glands in the skin of mammals. Sweat also contains the chemicals or odorants such as 2-methylphenol (o-cresol) and 4-methylphenol (p-cresol).
# Classification
There are four types of sweats:
- Diaphoresis: Diaphoresis is a cold sweat. Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions. It is distinguished from hyperhidrosis by the "clammy" or "cold state" state of the patient.
- Primary Hyperhidrosis: Primary hyperhidrosis is a condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature. This is not a cold sweat.
- Secondary Hyperhidrosis: Secondary hyperhidrosis is a condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature that is secondary to an underlying pathologic process such as infections, disorders of the thyroid or pituitary gland, diabetes mellitus, tumors, gout, menopause, certain drugs, or mercury poisoning. This is not a cold sweat.
- Night sweats: Sleep hyperhidrosis, more commonly known as the night sweats, is the occurrence of excessive sweating (hyperhidrosis) during sleep. The sufferer may or may not also suffer from excessive perspiration while awake.
In humans, sweating is primarily a means of thermoregulation, although it has been proposed that components of male sweat can act as pheromonal cues. Evaporation of sweat from the skin surface has a cooling effect due to the latent heat of evaporation of water. Hence, in hot weather, or when the individual's muscles heat up due to exertion, more sweat is produced. Sweating is increased by nervousness and nausea and decreased by cold. Animals with few sweat glands, such as dogs, accomplish similar temperature regulation results by panting, which evaporates water from the moist lining of the oral cavity and pharynx. Primates and horses have armpits that sweat similarly to those of humans.
# Pathophysiology
Sweat glands are innervated by the sympathetic nervous system; however, because the primary neurotransmitter involved with the innervation of sweat receptors is acetylcholine. Many of the glands are under the control of the hippocampus via nerve pathways typically thought of as parasympathetic. The nerve terminal releases acetylcholine, which binds to M3 receptors on the sweat gland and causes the secretion of sweat. Acetylcholine is partially degraded by Cholinesterase enzyme (AchE), thus anything which interferes with AchE activity causes excessive sweating.
There are two kinds of sweat glands, and they differ greatly in both the composition of the sweat and its purpose:
- Eccrine sweat glands are distributed over the entire body surface, but are particularly abundant on the palms of hands, soles of feet, and on the forehead. These produce sweat that is composed chiefly of water with various salts. These glands are used for body temperature regulation.
- Apocrine sweat glands produce sweat that contains fatty materials. These glands are mainly present in the armpits and around the genital area and their activity is the main cause of sweat odor, due to the bacteria that break down the organic compounds in the sweat from these glands.
# Causes
- Drugs causing increased sweating
- Acamprosate calcium
- Ambenonium
- Butorphanol
- clozapine
- Epinephrine (aerosol)
- Exemestane
- Megestrol
- Methylene blue
- Oxaprozin
- prednisolone
- prednisone
- Tiagabine
- Toremifene
- Drugs causing diminished sweating
- Thioridazine hydrochloride
- Endocrine
- Multiple endocrine neoplasia type 1
# Related Chapters
- Diaphoresis
- Hyperhidrosis
- Anhidrosis
- Hyponatremia
- Hyperthermia
- Body odor
- Hidradenitis suppurativa
- Pheromones
- Sweat therapy | Perspiration
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Perspiration (also called sweating or sometimes transpiration) is the production and evaporation of a fluid, consisting primarily of water as well as a smaller amount of sodium chloride (the main constituent of table salt), that is excreted by the sweat glands in the skin of mammals. Sweat also contains the chemicals or odorants such as 2-methylphenol (o-cresol) and 4-methylphenol (p-cresol).
# Classification
There are four types of sweats:
- Diaphoresis: Diaphoresis is a cold sweat. Diaphoresis is excessive sweating commonly associated with shock and other medical emergency conditions. It is distinguished from hyperhidrosis by the "clammy" or "cold state" state of the patient.
- Primary Hyperhidrosis: Primary hyperhidrosis is a condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature. This is not a cold sweat.
- Secondary Hyperhidrosis: Secondary hyperhidrosis is a condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature that is secondary to an underlying pathologic process such as infections, disorders of the thyroid or pituitary gland, diabetes mellitus, tumors, gout, menopause, certain drugs, or mercury poisoning. This is not a cold sweat.
- Night sweats: Sleep hyperhidrosis, more commonly known as the night sweats, is the occurrence of excessive sweating (hyperhidrosis) during sleep. The sufferer may or may not also suffer from excessive perspiration while awake.
In humans, sweating is primarily a means of thermoregulation, although it has been proposed that components of male sweat can act as pheromonal cues.[1] Evaporation of sweat from the skin surface has a cooling effect due to the latent heat of evaporation of water. Hence, in hot weather, or when the individual's muscles heat up due to exertion, more sweat is produced. Sweating is increased by nervousness and nausea and decreased by cold. Animals with few sweat glands, such as dogs, accomplish similar temperature regulation results by panting, which evaporates water from the moist lining of the oral cavity and pharynx. Primates and horses have armpits that sweat similarly to those of humans.
# Pathophysiology
Sweat glands are innervated by the sympathetic nervous system; however, because the primary neurotransmitter involved with the innervation of sweat receptors is acetylcholine. Many of the glands are under the control of the hippocampus via nerve pathways typically thought of as parasympathetic. The nerve terminal releases acetylcholine, which binds to M3 receptors on the sweat gland and causes the secretion of sweat. Acetylcholine is partially degraded by Cholinesterase enzyme (AchE), thus anything which interferes with AchE activity causes excessive sweating.
There are two kinds of sweat glands, and they differ greatly in both the composition of the sweat and its purpose:
- Eccrine sweat glands are distributed over the entire body surface, but are particularly abundant on the palms of hands, soles of feet, and on the forehead. These produce sweat that is composed chiefly of water with various salts. These glands are used for body temperature regulation.
- Apocrine sweat glands produce sweat that contains fatty materials. These glands are mainly present in the armpits and around the genital area and their activity is the main cause of sweat odor, due to the bacteria that break down the organic compounds in the sweat from these glands.
# Causes
- Drugs causing increased sweating
- Acamprosate calcium
- Ambenonium
- Butorphanol
- clozapine
- Epinephrine (aerosol)
- Exemestane
- Megestrol
- Methylene blue
- Oxaprozin
- prednisolone
- prednisone
- Tiagabine
- Toremifene
- Drugs causing diminished sweating
- Thioridazine hydrochloride
- Endocrine
- Multiple endocrine neoplasia type 1
# Related Chapters
- Diaphoresis
- Hyperhidrosis
- Anhidrosis
- Hyponatremia
- Hyperthermia
- Body odor
- Hidradenitis suppurativa
- Pheromones
- Sweat therapy | https://www.wikidoc.org/index.php/Increased_sweating | |
7bf01ed0456edbf54069c029a77c97c2dafb2442 | wikidoc | Index finger | Index finger
The second digit of a human hand is also referred to as the index finger, pointer finger, forefinger, digitus secundus, or digitus II.
It is located between the first and third digits - that is, between the thumb and the middle finger. It is usually the most dextrous and sensitive finger of the hand, though not the longest. It may be used to point to things, for hunt and peck typing, to press an elevator button, or to tap on a window. A lone index finger often is used to represent the number 1, or when held up or moved side to side (finger-wagging), it can be an admonitory gesture. With the hand held palm out, it represents the letter d in the American Sign Language alphabet. In sports, it can also represent victory, as some championship-winning teams raise their index finger while posing for a championship team photo.
Studies have also found that a smaller index finger compared with the ring finger indicates a better athlete.
# Gestures
As mentioned above, the forefinger can be used for pointing. However, this gesture is considered rude in some countries (Brunei, for instance), and other gestures are used instead.
During the Bosnian war, Serbo-Bosnian troops raised three fingers in a sign of victory, Bosnian Croats raised the two-finger V-sign and Muslims (Bosniaks) raised one (after the strict monotheism of Islam).
# Unicode
There are six index finger symbols in Unicode.
- Black left pointing index: U+261A ☚
- Black right pointing index: U+261B ☛
- White left pointing index: U+261C ☜
- White up pointing index: U+261D ☝
- White right pointing index: U+261E ☞
- White down pointing index: U+261F ☟ | Index finger
Template:Infobox Anatomy
The second digit of a human hand is also referred to as the index finger, pointer finger, forefinger, digitus secundus, or digitus II.
It is located between the first and third digits - that is, between the thumb and the middle finger. It is usually the most dextrous and sensitive finger of the hand, though not the longest. It may be used to point to things, for hunt and peck typing, to press an elevator button, or to tap on a window. A lone index finger often is used to represent the number 1, or when held up or moved side to side (finger-wagging), it can be an admonitory gesture. With the hand held palm out, it represents the letter d in the American Sign Language alphabet. In sports, it can also represent victory, as some championship-winning teams raise their index finger while posing for a championship team photo.
Studies have also found that a smaller index finger compared with the ring finger indicates a better athlete.[1]
# Gestures
As mentioned above, the forefinger can be used for pointing. However, this gesture is considered rude in some countries (Brunei, for instance), and other gestures are used instead.
During the Bosnian war, Serbo-Bosnian troops raised three fingers in a sign of victory, Bosnian Croats raised the two-finger V-sign and Muslims (Bosniaks) raised one (after the strict monotheism of Islam).
# Unicode
There are six index finger symbols in Unicode.
- Black left pointing index: U+261A ☚
- Black right pointing index: U+261B ☛
- White left pointing index: U+261C ☜
- White up pointing index: U+261D ☝
- White right pointing index: U+261E ☞
- White down pointing index: U+261F ☟ | https://www.wikidoc.org/index.php/Index_finger | |
7520d63312213916f11247ef02de95c216e3f8fd | wikidoc | Index fossil | Index fossil
Index fossils (also known as guide fossils or zone fossils) are fossils used to define and identify geologic periods (or faunal stages). They work on the premise that, although different sediments may look different depending on the conditions under which they were laid down, they may include the remains of the same species of fossil. If the species concerned were short-lived (in geological terms, lasting a few hundred thousand years), then it is certain that the sediments in question were deposited within that narrow time period. The shorter the lifespan of a species, the more precisely different sediments can be correlated, and so rapidly evolving types of fossils are particularly valuable. The best index fossils are common, easy-to-identify at species level, and have a broad distribution—otherwise the likelihood of finding and recognizing one in the two sediments is low.
Ammonites fit these demands well, and are the best-known fossils that have been widely used for this. Other important groups that provide index fossils are the corals, graptolites, brachiopods, trilobites, and echinoids (sea urchins). Conodonts may be identified by experts using light microscopy such that they can be used to index a given sample with good resolution. Fossilized teeth of mammals, have also been used.
Geologists use both large fossils (called macrofossils) and microscopic fossils (called microfossils) for this process, known as biostratigraphy. Macrofossils have the advantage of being easy to see in the field, but they are rarer, and microfossils are very commonly used by oil prospectors and other industries interested in mineral resources when accurate knowledge of the age of the rocks being looked at is needed.
# Common Index Fossils
# In Popular Culture
Musical Group Bad Religion have a song titled "Part IV (The Index Fossil)" on their 1987 album Suffer. The song suggests that one day humanity will be "an index fossil buried in own debris".
# References and Links
- ↑ Index Fossils, from the US Geological Survey. Updated July 28, 1997.
de:Leitfossil
hu:Jelzőfosszília
nl:Gidsfossiel | Index fossil
Index fossils (also known as guide fossils or zone fossils) are fossils used to define and identify geologic periods (or faunal stages). They work on the premise that, although different sediments may look different depending on the conditions under which they were laid down, they may include the remains of the same species of fossil. If the species concerned were short-lived (in geological terms, lasting a few hundred thousand years), then it is certain that the sediments in question were deposited within that narrow time period. The shorter the lifespan of a species, the more precisely different sediments can be correlated, and so rapidly evolving types of fossils are particularly valuable. The best index fossils are common, easy-to-identify at species level, and have a broad distribution—otherwise the likelihood of finding and recognizing one in the two sediments is low.
Ammonites fit these demands well, and are the best-known fossils that have been widely used for this. Other important groups that provide index fossils are the corals, graptolites, brachiopods, trilobites, and echinoids (sea urchins). Conodonts may be identified by experts using light microscopy such that they can be used to index a given sample with good resolution. Fossilized teeth of mammals, have also been used.
Geologists use both large fossils (called macrofossils) and microscopic fossils (called microfossils) for this process, known as biostratigraphy. Macrofossils have the advantage of being easy to see in the field, but they are rarer, and microfossils are very commonly used by oil prospectors and other industries interested in mineral resources when accurate knowledge of the age of the rocks being looked at is needed.
## Common Index Fossils
## In Popular Culture
Musical Group Bad Religion have a song titled "Part IV (The Index Fossil)" on their 1987 album Suffer. The song suggests that one day humanity will be "an index fossil buried in [its] own debris".
## References and Links
- ↑ Index Fossils, from the US Geological Survey. Updated July 28, 1997.
de:Leitfossil
hu:Jelzőfosszília
nl:Gidsfossiel
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Index_fossil | |
d1a7c77cd01d42903113867a07e2b9fc3b08f461 | wikidoc | Induced coma | Induced coma
A barbiturate-induced coma, or barb coma, is a temporary coma (a deep state of unconsciousness) brought on by a controlled dose of a barbiturate drug, usually pentobarbital or thiopental. Barbiturate comas are used to protect the brain during major surgery, and as a last line of treatment in certain cases of status epilepticus that have not responded to other treatments.
Barbiturates reduce the metabolic rate of brain tissue, as well as the cerebral blood flow. With these reductions, the blood vessels in the brain narrow, decreasing the amount of volume occupied by the brain, and hence the intra-cranial pressure. The hope is that, with the swelling relieved, the pressure decreases and some or all brain damage may be averted. Several studies have supported this theory by showing reduced mortality when treating refractory intracranial hypertension with a barbiturate coma.
Controversy exists, however, over the benefits of using barbiturates to control intracranial hypertension. Some studies have shown that barbiturate-induced coma can reduce intracranial hypertension but does not necessarily prevent brain damage. Furthermore, the reduction in intracranial hypertension may not be sustained. Some randomized trials have failed to demonstrate any survival or morbidity benefit of induced coma in diverse conditions such as neurosurgical operations, head trauma , intracranial aneurysm rupture, intracranial hemorrhage, ischemic stroke, and status epilepticus. If the patient survives, cognitive impairment may also follow recovery from the coma.
About 55% of the glucose and oxygen utilisation by the brain is meant for its electrical activity and the rest for all other activities like metabolism. This is recognised by something such as an Electro encephalogram (EEG), which measures electrical activity in the brain. When barbiturates are given to a brain injured patients for Induced coma, they act by reducing the electrical activity of the brain, which in theory reduces the metabolic and oxygen demand. Once there is improvement in the patient's general condition, the barbiturates are withdrawn gradually and the patient regains consciousness.
Induced coma was used in the treatment of symptomatic rabies. See the case of Jeanna Giese. | Induced coma
A barbiturate-induced coma, or barb coma, is a temporary coma (a deep state of unconsciousness) brought on by a controlled dose of a barbiturate drug, usually pentobarbital or thiopental. Barbiturate comas are used to protect the brain during major surgery, and as a last line of treatment in certain cases of status epilepticus that have not responded to other treatments.
Barbiturates reduce the metabolic rate of brain tissue, as well as the cerebral blood flow. With these reductions, the blood vessels in the brain narrow, decreasing the amount of volume occupied by the brain, and hence the intra-cranial pressure. The hope is that, with the swelling relieved, the pressure decreases and some or all brain damage may be averted. Several studies have supported this theory by showing reduced mortality when treating refractory intracranial hypertension with a barbiturate coma. [1] [2] [3]
Controversy exists, however, over the benefits of using barbiturates to control intracranial hypertension. Some studies have shown that barbiturate-induced coma can reduce intracranial hypertension but does not necessarily prevent brain damage. Furthermore, the reduction in intracranial hypertension may not be sustained. Some randomized trials have failed to demonstrate any survival or morbidity benefit of induced coma in diverse conditions such as neurosurgical operations, head trauma [4], intracranial aneurysm rupture, intracranial hemorrhage, ischemic stroke, and status epilepticus. If the patient survives, cognitive impairment may also follow recovery from the coma. [5]
About 55% of the glucose and oxygen utilisation by the brain is meant for its electrical activity and the rest for all other activities like metabolism. This is recognised by something such as an Electro encephalogram (EEG), which measures electrical activity in the brain. When barbiturates are given to a brain injured patients for Induced coma, they act by reducing the electrical activity of the brain, which in theory reduces the metabolic and oxygen demand. Once there is improvement in the patient's general condition, the barbiturates are withdrawn gradually and the patient regains consciousness.
Induced coma was used in the treatment of symptomatic rabies. See the case of Jeanna Giese.
# External links
- Use of barbiturates in the control of intracranial hypertension. J Neurotrauma. 2000 Jun-Jul;17(6-7):527-30.
- Lee MW, et al. The efficacy of barbiturate coma in the management of uncontrolled intracranial hypertension following neurosurgical trauma. J Neurotrauma. 1994 Jun;11(3):325-31.
- Nordby HK, Nesbakken R. The effect of high dose barbiturate decompression after severe head injury. A controlled clinical trial. Acta Neurochir (Wien). 1984;72(3-4):157-66.
- Schwartz ML, et al. The University of Toronto head injury treatment study: a prospective, randomized comparison of pentobarbital and mannitol. Can J Neurol Sci. 1984 Nov;11(4):434-40.
- Schalen W, et al. Clinical outcome and cognitive impairment in patients with severe head injuries treated with barbiturate coma. Acta Neurochir (Wien). 1992;117(3-4):153-9.
Template:WikiDoc Sources
Template:WH
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e61cba07b36f5bfa1137825ebcf6ad15117276dd | wikidoc | Infibulation | Infibulation
see also Female genital cutting
Infibulation, in modern usage, is the practice of surgical closure of the labia majora (outer lips of the vulva) by sewing them together to partially seal the vagina, leaving only a small hole for the passage of urine and menstrual blood. The legs are bound together for a fortnight (approximately) to allow the labia to heal into a barrier. The procedure is usually done on young girls before the onset of puberty, to ensure chastity. It is usually performed at the same time as female circumcision (removal of the clitoris) The labia minora (inner lips of the vulva) are often also removed.
Infibulation is believed by practitioners to render women sexually inactive, unlikely to engage in intercourse, and the visibly intact barrier of infibulation assures a husband he has married a virgin.
The barrier produced by infibulation is usually penetrated at the time of a girl's marriage by the forcible action of the penis of her new husband, or, if he is unsuccessful, by cutting the connected tissue surgically.
Female circumcision is often confused with infibulation, but they are distinct procedures.
Both procedures are typically performed without anesthetic, in unsanitary conditions, on children well below the age capable of giving informed consent. Some subjects of infibulation have experienced infections, severe reproductive disorders, and/or death.
These practices have been widely condemned by other cultures as barbaric and cruel. According to the United Nations' End Fistula Campaign, this particular form of female genital cutting frequently results in organ damage, urinary incontinence, and obstetric fistula.
Historically, infibulation also referred to suturing the foreskin of the male organ. This was performed on slaves in ancient Rome to ensure chastity, as well as voluntarily in some cultures. Without removing tissue, it was intended to prevent sexual intercourse, but not masturbation. The use of the word 'infibulation' has recently been applied to the more severe African practice. Traditionally, the African practice was called pharaonic circumcision, and is not technically infibulation. | Infibulation
see also Female genital cutting
Infibulation, in modern usage, is the practice of surgical closure of the labia majora (outer lips of the vulva) by sewing them together to partially seal the vagina, leaving only a small hole for the passage of urine and menstrual blood. The legs are bound together for a fortnight (approximately) to allow the labia to heal into a barrier. The procedure is usually done on young girls before the onset of puberty, to ensure chastity. It is usually performed at the same time as female circumcision (removal of the clitoris) The labia minora (inner lips of the vulva) are often also removed.
Infibulation is believed by practitioners to render women sexually inactive, unlikely to engage in intercourse, and the visibly intact barrier of infibulation assures a husband he has married a virgin.
The barrier produced by infibulation is usually penetrated at the time of a girl's marriage by the forcible action of the penis of her new husband, or, if he is unsuccessful, by cutting the connected tissue surgically. [1]
Female circumcision is often confused with infibulation, but they are distinct procedures.
Both procedures are typically performed without anesthetic, in unsanitary conditions, on children well below the age capable of giving informed consent. Some subjects of infibulation have experienced infections, severe reproductive disorders, and/or death.
These practices have been widely condemned by other cultures as barbaric and cruel. According to the United Nations' End Fistula Campaign, this particular form of female genital cutting frequently results in organ damage, urinary incontinence, and obstetric fistula.
Historically, infibulation also referred to suturing the foreskin of the male organ. This was performed on slaves in ancient Rome to ensure chastity, as well as voluntarily in some cultures. Without removing tissue, it was intended to prevent sexual intercourse, but not masturbation. The use of the word 'infibulation' has recently been applied to the more severe African practice. Traditionally, the African practice was called pharaonic circumcision, and is not technically infibulation. | https://www.wikidoc.org/index.php/Infibulation | |
ae0d7b151cfb78e79702f0f2dd28f4f345733811 | wikidoc | Inflammation | Inflammation
# Overview
Inflammation (Latin, inflammatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a synonym for infection. Even in cases where inflammation is caused by infection it is incorrect to use the terms as synonyms: infection is caused by an exogenous pathogen, while inflammation is the response of the organism to the pathogen.
In the absence of inflammation, wounds and infections would never heal and progressive destruction of the tissue would compromise the survival of the organism. However, inflammation which runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally tightly regulated by the body.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterised by simultaneous destruction and healing of the tissue from the inflammatory process.
# Causes
- Burns
- Chemical irritants
- Frostbite
- Toxins
- Infection by pathogens
- Necrosis
- Physical injury, blunt or penetrating
- Immune reactions due to hypersensitivity
- Ionizing radiation
- Foreign bodies, including splinters and dirt
# Types
## Acute inflammation
Acute inflammation is a short-term process which is characterized by the classic signs of inflammation - swelling, redness, pain, heat, and loss of function - due to the infiltration of the tissues by plasma and leukocytes. It occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed, broken down, or walled off by scarring (fibrosis). The first four characteristics have been known since ancient times and are attributed to Celsus. Loss of function was added to the definition of inflammation by Ahmed Abou Samra in the 19th century.
The process of acute inflammation is initiated by the blood vessels local to the injured tissue, which alter to allow the exudation of plasma proteins and leukocytes into the surrounding tissue. The increased flow of fluid into the tissue causes the characteristic swelling associated with inflammation since the lymphatic system doesn't have the capacity to compensate for it, and the increased blood flow to the area causes the reddened colour and increased heat. The blood vessels also alter to permit the extravasation of leukocytes through the endothelium and basement membrane constituting the blood vessel. Once in the tissue, the cells migrate along a chemotactic gradient to reach the site of injury, where they can attempt to remove the stimulus and repair the tissue.
Meanwhile, several biochemical cascade systems, consisting of chemicals known as plasma-derived inflammatory mediators, act in parallel to propagate and mature the inflammatory response. These include the complement system, coagulation system and fibrinolysis system.
Finally, down-regulation of the inflammatory response concludes acute inflammation. Removal of the injurious stimuli halts the response of the inflammatory mechanisms, which require constant stimulation to propagate the process. Additionally, many inflammatory mediators have short half lives and are quickly degraded in the tissue, helping to quickly cease the inflammatory response once the stimulus has been removed.
## Chronic inflammation
Chronic inflammation is a pathological condition characterised by concurrent active inflammation, tissue destruction, and attempts at repair. Chronic inflammation is not characterised by the classic signs of acute inflammation listed above. Instead, chronically inflamed tissue is characterised by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
Endogenous causes include persistent acute inflammation. Exogenous causes are varied and include bacterial infection, especially by Mycobacterium tuberculosis, prolonged exposure to chemical agents such as silica, or autoimmune reactions such as rheumatoid arthritis.
In acute inflammation, removal of the stimulus halts the recruitment of monocytes (which become macrophages under appropriate activation) into the inflamed tissue, and existing macrophages exit the tissue via lymphatics. However in chronically inflamed tissue the stimulus is persistent, and therefore recruitment of monocytes is maintained, existing macrophages are tethered in place, and proliferation of macrophages is stimulated (especially in atheromatous plaques).
# Exudative component
The exudative component involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue. This movement is achieved via the chemically-induced dilation and increased permeability of blood vessels, which results in a net loss of blood plasma. The increased collection of fluid into the tissue causes it to swell (edema).
## Vascular changes
Acute inflammation is characterised by marked vascular changes, including vasodilation, increased permeability, and the slowing of blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood - a condition characterised by enlarged vessels packed with cells. Stasis allows leukocytes to marginate along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.
## Plasma cascade systems
- The complement system, when activated, results in the increased removal of pathogens via opsonisation and phagocytosis.
- The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.
- The coagulation system or clotting cascade which forms a protective protein mesh over sites of injury.
- The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.
## Plasma derived mediators
- non-exhaustive list
# Cellular component
The cellular component involves leukocytes, which normally reside in blood and must move into the inflamed tissue via extravasation to aid in inflammation. Some act as phagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymatic granules which damage pathogenic invaders. Leukocytes also release inflammatory mediators which develop and maintain the inflammatory response. Generally speaking, acute inflammation is mediated by granulocytes, while chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.
## Leukocyte extravasation
Various leukocytes are critically involved in the initiation and maintenance of inflammation. These cells must be able to get to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasation, and can be divided up into a number of broad steps:
- Leukocyte localisation and recruitment to the endothelium local to the site of inflammation – involving margination and adhesion to the endothelial cells: Recruitment of leukocytes is receptor-mediated. The products of inflammation, such as histamine, promote the immediate expression of P-selectin on endothelial cell surfaces. This receptor binds weakly to carbohydrate ligands on leukocyte surfaces and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines from injured cells induce the expression of E-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of integrin ligands on endothelial cells, which further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue. Activation increases the affinity of bound integrin receptors for ligands on the endothelial cell surface, firmly binding the leukocytes to the endothelium.
- Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between endothelial cells and pass the basement membrane into the tissues.
- Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrix proteins via expressed integrins and CD44 to prevent their loss from the site. Chemoattractants cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.
## Cell derived mediators
- non-exhaustive list
# Morphologic patterns
Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved.
- Granulomatous inflammation: characterised by the formation of granulomas, they are the result of a limited but diverse number of diseases, which include among others tuberculosis, leprosy, and syphilis.
- Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows the blood vessels to pass through fibrin. If an appropriate procoagulative stimulus is present, such as cancer cells, a fibrinous exudate is deposited. This is commonly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function.
- Purulent inflammation: Inflammation resulting in large amount of pus, which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are called abscesses.
- Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may which also be derived from blood plasma. Skin blisters exemplify this pattern of inflammation.
- Ulcerative inflammation: Inflammation occurring near an epithelium can result in the necrotic loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as an ulcer.
# Inflammatory disorders
Abnormalities associated with inflammation comprise a large, unrelated group of disorders which underly a variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with aetiological origins in inflammatory processes are thought to include cancer, atherosclerosis, and ischaemic heart disease.
A large variety of proteins are involved in inflammation, and any one of them is open to a genetic mutation which impairs or otherwise dysregulates the normal function and expression of that protein.
Examples of disorders associated with inflammation include:
- Asthma
- Autoimmune diseases
- Chronic inflammation
- Chronic prostatitis
- Glomerulonephritis
- Hypersensitivities
- Inflammatory bowel diseases
- Pelvic inflammatory disease
- Reperfusion injury
- Rheumatoid arthritis
- Transplant rejection
- Vasculitis
## Allergies
An allergic reaction, formally known as type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation. A common example is hay fever, which is caused by a hypersensitive response by skin mast cells to allergens. Pre-sensitised mast cells respond by degranulating, releasing vasoactive chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes. Severe inflammatory response may mature into a systemic response known as anaphylaxis.
Other hypersensitivity reactions (type 2 and type 3) are mediated by antibody reactions and induce inflammation by attracting leukocytes which damage surrounding tissue.
## Myopathies
Inflammatory myopathies are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis.
## Leukocyte defects
Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte function often result in a decreased capacity for inflammatory defence with subsequent vulnerability to infection. Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria (Chediak-Higashi syndrome), or produce microbicides (chronic granulomatous disease). Additionally, diseases affecting the bone marrow may result in abnormal or few leukocytes.
## Pharmacological
Certain drugs or chemical compounds are known to affect inflammation. Vitamin A deficiency causes an increase in inflammatory responses, and anti-inflammatory drugs work specifically by inhibiting normal inflammatory components.
## Cancer
Inflammation orchestrates the microenvironment around tumours, contributing to proliferation, survival and migration. Cancer cells use selectins, chemokines and their receptors for invasion, migration and metastasis. On the other hand, many cells of the immune system contribute to cancer immunology, suppressing cancer.
# Termination
The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues. Failure to do so results in chronic inflammation, cellular destruction, and attempts to heal the inflamed tissue. One intrinsic mechanism employed to terminate inflammation is the short half-life of inflammatory mediators in vivo. They have a limited time frame to affect their target before breaking down into non-functional components, therefore constant inflammatory stimulation is needed to propagate their effects.
Active mechanisms which serve to terminate inflammation include:
- TGF-β from macrophages
- Anti-inflammatory lipoxins
- Inhibition of pro-inflammatory molecules, such as leukotrienes
# Systemic effects
An organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.
When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.
## Acute-phase proteins
Inflammation also induces high systemic levels of acute-phase proteins. In acute inflammation, these proteins prove beneficial, however in chronic inflammation they can contribute to amyloidosis These proteins include C-reactive protein, serum amyloid A, serum amyloid P, vasopressin, and glucocorticoids, which cause a range of systemic effects including:
- Fever
- Increased blood pressure
- Decreased sweating
- Malaise
- Loss of appetite
- Somnolence
## Leukocyte numbers
Inflammation often affects the numbers of leukocytes present in the body:
- Leukocytosis is often seen during inflammation induced by infection, where it results in a large increase in the amount of leukocytes in the blood, especially immature cells. Leukocyte numbers usually increase to between 15 000 and 20 000 cells per ml, but extreme cases can see it approach 100 000 cells per ml. Bacterial infection usually results in an increase of neutrophils, creating neutrophilia, whereas diseases such as asthma, hay fever, and parasite infestation result in an increase in eosinophils, creating eosinophilia.
- Leukopenia can be induced by certain infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis, and some cancers.
## Systemic inflammation and obesity
With the discovery of interleukins (IL), the concept of systemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium and other organ systems.
High levels of several inflammation-related markers such as IL-6, IL-8, and TNF-α are associated with obesity. During clinical studies, inflammatory-related molecule levels were reduced and increased levels of anti-inflammatory molecules were seen within four weeks after patients began a very low calorie diet. The association of systemic inflammation with insulin resistance and atherosclerosis is the subject of intense
research.
# Outcomes
The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred and the injurious agent that is causing it. There are three possible outcomes to inflammation:
- ResolutionThe complete restoration of the inflamed tissue back to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease, and damaged parenchymal cells regenerate. In situations where limited or short lived inflammation has occurred this is usually the outcome.
- FibrosisLarge amounts of tissue destruction, or damage in tissues unable to regenerate, can not be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen. The scar will not contain any specialized structures, such as parenchymal cells, hence functional impairment may occur.
- Abscess FormationA cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells.
- Chronic inflammationIn acute inflammation, if the injurious agent persists then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a chronic wound. Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release (including reactive oxygen species) are injurious to the organism's own tissues as well as invading agents. Consequently, chronic inflammation is almost always accompanied by tissue destruction.
# Examples
Inflammation is usually indicated by adding the suffix "-itis", as shown below. However, some conditions such as asthma and pneumonia do not follow this convention. More examples are available at list of types of inflammation.
- Acute appendicitis
- Acute dermatitis
- Acute infective meningitis
- Acute tonsillitis
- An abscess on the skin, showing the redness and swelling characteristic of inflammation (presents as darkening in people with dark skin). Black rings of necrotic tissue surround central areas of pus
- Infected ingrown toenail showing the characteristic redness and swelling associated with acute inflammation
# Related Chapters
- Anaphylatoxin
- Anti-inflammatories
- Healing
- Interleukin
- Lipoxin
- Substance P | Inflammation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Inflammation (Latin, inflammatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue. Inflammation is not a synonym for infection. Even in cases where inflammation is caused by infection it is incorrect to use the terms as synonyms: infection is caused by an exogenous pathogen, while inflammation is the response of the organism to the pathogen.
In the absence of inflammation, wounds and infections would never heal and progressive destruction of the tissue would compromise the survival of the organism. However, inflammation which runs unchecked can also lead to a host of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis. It is for this reason that inflammation is normally tightly regulated by the body.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterised by simultaneous destruction and healing of the tissue from the inflammatory process.
# Causes
- Burns
- Chemical irritants
- Frostbite
- Toxins
- Infection by pathogens
- Necrosis
- Physical injury, blunt or penetrating
- Immune reactions due to hypersensitivity
- Ionizing radiation
- Foreign bodies, including splinters and dirt
# Types
## Acute inflammation
Acute inflammation is a short-term process which is characterized by the classic signs of inflammation - swelling, redness, pain, heat, and loss of function - due to the infiltration of the tissues by plasma and leukocytes. It occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed, broken down, or walled off by scarring (fibrosis). The first four characteristics have been known since ancient times and are attributed to Celsus. Loss of function was added to the definition of inflammation by Ahmed Abou Samra in the 19th century.[3]
The process of acute inflammation is initiated by the blood vessels local to the injured tissue, which alter to allow the exudation of plasma proteins and leukocytes into the surrounding tissue. The increased flow of fluid into the tissue causes the characteristic swelling associated with inflammation since the lymphatic system doesn't have the capacity to compensate for it, and the increased blood flow to the area causes the reddened colour and increased heat. The blood vessels also alter to permit the extravasation of leukocytes through the endothelium and basement membrane constituting the blood vessel. Once in the tissue, the cells migrate along a chemotactic gradient to reach the site of injury, where they can attempt to remove the stimulus and repair the tissue.
Meanwhile, several biochemical cascade systems, consisting of chemicals known as plasma-derived inflammatory mediators, act in parallel to propagate and mature the inflammatory response. These include the complement system, coagulation system and fibrinolysis system.
Finally, down-regulation of the inflammatory response concludes acute inflammation. Removal of the injurious stimuli halts the response of the inflammatory mechanisms, which require constant stimulation to propagate the process. Additionally, many inflammatory mediators have short half lives and are quickly degraded in the tissue, helping to quickly cease the inflammatory response once the stimulus has been removed.[3]
## Chronic inflammation
Chronic inflammation is a pathological condition characterised by concurrent active inflammation, tissue destruction, and attempts at repair. Chronic inflammation is not characterised by the classic signs of acute inflammation listed above. Instead, chronically inflamed tissue is characterised by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
Endogenous causes include persistent acute inflammation. Exogenous causes are varied and include bacterial infection, especially by Mycobacterium tuberculosis, prolonged exposure to chemical agents such as silica, or autoimmune reactions such as rheumatoid arthritis.
In acute inflammation, removal of the stimulus halts the recruitment of monocytes (which become macrophages under appropriate activation) into the inflamed tissue, and existing macrophages exit the tissue via lymphatics. However in chronically inflamed tissue the stimulus is persistent, and therefore recruitment of monocytes is maintained, existing macrophages are tethered in place, and proliferation of macrophages is stimulated (especially in atheromatous plaques).[3]
# Exudative component
The exudative component involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue. This movement is achieved via the chemically-induced dilation and increased permeability of blood vessels, which results in a net loss of blood plasma. The increased collection of fluid into the tissue causes it to swell (edema).
## Vascular changes
Acute inflammation is characterised by marked vascular changes, including vasodilation, increased permeability, and the slowing of blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood - a condition characterised by enlarged vessels packed with cells. Stasis allows leukocytes to marginate along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.
## Plasma cascade systems
- The complement system, when activated, results in the increased removal of pathogens via opsonisation and phagocytosis.
- The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.
- The coagulation system or clotting cascade which forms a protective protein mesh over sites of injury.
- The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.
## Plasma derived mediators
* non-exhaustive list
# Cellular component
The cellular component involves leukocytes, which normally reside in blood and must move into the inflamed tissue via extravasation to aid in inflammation. Some act as phagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymatic granules which damage pathogenic invaders. Leukocytes also release inflammatory mediators which develop and maintain the inflammatory response. Generally speaking, acute inflammation is mediated by granulocytes, while chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.
## Leukocyte extravasation
Various leukocytes are critically involved in the initiation and maintenance of inflammation. These cells must be able to get to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasation, and can be divided up into a number of broad steps:
- Leukocyte localisation and recruitment to the endothelium local to the site of inflammation – involving margination and adhesion to the endothelial cells: Recruitment of leukocytes is receptor-mediated. The products of inflammation, such as histamine, promote the immediate expression of P-selectin on endothelial cell surfaces. This receptor binds weakly to carbohydrate ligands on leukocyte surfaces and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines from injured cells induce the expression of E-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of integrin ligands on endothelial cells, which further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue. Activation increases the affinity of bound integrin receptors for ligands on the endothelial cell surface, firmly binding the leukocytes to the endothelium.
- Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between endothelial cells and pass the basement membrane into the tissues.
- Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrix proteins via expressed integrins and CD44 to prevent their loss from the site. Chemoattractants cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.
## Cell derived mediators
* non-exhaustive list
# Morphologic patterns
Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved.
- Granulomatous inflammation: characterised by the formation of granulomas, they are the result of a limited but diverse number of diseases, which include among others tuberculosis, leprosy, and syphilis.
- Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows the blood vessels to pass through fibrin. If an appropriate procoagulative stimulus is present, such as cancer cells,[3] a fibrinous exudate is deposited. This is commonly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function.
- Purulent inflammation: Inflammation resulting in large amount of pus, which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are called abscesses.
- Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may which also be derived from blood plasma. Skin blisters exemplify this pattern of inflammation.
- Ulcerative inflammation: Inflammation occurring near an epithelium can result in the necrotic loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as an ulcer.
# Inflammatory disorders
Abnormalities associated with inflammation comprise a large, unrelated group of disorders which underly a variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with aetiological origins in inflammatory processes are thought to include cancer, atherosclerosis, and ischaemic heart disease.[3]
A large variety of proteins are involved in inflammation, and any one of them is open to a genetic mutation which impairs or otherwise dysregulates the normal function and expression of that protein.
Examples of disorders associated with inflammation include:
- Asthma
- Autoimmune diseases
- Chronic inflammation
- Chronic prostatitis
- Glomerulonephritis
- Hypersensitivities
- Inflammatory bowel diseases
- Pelvic inflammatory disease
- Reperfusion injury
- Rheumatoid arthritis
- Transplant rejection
- Vasculitis
## Allergies
An allergic reaction, formally known as type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation. A common example is hay fever, which is caused by a hypersensitive response by skin mast cells to allergens. Pre-sensitised mast cells respond by degranulating, releasing vasoactive chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes.[3] Severe inflammatory response may mature into a systemic response known as anaphylaxis.
Other hypersensitivity reactions (type 2 and type 3) are mediated by antibody reactions and induce inflammation by attracting leukocytes which damage surrounding tissue.[3]
## Myopathies
Inflammatory myopathies are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis.[3]
## Leukocyte defects
Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte function often result in a decreased capacity for inflammatory defence with subsequent vulnerability to infection.[3] Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria (Chediak-Higashi syndrome), or produce microbicides (chronic granulomatous disease). Additionally, diseases affecting the bone marrow may result in abnormal or few leukocytes.
## Pharmacological
Certain drugs or chemical compounds are known to affect inflammation. Vitamin A deficiency causes an increase in inflammatory responses,[4] and anti-inflammatory drugs work specifically by inhibiting normal inflammatory components.
## Cancer
Inflammation orchestrates the microenvironment around tumours, contributing to proliferation, survival and migration. Cancer cells use selectins, chemokines and their receptors for invasion, migration and metastasis.[5] On the other hand, many cells of the immune system contribute to cancer immunology, suppressing cancer.
# Termination
The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues.[3] Failure to do so results in chronic inflammation, cellular destruction, and attempts to heal the inflamed tissue. One intrinsic mechanism employed to terminate inflammation is the short half-life of inflammatory mediators in vivo. They have a limited time frame to affect their target before breaking down into non-functional components, therefore constant inflammatory stimulation is needed to propagate their effects.
Active mechanisms which serve to terminate inflammation include[3]:
- TGF-β from macrophages
- Anti-inflammatory lipoxins
- Inhibition of pro-inflammatory molecules, such as leukotrienes
# Systemic effects
An organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.
When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.
## Acute-phase proteins
Inflammation also induces high systemic levels of acute-phase proteins. In acute inflammation, these proteins prove beneficial, however in chronic inflammation they can contribute to amyloidosis[3] These proteins include C-reactive protein, serum amyloid A, serum amyloid P, vasopressin, and glucocorticoids, which cause a range of systemic effects including[3]:
- Fever
- Increased blood pressure
- Decreased sweating
- Malaise
- Loss of appetite
- Somnolence
## Leukocyte numbers
Inflammation often affects the numbers of leukocytes present in the body:
- Leukocytosis is often seen during inflammation induced by infection, where it results in a large increase in the amount of leukocytes in the blood, especially immature cells. Leukocyte numbers usually increase to between 15 000 and 20 000 cells per ml, but extreme cases can see it approach 100 000 cells per ml.[3] Bacterial infection usually results in an increase of neutrophils, creating neutrophilia, whereas diseases such as asthma, hay fever, and parasite infestation result in an increase in eosinophils, creating eosinophilia.[3]
- Leukopenia can be induced by certain infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis, and some cancers.[3]
## Systemic inflammation and obesity
With the discovery of interleukins (IL), the concept of systemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium and other organ systems.
High levels of several inflammation-related markers such as IL-6, IL-8, and TNF-α are associated with obesity.[7][8] During clinical studies, inflammatory-related molecule levels were reduced and increased levels of anti-inflammatory molecules were seen within four weeks after patients began a very low calorie diet.[9] The association of systemic inflammation with insulin resistance and atherosclerosis is the subject of intense
research.[10]
# Outcomes
The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred and the injurious agent that is causing it. There are three possible outcomes to inflammation:[3]
- ResolutionThe complete restoration of the inflamed tissue back to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease, and damaged parenchymal cells regenerate. In situations where limited or short lived inflammation has occurred this is usually the outcome.
- FibrosisLarge amounts of tissue destruction, or damage in tissues unable to regenerate, can not be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen. The scar will not contain any specialized structures, such as parenchymal cells, hence functional impairment may occur.
- Abscess FormationA cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells.
- Chronic inflammationIn acute inflammation, if the injurious agent persists then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a chronic wound. Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release (including reactive oxygen species) are injurious to the organism's own tissues as well as invading agents. Consequently, chronic inflammation is almost always accompanied by tissue destruction.
# Examples
Inflammation is usually indicated by adding the suffix "-itis", as shown below. However, some conditions such as asthma and pneumonia do not follow this convention. More examples are available at list of types of inflammation.
- Acute appendicitis
- Acute dermatitis
- Acute infective meningitis
- Acute tonsillitis
- An abscess on the skin, showing the redness and swelling characteristic of inflammation (presents as darkening in people with dark skin). Black rings of necrotic tissue surround central areas of pus
- Infected ingrown toenail showing the characteristic redness and swelling associated with acute inflammation
# Related Chapters
- Anaphylatoxin
- Anti-inflammatories
- Healing
- Interleukin
- Lipoxin
- Substance P | https://www.wikidoc.org/index.php/Inflamed | |
bcd8e5bde67d8af680798582fefc93f0578fff0d | wikidoc | Infusion set | Infusion set
An infusion set is used with an insulin pump as part of intensive insulin therapy. The purpose of an infusion set is to deliver insulin under the skin. It is a complete tubing system to connect an insulin pump to the pump user: it includes a subcutaneous cannula, adhesive mount, quick-disconnect, and a pump cartridge connector.
# Using an infusion set
Firstly, the user must attach a reservoir of insulin to the set and connect it to the pump. The set is then "primed" - the pump pushes insulin quickly through the tubing and the cannula to ensure no air is in the system before insertion. Note that it is vital that the infusion set is not inserted into the skin when the set is being primed (as this could result in the accidental delivery of a large dose of insulin). The user then peels off the paper protecting the adhesive pad and carefully inserts the needle beneath the skin.
The cannula is usually made of flexible plastic, which allows it to move without causing discomfort to the patient. The needle is pushed into the layer of fat below the skin, taking the plastic cannula with it. The needle is then removed, leaving the cannula in place. Insertion should be done in a fairly swift movement to avoid the cannula "bunching up" around the needle. The needle is then removed, leaving the cannula below the skin.
A few pump users prefer an infusion set with a steel needle instead of a cannula. The cannula surrounds a steel needle similar to that found on a hypodermic syringe.
## Insertion devices
Some pump users prefer to use an insertion device to insert their sets, rather than pushing the needle in by hand. These are spring-loaded and are designed to push the needle into the skin quickly and (usually) painlessly. The user simply loads the primed set into the insertion device, peels off the paper protecting the adhesive pad, places the device against the skin and presses a button. This may be an advantage for those with needle phobia.
## Sites for infusion sets
Many pump users site their infusion sets on the abdomen, in a roughly semicircular area around and below the navel. Other sites include the upper leg, upper buttocks, hips, upper arms and lower back. Insulin absorption may vary from site to site, so it is important that patients are advised of the most effective sites to use by their diabetes adviser.
## Rotation of sites
The infusion set must be replaced regularly, usually every 2-3 days. Insulin absorption becomes less effective the longer the set is left in place, leading to poorer control of blood glucose. For this reason, the site of the infusion set is moved when the set is changed. Often a number of favorite sites for the infusion set are used on a rotation basis.
## Disconnecting the set
The set can be disconnected from the pump and tubing with a quick-release that leaves the cannula and adhesive pad in place. This is convenient when swimming or showering (since most pumps are not fully waterproof), or when engaging in any activity when it is not desirable to be attached to the pump.
# Types of infusion set
There are several types, styles, and sizes of infusion sets available to allow an insulin pump user a choice to customize what works best for them. These vary in cannula length, cannula entry angle and in the length of tube connecting the cannula to the pump. For instance, an individual with little body fat may choose to use a set with a short cannula that enters the skin at a shallow angle, whereas an individual with more body fat may find that a longer cannula entering at right angles to the skin works best. Most infusion sets have a standard Luer Lock connector so that they will mate to most insulin pumps. However, this is not always the case: some pump manufactures use a proprietary connector, and so their customers must buy only their infusion sets.
# For additional information
For help choosing an appropriate infusion set, pump users may contact their certified diabetes educator or one of the following support groups for insulin pumpers:
For more information, see the manufacturers websites:
:30/article/DCM_general_article_295.htm
Various infusion sets at a glance:
Chose the right infusion set for you: | Infusion set
An infusion set is used with an insulin pump as part of intensive insulin therapy. The purpose of an infusion set is to deliver insulin under the skin. It is a complete tubing system to connect an insulin pump to the pump user: it includes a subcutaneous cannula, adhesive mount, quick-disconnect, and a pump cartridge connector.
# Using an infusion set
Firstly, the user must attach a reservoir of insulin to the set and connect it to the pump. The set is then "primed" - the pump pushes insulin quickly through the tubing and the cannula to ensure no air is in the system before insertion. Note that it is vital that the infusion set is not inserted into the skin when the set is being primed (as this could result in the accidental delivery of a large dose of insulin). The user then peels off the paper protecting the adhesive pad and carefully inserts the needle beneath the skin.
The cannula is usually made of flexible plastic, which allows it to move without causing discomfort to the patient. The needle is pushed into the layer of fat below the skin, taking the plastic cannula with it. The needle is then removed, leaving the cannula in place. Insertion should be done in a fairly swift movement to avoid the cannula "bunching up" around the needle. The needle is then removed, leaving the cannula below the skin.
A few pump users prefer an infusion set with a steel needle instead of a cannula. The cannula surrounds a steel needle similar to that found on a hypodermic syringe.
## Insertion devices
Some pump users prefer to use an insertion device to insert their sets, rather than pushing the needle in by hand. These are spring-loaded and are designed to push the needle into the skin quickly and (usually) painlessly. The user simply loads the primed set into the insertion device, peels off the paper protecting the adhesive pad, places the device against the skin and presses a button. This may be an advantage for those with needle phobia.
## Sites for infusion sets
Many pump users site their infusion sets on the abdomen, in a roughly semicircular area around and below the navel. Other sites include the upper leg, upper buttocks, hips, upper arms and lower back. Insulin absorption may vary from site to site, so it is important that patients are advised of the most effective sites to use by their diabetes adviser.
## Rotation of sites
The infusion set must be replaced regularly, usually every 2-3 days. Insulin absorption becomes less effective the longer the set is left in place, leading to poorer control of blood glucose. For this reason, the site of the infusion set is moved when the set is changed. Often a number of favorite sites for the infusion set are used on a rotation basis.
## Disconnecting the set
The set can be disconnected from the pump and tubing with a quick-release that leaves the cannula and adhesive pad in place. This is convenient when swimming or showering (since most pumps are not fully waterproof), or when engaging in any activity when it is not desirable to be attached to the pump.
# Types of infusion set
There are several types, styles, and sizes of infusion sets available to allow an insulin pump user a choice to customize what works best for them. These vary in cannula length, cannula entry angle and in the length of tube connecting the cannula to the pump. For instance, an individual with little body fat may choose to use a set with a short cannula that enters the skin at a shallow angle, whereas an individual with more body fat may find that a longer cannula entering at right angles to the skin works best. Most infusion sets have a standard Luer Lock connector so that they will mate to most insulin pumps. However, this is not always the case: some pump manufactures use a proprietary connector, and so their customers must buy only their infusion sets.
# For additional information
For help choosing an appropriate infusion set, pump users may contact their certified diabetes educator or one of the following support groups for insulin pumpers:
http://insulin-pumpers.org/
http://www.childrenwithdiabetes.com/pumps/links.htm
http://insulin-pumpers.org/pkids.shtml
For more information, see the manufacturers websites:
http://www.animascorp.com/products/pr_infusion.shtml
http://www.infusion-set.com/
http://www.disetronic-usa.com/dstrnc_us/rewrite/content/en_US/3.3:30/article/DCM_general_article_295.htm
http://www.minimed.com/products/infusionsets/index.html
http://www.cleoinfusionsets.com/
http://www.mysimplechoice.com/prod.htm
Various infusion sets at a glance:
http://www.codan.de/
http://www.diabetesnet.com/diabetes_technology/infusion_sets.php
Chose the right infusion set for you:
http://www.medtronic-diabetes.co.uk/ProductInformation/InfusionSets/whichinfusionset.html
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Infusion_set | |
d33428f11b31030ac1056e10f997e056503ed56d | wikidoc | Ingrown hair | Ingrown hair
Ingrown hair is a condition where the hair curls back or grows sideways into the skin. It may or may not be accompanied by an infection of the hair follicle (folliculitis) or "razor bumps" (Pseudofolliculitis barbae). While ingrown hair most commonly appears in areas where the skin is shaved (beard, legs, pubic region), it can appear anywhere.
# Causes
Anything which causes the hair to be broken off short with a sharp tip can cause ingrown hair. Shaving is the leading cause, followed by tight clothing. The embedded hair causes a localized inflammation (sometimes painful) response in the skin with prostanoid involvement.
# Symptoms
- rash (reddened skin area)
- itching skin
- hair which remains in spite of shaving
# Treatment
- Manually removing ingrown hairs with special tweezers
- Shaving in a different direction
- Allowing the hair to grow in order to cause the hair to come out straighter
- Using special razors that leave the hair longer
- Exfoliating with facial scrubs, sponges, towels, or creams containing acids
- Treatment with Ibuprofen or other NSAIDs promotes resolution of stubborn cases
- Prophylaxis with twice daily topical application of diluted Glycolic acid
- Ensuring skin and razor are sterile before shaving
If the area is infected, see a dermatologist. | Ingrown hair
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Ingrown hair is a condition where the hair curls back or grows sideways into the skin. It may or may not be accompanied by an infection of the hair follicle (folliculitis) or "razor bumps" (Pseudofolliculitis barbae). While ingrown hair most commonly appears in areas where the skin is shaved (beard, legs, pubic region), it can appear anywhere.
# Causes
Anything which causes the hair to be broken off short with a sharp tip can cause ingrown hair. Shaving is the leading cause, followed by tight clothing. The embedded hair causes a localized inflammation (sometimes painful) response in the skin with prostanoid involvement.
# Symptoms
- rash (reddened skin area)
- itching skin
- hair which remains in spite of shaving
# Treatment
- Manually removing ingrown hairs with special tweezers
- Shaving in a different direction
- Allowing the hair to grow in order to cause the hair to come out straighter
- Using special razors that leave the hair longer
- Exfoliating with facial scrubs, sponges, towels, or creams containing acids
- Treatment with Ibuprofen or other NSAIDs promotes resolution of stubborn cases
- Prophylaxis with twice daily topical application of diluted Glycolic acid
- Ensuring skin and razor are sterile before shaving
If the area is infected, see a dermatologist.
# External links
- Medline Plus (NIH) article on Folliculitis
- Links to folliculitis pictures (Hardin MD/Univ of Iowa)
- Glycolic acid report
- Home remedies for ingrown hair
- Guides on ingrown hair removal
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ingrown_hair | |
7f5bfccbc8a8e939930637b8e3faf97d1e28755e | wikidoc | Iniencephaly | Iniencephaly
# Overview
Iniencephaly is a type of cephalic disorder. It is a rare neural tube defect that combines extreme retroflexion (backward bending) of the head with severe defects of the spine.
# Presentation
The affected infant tends to be short, with a disproportionately large head. Diagnosis can be made immediately after birth because the head is so severely retroflexed that the face looks upward. The skin of the face is connected directly to the skin of the chest and the scalp is directly connected to the skin of the back. Generally, the neck is absent.
Most individuals with iniencephaly have other associated anomalies such as anencephaly, encephalocele (a disorder in which part of the cranial contents protrudes from the skull), hydrocephalus, cyclopia, absence of the mandible (lower jaw bone), cleft lip and palate, cardiovascular disorders, diaphragmatic hernia, and gastrointestinal malformation. The disorder is more common among females.
# Prognosis
The prognosis for those with iniencephaly is extremely poor. Newborns with iniencephaly seldom live more than a few hours. The distortion of the fetal body may also pose a danger to the mother's life. | Iniencephaly
Template:DiseaseDisorder infobox
# Overview
Iniencephaly is a type of cephalic disorder. It is a rare neural tube defect that combines extreme retroflexion (backward bending) of the head with severe defects of the spine.
# Presentation
The affected infant tends to be short, with a disproportionately large head. Diagnosis can be made immediately after birth because the head is so severely retroflexed that the face looks upward. The skin of the face is connected directly to the skin of the chest and the scalp is directly connected to the skin of the back. Generally, the neck is absent.
Most individuals with iniencephaly have other associated anomalies such as anencephaly, encephalocele (a disorder in which part of the cranial contents protrudes from the skull), hydrocephalus, cyclopia, absence of the mandible (lower jaw bone), cleft lip and palate, cardiovascular disorders, diaphragmatic hernia, and gastrointestinal malformation. The disorder is more common among females.
# Prognosis
The prognosis for those with iniencephaly is extremely poor. Newborns with iniencephaly seldom live more than a few hours. The distortion of the fetal body may also pose a danger to the mother's life.
# External links
- TheFetus.Net
Template:Congenital malformations and deformations of nervous system
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Iniencephaly | |
eaa77b35f7e03bd6c4190288f8e4842044388471 | wikidoc | Lipodissolve | Lipodissolve
# Overview
Lipo-dissolve or Lipodissolve, LipoShape or Lipostabil, also called injection lipolysis, is a controversial cosmetic procedure in which various non-FDA approved drug mixtures, often called PCDC, or phosphatidylcholine deoxycholate, are injected into patients to remove fat. This practice evolved from the initial intravenous use of PC-containing drug formulations to treat blood disorders. In 1966, investigators noted that the intravenous infusion of PC-containing solutions could remove fat emboli. Later, a drug formulation called LIPOSTABIL® containing 5% PC and 4.75% deoxycholate (DC) was approved in Germany and used in the treatment of fat embolism, dyslipidemia, and alcohol-induced liver cirrhosis. The first report of LIPOSTABIL® injection for fat removal demonstrated that infra-orbital (‘under the eyelid’) fat could be removed by LIPOSTABIL® injection. While no placebo-controlled studies have demonstrated the safety or efficacy of this therapy, numerous retrospective studies of LIPOSTABIL® injections have reported the efficacy of this unapproved practice. While the safety of Lipodissolve injections has yet to be proven in a prospective, placebo-controlled, double-blind clinical study, retrospective studies suggest that this practice does not present significant medical risk. The American Society for Aesthetic Plastic Surgery (ASAPS) received FDA authorization to initiate a double-blind, placebo-controlled 46-week study to experimentally examine the safety and efficacy of Lipodissolve injections . The mixture is injected directly into the subcutaneous fat through multiple microinjections administered over multiple treatment sessions. The desired end result is the removal of localized fat deposits.
The injection of Lipodissolve for fat removal remains somewhat controversial. In statements to the New York Times and USA Today , the FDA has taken the position that the injection of Lipodissolve mixtures for fat removal is an example of “unapproved drugs for unapproved uses.” Despite that, multiple businesses have initiated commercialization of Lipodissolve by opening clinics that advertise and administer Lipodissolve injections for fat removal ,. One of these businesses states on its website that "Pharmacies are permitted to compound drugs pursuant to a valid patient/physician/pharmacist relationship - even if the drugs have not been approved by the FDA." The FDA has stated that it is “investigating and evaluating” the situation .
# Lipodissolve regulation in the state of Kansas
On August 18, 2007, the Kansas State Board of Healing Arts voted unanimously to ban all commercial use of Lipodissolve and to allow the use of the drug only as part of FDA-sanctioned clinical trials under an Investigational New Drug Application. “We have to protect the public from the potentially disastrous effects of unproven drugs,” said Mark Stafford, the board’s general counsel, who noted that Lipodissolve is not approved for treating fat by the Food and Drug Administration . Stafford also stated that the board had received at least half a dozen complaints about the procedure, including side effects such as nodules, infections and nausea.
On August 31, fig. a company that manages or operates 15 medical body shaping centers offering the Lipodissolve procedure (), filed a petition for a temporary restraining order in Shawnee, Kansas to prevent the ban from going into effect . .Fig states on their public website "Pharmacies are permitted to compound drugs pursuant to a valid patient/physician/pharmacist relationship - even if the drugs have not been approved by the FDA." . FDA spokesperson Karen Riley told USA Today on September 10, 2007 that FDA maintains a different view and considers injection of compounded Lipodissolve mixtures for fat removal as "unapproved drugs for unapproved uses" and noted that FDA is "investigating and evaluating" the situation .
On September 10, 2007 at a special meeting the Kansas State Board moved to "replace its permanent Lipodissolve ban with a temporary ban to allow public comment on the move, which could still begin Friday", according to Mark Stafford, general counsel of the healing arts board .
On September 13, 2007, Shawnee County District Judge David Bruns blocked the State Board's ban stating that the board erred by approving the ban without enough public input .
# Health Warnings
Three medical associations have issued health warnings cautioning against the use of injection lypolysis, including the American Society of Plastic Surgeons (ASPS), the American Society of Aesthetic Plastic Surgery (ASAPS), and the American Society of Dermatologic Surgery (ASDS).
- ASPS Health Warning:
- ASAPS Health Warning:
- ASDS Health Warning:
ASAL Responds to ASAPS Warnings:
- ASAL Responds to ASAPS Warnings:
# International Regulation: Lipodissolve banned in Brazil. Promotion of Lipodissolve curtailed in England and Canada
ANVISA (Agencia Nacional de Vigilancia), the governmental body regulating the manufacture and commercialization of drugs in Brazil, banned the manufacture, use, and sale of injection lipolysis agents containing phosphatidylcholine on December 30, 2002. The ANVISA statement justified the ban by stating that such agents were not approved for the removal of subcutaneous fat, and that the long term effects this unapproved therapy were unknown. For an English translation of the ANVISA statement, see . Health Canada issued a similar warning in 2004 , though the drug is still being injected by various medspas. The MHRA (Medicines and Healthcare Products Regulatory Agency), the governmental body regulating the manufacture and commercialization of drugs in the United Kingdom, issued a similar warning to physicians considering the use of these substances for cosmetic purposes. The MHRA stated that these drugs "are being unlawfully advertised in the UK as a cosmetic product for the reduction of fat." The MHRA also pointed out that considerable safety concerns remain due to the fact that these agents have not been tested in controlled clinical trials. While British physicians can still inject Lipodissolve for fat removal, the drug cannot be promoted as a drug for that purpose. As of July, 2005, The Medical Protection Society, the organization that provides British doctors with legal advice and coverage against litigation costs and damages, ceased offering malpractice insurance for use of Lipodissolve because of safety concerns .
# FDA currently investigating the marketing and distribution of 'Lipodissolve'
In September 2007, FDA spokesperson Karen Riley told USA Today , the New York Times , and KVBC News (Las Vegas) that FDA views injection of compounded Lipodissolve mixtures for fat removal as "unapproved drugs for unapproved uses" and noted that FDA is "investigating and evaluating" the situation. In June 2007, the FDA stated to NPR and the Washington Post that the Agency is investigating organizations marketing and/or distributing Lipodissolve. In 2003, the FDA sent a warning letter to a physician engaged in the unlawful marketing and distribution of Lipodissolve. The June 22, 2003 letter orders the physician to "immediately cease marketing and distributing this product." The letter uses the term 'Lipostabil' rather than 'Lipodissolve,' but these terms refer to mixtures with the same compositions. The letter also reiterated FDA's position that the product in question is a "new drug" per section 210(ff)(2)(A)(i) of the Federal Food, Drug, and Cosmetic Act, in that the product in an injectable agent that "alters the structure or function of the body." Both the route of administration (i.e., injection) and the claim that the agent alters "structure or function of the body" (i.e., it removes fat) qualifies the product as a "new drug" under the Federal Food, Drug, and Cosmetic Act and thus requires that a New Drug Application (NDA; section 505(a) of the Act) be filed with the FDA prior to marketing.
- July 22, 2003 FDA warning letter, p. 1
- July 22, 2003 FDA warning letter, p. 2
- July 22, 2003 FDA warning letter, p. 3
# FDA OASIS (Operational and Administrative System for Import Support) Refuses Delivery of Compounded PCDC mixtures for fat removal—declares the mixture as a “New Drug” Requiring Filing of NDA Prior to Commercialization
On June 18, 2007, the FDA OASIS (Operational and Administrative System for Import Support, see ) posted to its public access website that the Agency had refused to allow the delivery of PCDC mixtures prepared at a US-based compounding pharmacy. On its website, the FDA stated that the two reasons for the “refusal” were as follows:
1. Reason: DRUG GMPS
Section: 501(a)(2)(B), 801(a)(3); ADULTERATION
Charge: It appears that the methods used in or the facilities or controls used for manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing.
2. Reason: UNAPPROVED. Section: 505(a), 801(a)(3); UNAPPROVED NEW DRUG
Charge: The article appears to be a new drug without an approved new drug application. | Lipodissolve
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2]
# Overview
Lipo-dissolve or Lipodissolve, LipoShape or Lipostabil, also called injection lipolysis, is a controversial cosmetic procedure in which various non-FDA approved drug mixtures, often called PCDC, or phosphatidylcholine deoxycholate, are injected into patients to remove fat[1][2]. This practice evolved from the initial intravenous use of PC-containing drug formulations to treat blood disorders. In 1966, investigators noted that the intravenous infusion of PC-containing solutions could remove fat emboli[3]. Later, a drug formulation called LIPOSTABIL® containing 5% PC and 4.75% deoxycholate (DC) was approved in Germany and used in the treatment of fat embolism[4][5], dyslipidemia[6], and alcohol-induced liver cirrhosis[7]. The first report of LIPOSTABIL® injection for fat removal demonstrated that infra-orbital (‘under the eyelid’) fat could be removed by LIPOSTABIL® injection[8]. While no placebo-controlled studies have demonstrated the safety or efficacy of this therapy, numerous retrospective studies of LIPOSTABIL® injections have reported the efficacy of this unapproved practice[9][10][11][12][13][14][15][16][17]. While the safety of Lipodissolve injections has yet to be proven in a prospective, placebo-controlled, double-blind clinical study, retrospective studies suggest that this practice does not present significant medical risk[18]. The American Society for Aesthetic Plastic Surgery (ASAPS) received FDA authorization to initiate a double-blind, placebo-controlled 46-week study to experimentally examine the safety and efficacy of Lipodissolve injections [3]. The mixture is injected directly into the subcutaneous fat through multiple microinjections administered over multiple treatment sessions. The desired end result is the removal of localized fat deposits[19].
The injection of Lipodissolve for fat removal remains somewhat controversial. In statements to the New York Times [4] and USA Today [5], the FDA has taken the position that the injection of Lipodissolve mixtures for fat removal is an example of “unapproved drugs for unapproved uses.” Despite that, multiple businesses have initiated commercialization of Lipodissolve by opening clinics that advertise and administer Lipodissolve injections for fat removal [6],[7]. One of these businesses states on its website that "Pharmacies are permitted to compound drugs pursuant to a valid patient/physician/pharmacist relationship - even if the drugs have not been approved by the FDA." [8] The FDA has stated that it is “investigating and evaluating” the situation [9].
# Lipodissolve regulation in the state of Kansas
On August 18, 2007, the Kansas State Board of Healing Arts voted unanimously to ban all commercial use of Lipodissolve and to allow the use of the drug only as part of FDA-sanctioned clinical trials under an Investigational New Drug Application. “We have to protect the public from the potentially disastrous effects of unproven drugs,” said Mark Stafford, the board’s general counsel, who noted that Lipodissolve is not approved for treating fat by the Food and Drug Administration [10]. Stafford also stated that the board had received at least half a dozen complaints about the procedure, including side effects such as nodules, infections and nausea.
On August 31, fig. a company that manages or operates 15 medical body shaping centers offering the Lipodissolve procedure ([11]), filed a petition for a temporary restraining order in Shawnee, Kansas to prevent the ban from going into effect [12]. .Fig states on their public website "Pharmacies are permitted to compound drugs pursuant to a valid patient/physician/pharmacist relationship - even if the drugs have not been approved by the FDA." [13]. FDA spokesperson Karen Riley told USA Today on September 10, 2007 that FDA maintains a different view and considers injection of compounded Lipodissolve mixtures for fat removal as "unapproved drugs for unapproved uses" and noted that FDA is "investigating and evaluating" the situation [14].
On September 10, 2007 at a special meeting the Kansas State Board moved to "replace its permanent Lipodissolve ban with a temporary ban to allow public comment on the move, which could still begin Friday", according to Mark Stafford, general counsel of the healing arts board [15].
On September 13, 2007, Shawnee County District Judge David Bruns blocked the State Board's ban stating that the board erred by approving the ban without enough public input [16].
# Health Warnings
Three medical associations have issued health warnings cautioning against the use of injection lypolysis, including the American Society of Plastic Surgeons (ASPS), the American Society of Aesthetic Plastic Surgery (ASAPS), and the American Society of Dermatologic Surgery (ASDS).
- ASPS Health Warning: [17]
- ASAPS Health Warning: [18]
- ASDS Health Warning: [19]
ASAL Responds to ASAPS Warnings: [20]
- ASAL Responds to ASAPS Warnings: [20]
# International Regulation: Lipodissolve banned in Brazil. Promotion of Lipodissolve curtailed in England and Canada
ANVISA (Agencia Nacional de Vigilancia), the governmental body regulating the manufacture and commercialization of drugs in Brazil, banned the manufacture, use, and sale of injection lipolysis agents containing phosphatidylcholine on December 30, 2002. The ANVISA statement [21] justified the ban by stating that such agents were not approved for the removal of subcutaneous fat, and that the long term effects this unapproved therapy were unknown. For an English translation of the ANVISA statement, see [22]. Health Canada issued a similar warning in 2004 [23], though the drug is still being injected by various medspas. The MHRA (Medicines and Healthcare Products Regulatory Agency), the governmental body regulating the manufacture and commercialization of drugs in the United Kingdom, issued a similar warning [24] to physicians considering the use of these substances for cosmetic purposes. The MHRA stated that these drugs "are being unlawfully advertised in the UK as a cosmetic product for the reduction of fat." The MHRA also pointed out that considerable safety concerns remain due to the fact that these agents have not been tested in controlled clinical trials. While British physicians can still inject Lipodissolve for fat removal, the drug cannot be promoted as a drug for that purpose. As of July, 2005, The Medical Protection Society, the organization that provides British doctors with legal advice and coverage against litigation costs and damages, ceased offering malpractice insurance for use of Lipodissolve because of safety concerns [25].
# FDA currently investigating the marketing and distribution of 'Lipodissolve'
In September 2007, FDA spokesperson Karen Riley told USA Today [26], the New York Times [27], and KVBC News (Las Vegas) [28] that FDA views injection of compounded Lipodissolve mixtures for fat removal as "unapproved drugs for unapproved uses" and noted that FDA is "investigating and evaluating" the situation. In June 2007, the FDA stated to NPR [29] and the Washington Post [30] that the Agency is investigating organizations marketing and/or distributing Lipodissolve. In 2003, the FDA sent a warning letter to a physician engaged in the unlawful marketing and distribution of Lipodissolve. The June 22, 2003 letter orders the physician to "immediately cease marketing and distributing this product." The letter uses the term 'Lipostabil' rather than 'Lipodissolve,' but these terms refer to mixtures with the same compositions. The letter also reiterated FDA's position that the product in question is a "new drug" per section 210(ff)(2)(A)(i) of the Federal Food, Drug, and Cosmetic Act, in that the product in an injectable agent that "alters the structure or function of the body." Both the route of administration (i.e., injection) and the claim that the agent alters "structure or function of the body" (i.e., it removes fat) qualifies the product as a "new drug" under the Federal Food, Drug, and Cosmetic Act and thus requires that a New Drug Application (NDA; section 505(a) of the Act) be filed with the FDA prior to marketing.
- July 22, 2003 FDA warning letter, p. 1
- July 22, 2003 FDA warning letter, p. 2
- July 22, 2003 FDA warning letter, p. 3
# FDA OASIS (Operational and Administrative System for Import Support) Refuses Delivery of Compounded PCDC mixtures for fat removal—declares the mixture as a “New Drug” Requiring Filing of NDA Prior to Commercialization
On June 18, 2007, the FDA OASIS (Operational and Administrative System for Import Support, see [31]) posted to its public access website [32] that the Agency had refused to allow the delivery of PCDC mixtures prepared at a US-based compounding pharmacy. On its website, the FDA stated that the two reasons for the “refusal” were as follows:
1. Reason: DRUG GMPS
Section: 501(a)(2)(B), 801(a)(3); ADULTERATION
Charge: It appears that the methods used in or the facilities or controls used for manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing.
2. Reason: UNAPPROVED. Section: 505(a), 801(a)(3); UNAPPROVED NEW DRUG
Charge: The article appears to be a new drug without an approved new drug application. | https://www.wikidoc.org/index.php/Injection_lipolysis | |
74a8a8f2ed02511a3a66161810a3eca3c5626885 | wikidoc | Injury cover | Injury cover
# Overview
Injury cover may refer to the act of receiving or claiming compensation for work related injuries.
It also may be used in conjunction with:
Health Insurance - A form of group insurance, where individuals pay premiums or taxes in order to help protect themselves from high or unexpected healthcare expenses.
Workers' compensation - To protect employees who have incurred work-related injuries.
Damages - legal term referring to the financial compensation recoverable by reason of another's breach of duty; the money paid or awarded to a plaintiff.
Personal Injury Service - Service by which an injury related claim is made. | Injury cover
# Overview
Injury cover may refer to the act of receiving or claiming compensation for work related injuries.
It also may be used in conjunction with:
Health Insurance - A form of group insurance, where individuals pay premiums or taxes in order to help protect themselves from high or unexpected healthcare expenses.
Workers' compensation - To protect employees who have incurred work-related injuries.
Damages - legal term referring to the financial compensation recoverable by reason of another's breach of duty; the money paid or awarded to a plaintiff.
Personal Injury Service - Service by which an injury related claim is made. | https://www.wikidoc.org/index.php/Injury_cover | |
d7fd58fedb26712a7680212f844c1ba99e87d37e | wikidoc | Nitric oxide | Nitric oxide
# 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
Nitric oxide is a vasodilator that is FDA approved for the treatment of treatment of hypoxic respiratory failure. Common adverse reactions include hypotension, methemoglobinemia, hypoxemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Nitric oxide FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nitric oxide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitric oxide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Nitric oxide is a vasodilator, which, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.
- Utilize additional therapies to maximize oxygen delivery with validated ventilation systems. In patients with collapsed alveoli, additional therapies might include surfactant and high-frequency oscillatory ventilation.
- The safety and effectiveness of nitric oxide have been established in a population receiving other therapies for hypoxic respiratory failure, including vasodilators, intravenous fluids, bicarbonate therapy, and mechanical ventilation. Different dose regimens for nitric oxide were used in the clinical studies.
- Monitor for PaO2, methemoglobin, and inspired NO2 during nitric oxide administration.
- To ensure safe and effective administration of nitric oxide to avoid adverse events associated with nitric oxide or NO2, administration of nitric oxide should only be performed by a health care professional who has completed and maintained training on the safe and effective use of a Nitric Oxide Delivery System provided by the manufacturer of the delivery system and the drug.
- Term and near-term neonates with hypoxic respiratory failure
- The recommended dose of nitric oxide is 20 ppm. Treatment should be maintained up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from nitric oxide therapy.
- As the risk of methemoglobinemia and elevated NO2 levels increases significantly when nitric oxide is administered at doses >20 ppm; doses above this level are not recommended.
- Methemoglobin should be measured within 4-8 hours after initiation of treatment with nitric oxide and periodically throughout treatment.
- Nitric oxide must be administered using the INOvent® Nitric Oxide Delivery Systems, which deliver operator-determined concentrations of nitric oxide in conjunction with a ventilator or breathing gas administration system after dilution with an oxygen/air mixture. A Nitric Oxide Delivery System includes a nitric oxide administration apparatus, a nitric oxide gas analyzer and a nitrogen dioxide gas analyzer. Failure to calibrate the Nitric Oxide Delivery System could result in under- or over- dosing of nitric oxide.
- To address potential power failure, keep available a backup battery power supply. To address potential system failure, keep available an independent reserve nitric oxide delivery system. Failure to transition to a reserve nitric oxide delivery system can result in abrupt or prolonged discontinuation of nitric oxide.
- The user of nitric oxide and Nitric Oxide Delivery Systems must complete a comprehensive training program for health care professionals provided by the delivery system and drug manufacturers.
- Health professional staff that administers nitric oxide therapy have access to supplier-provided 24 hour/365 days per year technical support on the delivery and administration of nitric oxide.
- Abrupt discontinuation of nitric oxide may lead to increasing pulmonary artery pressure (PAP) and worsening oxygenation even in neonates with no apparent response to nitric oxide for inhalation. To wean nitric oxide, downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Neonatal respiratory failure - Perinatal hypoxia - Pulmonary hypertension: neonates (greater than 34 wk gestation): 20 parts per million (ppm) via INHALATION for up to 14 days or until resolution of oxygen desaturation.
### Non–Guideline-Supported Use
- Acute respiratory distress syndrome.
- Cardiovascular surgical procedure - Pulmonary hypertension
- Congestive heart failure.
- Diagnostic procedure, Pulmonary vasodilator testing.
- High altitude pulmonary edema.
- Primary pulmonary hypertension.
- Repair of congenital heart disease - Secondary pulmonary hypertension.
- Respiratory distress syndrome in the newborn, In preterm neonates in conjunction with mechanical ventilation and exogenous surfactant.
- Respiratory failure, pediatricView additional information.
- Right-sided heart failure, acute, After implantation of left ventricular assist device (LVAD) in patients with reversible pulmonary hypertension.
# Contraindications
- It is contraindicated in the treatment of neonates known to be dependent on right-to-left shunting of blood.
# Warnings
- Abrupt discontinuation of nitric oxide may lead to worsening oxygenation and increasing pulmonary artery pressure, i.e., Rebound Pulmonary Hypertension Syndrome. Signs and symptoms of Rebound Pulmonary Hypertension Syndrome include hypoxemia, systemic hypotension, bradycardia, and decreased cardiac output. If Rebound Pulmonary Hypertension occurs, reinstate nitric oxide therapy immediately.
- Nitric oxide combines with hemoglobin to form methemoglobin, which does not transport oxygen. Methemoglobin levels increase with the dose of nitric oxide; it can take 8 hours or more before steady-state methemoglobin levels are attained. Monitor methemoglobin and adjust the dose of nitric oxide to optimize oxygenation.
- If methemoglobin levels do not resolve with decrease in dose or discontinuation of nitric oxide, additional therapy may be warranted to treat methemoglobinemia.
- Nitrogen dioxide (NO2) forms in gas mixtures containing NO and O2. Nitrogen dioxide may cause airway inflammation and damage to lung tissues. If the concentration of NO2 in the breathing circuit exceeds 0.5 ppm, decrease the dose of nitric oxide.
- If there is an unexpected change in NO2 concentration, when measured in the breathing circuit, then the delivery system should be assessed in accordance with the Nitric Oxide Delivery System O&M Manual troubleshooting section, and the NO2 analyzer should be recalibrated. The dose of nitric oxide and/or FiO2 should be adjusted as appropriate.
- Patients with left ventricular dysfunction treated with nitric oxide may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia and cardiac arrest. Discontinue nitric oxide while providing symptomatic care.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The adverse reaction information from the clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
- Controlled studies have included 325 patients on nitric oxide doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on nitric oxide, a result adequate to exclude nitric oxide mortality being more than 40% worse than placebo.
- In both the NINOS and CINRGI studies, the duration of hospitalization was similar in nitric oxide and placebo-treated groups.
- From all controlled studies, at least 6 months of follow-up is available for 278 patients who received nitric oxide and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for rehospitalization, special medical services, pulmonary disease, or neurological sequelae.
- In the NINOS study, treatment groups were similar with respect to the incidence and severity of intracranial hemorrhage, Grade IV hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage.
- In CINRGI, the only adverse reaction (>2% higher incidence on nitric oxide than on placebo) was hypotension (14% vs. 11%).
## Postmarketing Experience
- Based upon post-marketing experience, accidental exposure to nitric oxide for inhalation in hospital staff has been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.
# Drug Interactions
- No formal drug-interaction studies have been performed, and a clinically significant interaction with other medications used in the treatment of hypoxic respiratory failure cannot be excluded based on the available data. nitric oxide has been administered with dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation.
- Although there are no study data to evaluate the possibility, nitric oxide donor compounds, including sodium nitroprusside and nitroglycerin, may have an additive effect with nitric oxide on the risk of developing methemoglobinemia. An association between prilocaine and an increased risk of methemoglobinemia, particularly in infants, has specifically been described in a literature case report. This risk is present whether the drugs are administered as oral, parenteral, or topical formulations.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with nitric oxide. It is not known if nitric oxide can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. nitric oxide is not intended for adults.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitric oxide in women who are pregnant.
### Labor and Delivery
- The effect of nitric oxide on labor and delivery in humans is unknown.
### Nursing Mothers
- Nitric oxide is not indicated for use in the adult population, including nursing mothers. It is not known whether nitric oxide is excreted in human milk.
### Pediatric Use
- The safety and efficacy of nitric oxide for inhalation has been demonstrated in term and near-term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension.
- Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy. No information about its effectiveness in other age populations is available.
### Geriatic Use
- Nitric oxide is not indicated for use in the adult population.
### Gender
There is no FDA guidance on the use of Nitric oxide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nitric oxide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nitric oxide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nitric oxide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nitric oxide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nitric oxide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Inhalational
### Monitoring
There is limited information regarding Monitoring of Nitric oxide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Nitric oxide in the drug label.
# Overdosage
- Overdosage with nitric oxide will be manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO2. Elevated NO2 may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO2 levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or discontinuing, nitric oxide.
- Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.
# Pharmacology
## Mechanism of Action
- Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature.
- Nitric oxide appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.
## Structure
- Nitric oxide (nitric oxide gas) is a drug administered by inhalation. Nitric oxide, the active substance in nitric oxide, is a pulmonary vasodilator.
- Nitric oxide is a gaseous blend of nitric oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm; 0.01% and 99.99%, respectively for 100 ppm). nitric oxide is supplied in aluminum cylinders as a compressed gas under high pressure (2000 pounds per square inch gauge ).
- The structural formula of nitric oxide (NO) is shown below:
## Pharmacodynamics
- Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, nitric oxide improves oxygenation (as indicated by significant increases in PaO2).
## Pharmacokinetics
- Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, nitric oxide improves oxygenation (as indicated by significant increases in PaO2).
- The pharmacokinetics of nitric oxide has been studied in adults.
- Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides and methemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhemoglobin to produce methemoglobin and nitrate. Thus, the end products of nitric oxide that enter the systemic circulation are predominantly methemoglobin and nitrate.
- Methemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. The methemoglobin (MetHb) concentration-time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm nitric oxide are shown in Figure 1.
- Methemoglobin concentrations increased during the first 8 hours of nitric oxide exposure. The mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20 ppm nitric oxide groups, but reached approximately 5% in the 80 ppm nitric oxide group. Methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they comprised 35% of the group. The average time to reach peak methemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours.
- Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.
## Nonclinical Toxicology
- No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 hr/day for up to two years. Higher exposures have not been investigated.
- Nitric oxide has demonstrated genotoxicity in Salmonella (Ames Test), human lymphocytes, and after in vivo exposure in rats. There are no animal or human studies to evaluate nitric oxide for effects on fertility.
# Clinical Studies
- The efficacy of nitric oxide has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of etiologies. Inhalation of nitric oxide reduces the oxygenation index (OI= mean airway pressure in cm H2O × fraction of inspired oxygen concentration × 100 divided by systemic arterial concentration in mm Hg ) and increases PaO2.
- The Neonatal Inhaled Nitric Oxide Study (NINOS) was a double-blind, randomized, placebo-controlled, multicenter trial in 235 neonates with hypoxic respiratory failure.
- The objective of the study was to determine whether inhaled nitric oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of term or near-term neonates with hypoxic respiratory failure unresponsive to conventional therapy. Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (PPHN; 17%), or respiratory distress syndrome (RDS; 11%).
- Infants ≤14 days of age (mean, 1.7 days) with a mean PaO2 of 46 mm Hg and a mean oxygenation index (OI) of 43 cm H2O / mm Hg were initially randomized to receive 100% O2 with (n=114) or without (n=121) 20 ppm nitric oxide for up to 14 days. Response to study drug was defined as a change from baseline in PaO2 30 minutes after starting treatment (full response = >20 mm Hg, partial = 10–20 mm Hg, no response = <10 mm Hg). Neonates with a less than full response were evaluated for a response to 80 ppm nitric oxide or control gas. The primary results from the NINOS study are presented in Table 1.
- Although the incidence of death by 120 days of age was similar in both groups (NO, 14%; control, 17%), significantly fewer infants in the nitric oxide group required ECMO compared with controls (39% vs. 55%, p = 0.014). The combined incidence of death and/or initiation of ECMO showed a significant advantage for the nitric oxide treated group (46% vs. 64%, p = 0.006). The nitric oxide group also had significantly greater increases in PaO2 and greater decreases in the OI and the alveolar-arterial oxygen gradient than the control group (p<0.001 for all parameters).
- Significantly more patients had at least a partial response to the initial administration of study drug in the nitric oxide group (66%) than the control group (26%, p<0.001). Of the 125 infants who did not respond to 20 ppm nitric oxide or control, similar percentages of NO-treated (18%) and control (20%) patients had at least a partial response to 80 ppm nitric oxide for inhalation or control drug, suggesting a lack of additional benefit for the higher dose of nitric oxide.
- No infant had study drug discontinued for toxicity. Inhaled nitric oxide had no detectable effect on mortality. The adverse events collected in the NINOS trial occurred at similar incidence rates in both treatment groups.
- Follow-up exams were performed at 18–24 months for the infants enrolled in this trial. In the infants with available follow-up, the two treatment groups were similar with respect to their mental, motor, audiologic, or neurologic evaluations.
- This study was a double-blind, randomized, placebo-controlled, multicenter trial of 186 term and near-term neonates with pulmonary hypertension and hypoxic respiratory failure.
- The primary objective of the study was to determine whether nitric oxide would reduce the receipt of ECMO in these patients. Hypoxic respiratory failure was caused by MAS (35%), idiopathic PPHN (30%), pneumonia/sepsis (24%), or RDS (8%).
- Patients with a mean PaO2 of 54 mm Hg and a mean OI of 44 cm H2O / mm Hg were randomly assigned to receive either 20 ppm nitric oxide (n=97) or nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a PaO2 >60 mm Hg and a pH < 7.55 were weaned to 5 ppm nitric oxide or placebo. The primary results from the CINRGI study are presented in Table 2.
- Significantly fewer neonates in the nitric oxide group required ECMO compared to the control group (31% vs. 57%, p<0.001). While the number of deaths were similar in both groups (nitric oxide, 3%; placebo, 6%), the combined incidence of death and/or receipt of ECMO was decreased in the nitric oxide group (33% vs. 58%, p<0.001).
- In addition, the nitric oxide group had significantly improved oxygenation as measured by PaO2, OI, and alveolar-arterial gradient (p4%. The frequency and number of adverse events reported were similar in the two study groups.
- In clinical trials, reduction in the need for ECMO has not been demonstrated with the use of inhaled nitric oxide in neonates with congenital diaphragmatic hernia (CDH).
- In a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory distress syndrome (ARDS) associated with pneumonia (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pulmonary contusion (18%), and other causes, with PaO2/FiO2 <250 mm Hg despite optimal oxygenation and ventilation, received placebo (n=193) or nitric oxide (n=192), 5 ppm, for 4 hours to 28 days or until weaned because of improvements in oxygenation.
- Despite acute improvements in oxygenation, there was no effect of nitric oxide on the primary endpoint of days alive and off ventilator support. These results were consistent with outcome data from a smaller dose ranging study of nitric oxide (1.25 to 80 ppm). Nitric oxide is not indicated for use in ARDS.
- The safety and efficacy of nitric oxide for the prevention of chronic lung disease in neonates ≤ 34 weeks gestational age requiring respiratory support has been studied in three large, multi-center, double-blind, placebo-controlled clinical trials in a total of 2,149 preterm infants. Of these, 1,068 received placebo, and 1,081 received inhaled nitric oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days duration.
- The primary endpoint for these studies was alive and without BPD at 36 weeks postmenstrual age (PMA). The need for supplemental oxygen at 36 weeks PMA served as a surrogate endpoint for the presence of BPD.
- Overall, efficacy for the prevention of bronchopulmonary dysplasia in preterm infants was not established.
- There were no meaningful differences between treatment groups with regard to deaths, methemoglobin levels, or adverse events commonly observed in premature infants, including intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity. The use of nitric oxide for prevention of BPD in preterm neonates ≤ 34 weeks gestational age is not indicated.
# How Supplied
## Storage
- Store at 25°C (77°F) with excursions permitted between 15–30°C (59–86°F) .
- All regulations concerning handling of pressure vessels must be followed.
- Protect the cylinders from shocks, falls, oxidizing and flammable materials, moisture, and sources of heat or ignition.
- The cylinders should be appropriately transported to protect from risks of shocks and falls.
- The exposure limit set by the Occupational Safety and Health Administration (OSHA) for nitric oxide is 25 ppm, and for NO2 the limit is 5 ppm.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Nitric oxide in the drug label.
# Precautions with Alcohol
- Alcohol-Nitric oxide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- INOMAX ®
# Look-Alike Drug Names
There is limited information regarding Nitric oxide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nitric oxide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
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# Overview
Nitric oxide is a vasodilator that is FDA approved for the treatment of treatment of hypoxic respiratory failure. Common adverse reactions include hypotension, methemoglobinemia, hypoxemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Nitric oxide FDA-Labeled Indications and Dosage (Adult) in the drug label.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nitric oxide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nitric oxide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Nitric oxide is a vasodilator, which, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.
- Utilize additional therapies to maximize oxygen delivery with validated ventilation systems. In patients with collapsed alveoli, additional therapies might include surfactant and high-frequency oscillatory ventilation.
- The safety and effectiveness of nitric oxide have been established in a population receiving other therapies for hypoxic respiratory failure, including vasodilators, intravenous fluids, bicarbonate therapy, and mechanical ventilation. Different dose regimens for nitric oxide were used in the clinical studies.
- Monitor for PaO2, methemoglobin, and inspired NO2 during nitric oxide administration.
- To ensure safe and effective administration of nitric oxide to avoid adverse events associated with nitric oxide or NO2, administration of nitric oxide should only be performed by a health care professional who has completed and maintained training on the safe and effective use of a Nitric Oxide Delivery System provided by the manufacturer of the delivery system and the drug.
- Term and near-term neonates with hypoxic respiratory failure
- The recommended dose of nitric oxide is 20 ppm. Treatment should be maintained up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from nitric oxide therapy.
- As the risk of methemoglobinemia and elevated NO2 levels increases significantly when nitric oxide is administered at doses >20 ppm; doses above this level are not recommended.
- Methemoglobin should be measured within 4-8 hours after initiation of treatment with nitric oxide and periodically throughout treatment.
- Nitric oxide must be administered using the INOvent® Nitric Oxide Delivery Systems, which deliver operator-determined concentrations of nitric oxide in conjunction with a ventilator or breathing gas administration system after dilution with an oxygen/air mixture. A Nitric Oxide Delivery System includes a nitric oxide administration apparatus, a nitric oxide gas analyzer and a nitrogen dioxide gas analyzer. Failure to calibrate the Nitric Oxide Delivery System could result in under- or over- dosing of nitric oxide.
- To address potential power failure, keep available a backup battery power supply. To address potential system failure, keep available an independent reserve nitric oxide delivery system. Failure to transition to a reserve nitric oxide delivery system can result in abrupt or prolonged discontinuation of nitric oxide.
- The user of nitric oxide and Nitric Oxide Delivery Systems must complete a comprehensive training program for health care professionals provided by the delivery system and drug manufacturers.
- Health professional staff that administers nitric oxide therapy have access to supplier-provided 24 hour/365 days per year technical support on the delivery and administration of nitric oxide.
- Abrupt discontinuation of nitric oxide may lead to increasing pulmonary artery pressure (PAP) and worsening oxygenation even in neonates with no apparent response to nitric oxide for inhalation. To wean nitric oxide, downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Neonatal respiratory failure - Perinatal hypoxia - Pulmonary hypertension: neonates (greater than 34 wk gestation): 20 parts per million (ppm) via INHALATION for up to 14 days or until resolution of oxygen desaturation.
### Non–Guideline-Supported Use
- Acute respiratory distress syndrome.
- Cardiovascular surgical procedure - Pulmonary hypertension
- Congestive heart failure.
- Diagnostic procedure, Pulmonary vasodilator testing.
- High altitude pulmonary edema.
- Primary pulmonary hypertension.
- Repair of congenital heart disease - Secondary pulmonary hypertension.
- Respiratory distress syndrome in the newborn, In preterm neonates in conjunction with mechanical ventilation and exogenous surfactant.
- Respiratory failure, pediatricView additional information.
- Right-sided heart failure, acute, After implantation of left ventricular assist device (LVAD) in patients with reversible pulmonary hypertension.
# Contraindications
- It is contraindicated in the treatment of neonates known to be dependent on right-to-left shunting of blood.
# Warnings
- Abrupt discontinuation of nitric oxide may lead to worsening oxygenation and increasing pulmonary artery pressure, i.e., Rebound Pulmonary Hypertension Syndrome. Signs and symptoms of Rebound Pulmonary Hypertension Syndrome include hypoxemia, systemic hypotension, bradycardia, and decreased cardiac output. If Rebound Pulmonary Hypertension occurs, reinstate nitric oxide therapy immediately.
- Nitric oxide combines with hemoglobin to form methemoglobin, which does not transport oxygen. Methemoglobin levels increase with the dose of nitric oxide; it can take 8 hours or more before steady-state methemoglobin levels are attained. Monitor methemoglobin and adjust the dose of nitric oxide to optimize oxygenation.
- If methemoglobin levels do not resolve with decrease in dose or discontinuation of nitric oxide, additional therapy may be warranted to treat methemoglobinemia.
- Nitrogen dioxide (NO2) forms in gas mixtures containing NO and O2. Nitrogen dioxide may cause airway inflammation and damage to lung tissues. If the concentration of NO2 in the breathing circuit exceeds 0.5 ppm, decrease the dose of nitric oxide.
- If there is an unexpected change in NO2 concentration, when measured in the breathing circuit, then the delivery system should be assessed in accordance with the Nitric Oxide Delivery System O&M Manual troubleshooting section, and the NO2 analyzer should be recalibrated. The dose of nitric oxide and/or FiO2 should be adjusted as appropriate.
- Patients with left ventricular dysfunction treated with nitric oxide may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia and cardiac arrest. Discontinue nitric oxide while providing symptomatic care.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The adverse reaction information from the clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
- Controlled studies have included 325 patients on nitric oxide doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on nitric oxide, a result adequate to exclude nitric oxide mortality being more than 40% worse than placebo.
- In both the NINOS and CINRGI studies, the duration of hospitalization was similar in nitric oxide and placebo-treated groups.
- From all controlled studies, at least 6 months of follow-up is available for 278 patients who received nitric oxide and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for rehospitalization, special medical services, pulmonary disease, or neurological sequelae.
- In the NINOS study, treatment groups were similar with respect to the incidence and severity of intracranial hemorrhage, Grade IV hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage.
- In CINRGI, the only adverse reaction (>2% higher incidence on nitric oxide than on placebo) was hypotension (14% vs. 11%).
## Postmarketing Experience
- Based upon post-marketing experience, accidental exposure to nitric oxide for inhalation in hospital staff has been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.
# Drug Interactions
- No formal drug-interaction studies have been performed, and a clinically significant interaction with other medications used in the treatment of hypoxic respiratory failure cannot be excluded based on the available data. nitric oxide has been administered with dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation.
- Although there are no study data to evaluate the possibility, nitric oxide donor compounds, including sodium nitroprusside and nitroglycerin, may have an additive effect with nitric oxide on the risk of developing methemoglobinemia. An association between prilocaine and an increased risk of methemoglobinemia, particularly in infants, has specifically been described in a literature case report. This risk is present whether the drugs are administered as oral, parenteral, or topical formulations.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with nitric oxide. It is not known if nitric oxide can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. nitric oxide is not intended for adults.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitric oxide in women who are pregnant.
### Labor and Delivery
- The effect of nitric oxide on labor and delivery in humans is unknown.
### Nursing Mothers
- Nitric oxide is not indicated for use in the adult population, including nursing mothers. It is not known whether nitric oxide is excreted in human milk.
### Pediatric Use
- The safety and efficacy of nitric oxide for inhalation has been demonstrated in term and near-term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension.
- Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy. No information about its effectiveness in other age populations is available.
### Geriatic Use
- Nitric oxide is not indicated for use in the adult population.
### Gender
There is no FDA guidance on the use of Nitric oxide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nitric oxide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nitric oxide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nitric oxide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nitric oxide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nitric oxide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Inhalational
### Monitoring
There is limited information regarding Monitoring of Nitric oxide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Nitric oxide in the drug label.
# Overdosage
- Overdosage with nitric oxide will be manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO2. Elevated NO2 may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO2 levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or discontinuing, nitric oxide.
- Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.
# Pharmacology
## Mechanism of Action
- Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature.
- Nitric oxide appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.
## Structure
- Nitric oxide (nitric oxide gas) is a drug administered by inhalation. Nitric oxide, the active substance in nitric oxide, is a pulmonary vasodilator.
- Nitric oxide is a gaseous blend of nitric oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm; 0.01% and 99.99%, respectively for 100 ppm). nitric oxide is supplied in aluminum cylinders as a compressed gas under high pressure (2000 pounds per square inch gauge [psig]).
- The structural formula of nitric oxide (NO) is shown below:
## Pharmacodynamics
- Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, nitric oxide improves oxygenation (as indicated by significant increases in PaO2).
## Pharmacokinetics
- Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, nitric oxide improves oxygenation (as indicated by significant increases in PaO2).
- The pharmacokinetics of nitric oxide has been studied in adults.
- Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides and methemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhemoglobin to produce methemoglobin and nitrate. Thus, the end products of nitric oxide that enter the systemic circulation are predominantly methemoglobin and nitrate.
- Methemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. The methemoglobin (MetHb) concentration-time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm nitric oxide are shown in Figure 1.
- Methemoglobin concentrations increased during the first 8 hours of nitric oxide exposure. The mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20 ppm nitric oxide groups, but reached approximately 5% in the 80 ppm nitric oxide group. Methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they comprised 35% of the group. The average time to reach peak methemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours.
- Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.
## Nonclinical Toxicology
- No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 hr/day for up to two years. Higher exposures have not been investigated.
- Nitric oxide has demonstrated genotoxicity in Salmonella (Ames Test), human lymphocytes, and after in vivo exposure in rats. There are no animal or human studies to evaluate nitric oxide for effects on fertility.
# Clinical Studies
- The efficacy of nitric oxide has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of etiologies. Inhalation of nitric oxide reduces the oxygenation index (OI= mean airway pressure in cm H2O × fraction of inspired oxygen concentration [FiO2]× 100 divided by systemic arterial concentration in mm Hg [PaO2]) and increases PaO2.
- The Neonatal Inhaled Nitric Oxide Study (NINOS) was a double-blind, randomized, placebo-controlled, multicenter trial in 235 neonates with hypoxic respiratory failure.
- The objective of the study was to determine whether inhaled nitric oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of term or near-term neonates with hypoxic respiratory failure unresponsive to conventional therapy. Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (PPHN; 17%), or respiratory distress syndrome (RDS; 11%).
- Infants ≤14 days of age (mean, 1.7 days) with a mean PaO2 of 46 mm Hg and a mean oxygenation index (OI) of 43 cm H2O / mm Hg were initially randomized to receive 100% O2 with (n=114) or without (n=121) 20 ppm nitric oxide for up to 14 days. Response to study drug was defined as a change from baseline in PaO2 30 minutes after starting treatment (full response = >20 mm Hg, partial = 10–20 mm Hg, no response = <10 mm Hg). Neonates with a less than full response were evaluated for a response to 80 ppm nitric oxide or control gas. The primary results from the NINOS study are presented in Table 1.
- Although the incidence of death by 120 days of age was similar in both groups (NO, 14%; control, 17%), significantly fewer infants in the nitric oxide group required ECMO compared with controls (39% vs. 55%, p = 0.014). The combined incidence of death and/or initiation of ECMO showed a significant advantage for the nitric oxide treated group (46% vs. 64%, p = 0.006). The nitric oxide group also had significantly greater increases in PaO2 and greater decreases in the OI and the alveolar-arterial oxygen gradient than the control group (p<0.001 for all parameters).
- Significantly more patients had at least a partial response to the initial administration of study drug in the nitric oxide group (66%) than the control group (26%, p<0.001). Of the 125 infants who did not respond to 20 ppm nitric oxide or control, similar percentages of NO-treated (18%) and control (20%) patients had at least a partial response to 80 ppm nitric oxide for inhalation or control drug, suggesting a lack of additional benefit for the higher dose of nitric oxide.
- No infant had study drug discontinued for toxicity. Inhaled nitric oxide had no detectable effect on mortality. The adverse events collected in the NINOS trial occurred at similar incidence rates in both treatment groups.
- Follow-up exams were performed at 18–24 months for the infants enrolled in this trial. In the infants with available follow-up, the two treatment groups were similar with respect to their mental, motor, audiologic, or neurologic evaluations.
- This study was a double-blind, randomized, placebo-controlled, multicenter trial of 186 term and near-term neonates with pulmonary hypertension and hypoxic respiratory failure.
- The primary objective of the study was to determine whether nitric oxide would reduce the receipt of ECMO in these patients. Hypoxic respiratory failure was caused by MAS (35%), idiopathic PPHN (30%), pneumonia/sepsis (24%), or RDS (8%).
- Patients with a mean PaO2 of 54 mm Hg and a mean OI of 44 cm H2O / mm Hg were randomly assigned to receive either 20 ppm nitric oxide (n=97) or nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a PaO2 >60 mm Hg and a pH < 7.55 were weaned to 5 ppm nitric oxide or placebo. The primary results from the CINRGI study are presented in Table 2.
- Significantly fewer neonates in the nitric oxide group required ECMO compared to the control group (31% vs. 57%, p<0.001). While the number of deaths were similar in both groups (nitric oxide, 3%; placebo, 6%), the combined incidence of death and/or receipt of ECMO was decreased in the nitric oxide group (33% vs. 58%, p<0.001).
- In addition, the nitric oxide group had significantly improved oxygenation as measured by PaO2, OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with nitric oxide, 2 (2%) were withdrawn from study drug due to methemoglobin levels >4%. The frequency and number of adverse events reported were similar in the two study groups.
- In clinical trials, reduction in the need for ECMO has not been demonstrated with the use of inhaled nitric oxide in neonates with congenital diaphragmatic hernia (CDH).
- In a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory distress syndrome (ARDS) associated with pneumonia (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pulmonary contusion (18%), and other causes, with PaO2/FiO2 <250 mm Hg despite optimal oxygenation and ventilation, received placebo (n=193) or nitric oxide (n=192), 5 ppm, for 4 hours to 28 days or until weaned because of improvements in oxygenation.
- Despite acute improvements in oxygenation, there was no effect of nitric oxide on the primary endpoint of days alive and off ventilator support. These results were consistent with outcome data from a smaller dose ranging study of nitric oxide (1.25 to 80 ppm). Nitric oxide is not indicated for use in ARDS.
- The safety and efficacy of nitric oxide for the prevention of chronic lung disease [bronchopulmonary dysplasia, (BPD)] in neonates ≤ 34 weeks gestational age requiring respiratory support has been studied in three large, multi-center, double-blind, placebo-controlled clinical trials in a total of 2,149 preterm infants. Of these, 1,068 received placebo, and 1,081 received inhaled nitric oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days duration.
- The primary endpoint for these studies was alive and without BPD at 36 weeks postmenstrual age (PMA). The need for supplemental oxygen at 36 weeks PMA served as a surrogate endpoint for the presence of BPD.
- Overall, efficacy for the prevention of bronchopulmonary dysplasia in preterm infants was not established.
- There were no meaningful differences between treatment groups with regard to deaths, methemoglobin levels, or adverse events commonly observed in premature infants, including intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity. The use of nitric oxide for prevention of BPD in preterm neonates ≤ 34 weeks gestational age is not indicated.
# How Supplied
## Storage
- Store at 25°C (77°F) with excursions permitted between 15–30°C (59–86°F) [see USP Controlled Room Temperature].
- All regulations concerning handling of pressure vessels must be followed.
- Protect the cylinders from shocks, falls, oxidizing and flammable materials, moisture, and sources of heat or ignition.
- The cylinders should be appropriately transported to protect from risks of shocks and falls.
- The exposure limit set by the Occupational Safety and Health Administration (OSHA) for nitric oxide is 25 ppm, and for NO2 the limit is 5 ppm.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Nitric oxide in the drug label.
# Precautions with Alcohol
- Alcohol-Nitric oxide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- INOMAX ®[1]
# Look-Alike Drug Names
There is limited information regarding Nitric oxide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Inomax | |
471f3365b62d42b8aa3bd046898ca498f34dc5f9 | wikidoc | Insufflation | Insufflation
Insufflation (Latin insufflatio "blowing on or into") is the practice of inhaling substances into a body cavity. Insufflation has limited medical use, but is a common route of administration with many respiratory drugs used to treat conditions in the lungs (asthma or emphasyma) and paranasal sinus (allergy) .
The technique is common for many recreational drugs and is also used for some entheogens. Nasal insufflation is commonly used for many psychoactive drugs because it causes a much faster onset than orally and bioavailability is usually, but not always, higher than orally. This bioavailability occurs due to the quick absorption of chemical molecules into the bloodstream through the soft tissue in the mucous membrane of the sinus cavity.
# Medical uses
## As a medical procedure
Inert, nontoxic gases, such as carbon dioxide, are often insufflated into a body cavity, in order to expand the cavity and increase workroom, or reduce obstruction during investigative surgery.
## As a method of administering drugs
Insufflation can also be synonymous with inhalation. Psychoactive substances are often inhaled nasally for the purpose of intranasal absorption through the mucous membrane, which is often more rapid, or more complete, than gastrointestinal absorption. For a substance to be effective when insufflated, it must be water soluble so it can be absorbed into the mucous membranes. This practice is commonly referred to as "snorting", "huffing", "railing", or "blowing".
Commonly insufflated psychoactive substances include:
- Cocaine - benzoylmethyl ecgonine - a strong stimulant
- Ketamine - dissociative anesthetic
- Heroin/Morphine - powerful opiates
- Opioids - a class of narcotics, typically semi-synthetic (e.g. Oxycodone and Hydromorphone) or completely synthetic (e.g. Meperidine)
- Phencyclidine - dissociative anesthetic, more commonly known by the acronym PCP or slang term angel dust
- Amphetamines - d-methamphetamine and d,l-amphetamine (speed)
- Ritalin - methylphenidate, a stimulant closely related to amphetamine, but often reported to have effects similar to that of cocaine when insufflated
- MDMA/ecstasy - 3,4-methylenedioxy-N-methylamphetamine - an entactogen commonly associated with and used at raves
- Zolpidem (Ambien) - (Ambien CR) - a sedative hypnotic that can have various hallucinogenic effects with certain people and/or at high doses
- Tobacco Snuff - contains nicotine, a mild, but extremely addictive stimulant
Various other drugs can be snorted so long as they are water soluble, though the substances listed are insufflated regularly.
Note: some psychoactive substances such as benzodiazepines (valium, oxazepam, clonazepam) are water soluble to a small degree (about 350ml/1000mg). Though this means they will be somewhat effective when insufflated, they will not be as readily absorbed into the mucous membrane as highly soluble substances such as amphetamines and opiates. Even despite this, many benzodiazepines are still occasionally insufflated.
# Liturgical use
In religious and magical use, insufflation and exsufflation (they are frequently indistinguishable and are considered together here) are ritual acts of blowing, breathing, hissing, or puffing that signify variously expulsion or renunciation of evil or of the devil (the evil one), or infilling or blessing with good (especially, in religious use, with the Spirit or grace of God).
In historical Christian practice, such blowing appears most prominently in the liturgy, and is connected almost exclusively with baptism and other ceremonies of Christian initiation, achieving its greatest popularity during periods in which such ceremonies were given a heavily prophylactic or exorcistic significance, and were viewed as essential to the defeat of the devil or to the removal of the taint of original sin.
An act or acts of ritual blowing occur in the liturgies of catechumenate and baptism from a very early period and flourished there, surviving into the modern Roman Catholic, Greek Orthodox, Maronite, and Coptic rites. Catholic liturgy post Vatican-II (the so-called 'novus ordo' 1969) has largely done away with insufflation (except in a special rite for the consecration of chrism on Maundy Thursday), and Protestant liturgies typically abandoned it very early on, but the Tridentine Catholic liturgy retained both an insufflation of the baptismal water and (like the present-day Orthodox and Maronite rites) an exsufflation of the candidate for baptism, right up to the nineteen-sixties:
He breathes thrice upon the waters in the form of a cross, saying: Do You with Your mouth bless these pure waters: that besides their natural virtue of cleansing the body, they may also be effectual for purifying the soul.
THE EXSUFFLATION. The priest breathes three times on the child in the form of a cross, saying: Go out of him...you unclean spirit and give place to the Holy Spirit, the Paraclete.
## Insufflation vs. exsufflation
From an early period, too, as illustrated here, the act had broadly speaking two distinct but not always distinguishable meanings: it signified on the one hand the derisive repudiation or exorcism of the devil; and, on the other, purification and consecration by and inspiration with the Holy Spirit. The former is sometimes called "exsufflation" and the latter "insufflation" (i.e., "blowing out" and "blowing in") but the ancient and medieval texts (followed by modern scholarhip) only occasionally honor this distinction. For example, the texts use not only Latin "insufflare" ('blow in') and "exsufflare" ('blow out') (or their Greek or vernacular equivalents), but also the simplex "sufflare" ('blow'), "halare" ('breathe'), "inspirare," "exspirare," etc.
Typical is the 8th-century Libellus de mysterio baptismatis of Magnus of Sens, one of a number of responses to a questionnaire about baptism circulated by Charlemagne. In discussing insufflation as a means of exorcising catechumens, he unhesitatingly combines under that heading a variety of mostly exsufflation-like functions: "Those who are to be baptised are insufflated by the priest of God, so that the Prince of Sinners may be put to flight from out of them, and that entry for the Lord Christ might be prepared, and that by his insufflation they might be made worthy to receive the Holy Spirit." This double role appears as early as Cyril of Jerusalem's 4th-century Mystagogic Catacheses: as Yarnold says, "Cyril attributes both negative and positive effects .... The rite of breathing on the candidate has the negative effect of blowing away the devil (exsufflation) and the positive effect of breathing in grace (insufflation)."
## History
### Early period
What might neutrally be called "sufflation" is found in some of the earliest liturgies dealing with the protracted process of initiation known as the "catechumenate," which saw its heyday in the fourth and fifth centuries. The earliest extant liturgical use is possibly that of the Apostolic Tradition attributed to Hippolytus of Rome, perhaps from the fourth century, and therefore contemporary with Cyril in the east:
Those who are to be baptized should ... be gathered in one place.... And should lay his hands on them and exorcize all alien spirits, that they may flee out of them and ever return into them. And when he has finished exorcizing them, he shall breathe on their faces; and when he has signed their foreheads, ears, and noses, he shall raise them up.
### Distribution, geographical and functional
The practice entered the baptismal liturgy proper only as the catechumenate, rendered vestigial by the growth of routine infant baptism, was absorbed into the rite of baptism. Both exsufflation and insufflation are well established by the time of Augustine and in later centuries are found widely. By the Western high Middle Ages of the twelfth century, sufflation was geographically widespread, and had been applied not only to sufflating catechumens and baptizands, but also to exorcism of readmitted heretics; to admission of pagans to the catechumenate; to renunciation of the devil on the part of catechumens; to consecration and/or exorcism of the baptismal font and water; to consecration or exorcism of ashes; and to the consecration of the chrism or holy oil.
### Medieval period
Most of these variations persist in one branch or another of the hybrid Romano-Germanic rite that can be traced from fifth-century Rome through the western Middle Ages to the Council of Trent, and beyond that into modern (Tridentine) Roman Catholicism. As the 'national' rites such as the Ambrosian tradition in northern Italy and the Spanish Mozarabic rite faded away or were absorbed into international practice, it was this hybrid Roman-Gallican standard that came to dominate western Christendom, including Anglo-Saxon and medieval England, from the time of Charlemagne, and partly through his doing, through the high and late Middle Ages and into the modern period. Roman practice around the year 500 is reflected in a letter by a somewhat mysterious "John the Deacon" to a correspondent named Senarius. The letter discusses the exsufflation of catechumens at length. The Stowe Missal, Irish in origin but largely Gallican in form, contains a prebaptismal sufflation of unclear significance. The other Gallican rites are largely devoid of sufflation, though the so-called Missale Gothicum contains a triple exsufflation of baptismal water, and a prebaptismal insufflation of catechumens is found in the hybrid Bobbio Missal and the tenth-century Fulda sacramentary, alongside the more common baptismal exsufflation. The eleventh-century North-Italian baptismal ritual in the Ambrosian Library MS. T.27.Sup. makes heavy use of the practice, requiring both insufflation and triple exsufflation of the baptismal candidates in modum crucis, and insufflation of the font as well. The "Hadrianum" version of the Gregorian Sacramentary, sent to Charlemagne from Rome and augmented probably by Benedict of Aniane, contains an insufflation of the baptismal font, as does the mid-tenth-century Ordo Romanus L, the basis of the later Roman pontifical. Ordo Romanus L also contains a triple exsufflation of the candidates for baptism, immediately preceding the baptism itself.
Most of the numerous Carolingian expositions of baptism treat sufflation to some extent. One anonymous ninth-century catechism is unusual in distinguishing explicitly between the exsufflation of catechumens and the insufflation of baptismal water, but most of the tracts and florilegia, when they treat both, do so without referring one to the other; most confine themselves to exsufflation and are usually content to quote extracts from authorities, especially Isidore and Alcuin. Particularly popular was Isidore's lapidary remark in the Etymologies to the effect that it is not the human being ("God's creature") that is exsufflated, but the prince of sinners to whom that person is subjected by being born in sin, a remark that echoed Augustine's arguments against the Pelagians to the effect that it was not the human infant (God's image) that was attacked in sufflation, but the infant's possessor, the devil. Particularly influential was Alcuin's brief treatment of the subject, the so-called "Primo paganus," which in turn depended heavily on John the Deacon. The "Primo paganus" formed the basis of Charlemagne's famous circular questionnaire on baptism, part of his effort to harmonize liturgical practice across his empire; and many of the seventeen extant direct or indirect responses to the questionnaire are happy to echo Alcuin, making the process a little circular and the texts a little repetitious. The burden of Alcuin's remarks, in fact, appears above in the quotation from the Libellus of Magnus of Sens, one of the respondents. The questionnaire assumed that exsufflation of or on the part of the candidate for baptism was generally practiced--it merely asks what meaning is attached to the practice: "concerning the renunciation of Satan and all his works and pomps, what is the renunciation? and what are the works of the devil and his pomps? why is he breathed upon? ('cur exsufflatur?') why is he exorcised?" Most of the respondents answered that it was so that, with the devil sent fleeing, the entry of the Holy Spirit might be prepared for.
On the other side of the Channel, in Anglo-Saxon England, sufflation is mentioned in Bishop Wulfstan's collection of Carolingian baptismal expositions, the Incipit de baptisma, and in the two vernacular (Old English) homilies based on it, the Quando volueris and the Sermo de baptismate. The Incipit de baptisma reads: "On his face let the sign of the cross be made by exsufflation, so that, the devil having been put to flight, entry for our Lord Christ might be prepared." Among English liturgical texts proper, the tenth-century Leofric Pontifical (and Sacramentary) dictates an insufflation of baptizands, a triple insufflation of the baptismal water, and an 'exhalation' of holy oil. In the eleventh century, the Salisbury Pontifical (BL Cotton MS Tiberius C.1) and the Pontifical of Thomas of Canterbury require insufflation of the font; the Missal of Robert of Jumièges (Canterbury) has an erased rubric where it may have done likewise, as well as having an illegible rubric where it probably directed the exsufflation of catechumens, and retaining the old ordo ad caticuminum ex pagano faciendum, complete with its sufflation ceremony; and an Engish Ordo Romanus (BL Cotton MS Vitellius E.12) contains a triple exsufflation of baptizands. Various twelfth-century texts include signing and triple exsufflation of the holy oil (Sarum), triple exsufflation of baptizands (the Ely, Magdalene, and Winton Pontificals), and insufflation of the font "in modum crucis" (Ely and Magdalene, followed by most later texts). Such are the origins of the late medieval sufflation rites, which were in turn retained in regularized form in post-Tridentine Catholicism.
### Sufflation in Protestantism
Sufflation did not last long in any of the churches arising from the magisterial or radical reformations. Martin Luther's first attempt at a baptismal liturgy, the Tauffbuchlin (Taufbüchlein) of 1523 (reprinted 1524 and 1525) did retain many ceremonies from the late Medieval ritual as it was known in Germany, including a triple exsufflation of baptizands. But in an epilogue, Luther listed this ceremony among the adiaphora--i.e., the inessential features that added nothing to the meaning of the sacrament:
The least importance attaches to these external things, namely breathing under the eyes, signing with the cross, placing salt in the mouth, putting spittle and clay on the ears and nose, anointing with oil the breast and shoulders, and signing the top of the head with chrism, vesting in the christening robe, and giving a burning candle into the hand, and whatever else ... men have added to embellish baptism. For ... they are not the kind of devices that the devil shuns.
The Lutheran Strassbourg Taufbüchlein of June 1524, composed by Diobald Schwartz, assistant to Cathedral preacher Martin Zell, on the basis of the medieval rite used in Strassbourg combined with elements of Luther's 1523 rite, also retains baptismal exsufflation; so does Andreas Osiander in Nuremberg, in the same year.
But thereafter the practice vanished from Lutheranism, and indeed from Protestantism generally. Luther's revised edition of 1526 and its successors omit exsufflation altogether, as do the Luther-influenced early reformed rites of England (Thomas Cranmer's Prayer Book of 1549) and Sweden (the Manual of Olavus Petri), despite the former's conservative basis in the medieval Sarum ritual and the latter's strong interest in exorcism as an essential part of the baptismal ritual.
Similarly in the Swiss Reformation (the Zwinglian/Reformed tradition), only the very earliest rites retain sufflation, namely the ceremony published by Leo Jud, pastor of St. Peter's in Zurich, in the same year (1523) as Luther's first baptismal manual.
### Sufflation in Protestant-Roman Catholic debate
Though sufflation does not appear in Protestant practice, it definitely appears in Protestant polemic, where it is usually treated as an un-Scriptural and superstitious (i.e., in the Protestant view, a typically Roman Catholic) practice, and even one reeking of enchantment or witchcraft. It appears as such, for example in the work of Henry More (the 'Cambridge Platonist') on evil. His argument essentially reverses that of Augustine. Augustine had said to the Pelagians (to paraphrase): "you see that we exorcize and exsufflate infants before baptising them; therefore they must be tainted with sin and possessed by the devil since birth." More replies, in effect, "Infants cannot be devil-possessed sinners; therefore, ceremonial exorcism and exsufflation is presumptuous, frightening, and ridiculous," in a word "the most gross and fundamental Superstitions, that look like Magick or Sorcery":
The conjuring the Devil also out of the Infant that is to be baptized would seem a frightful thing to the Infant himself, if he understood in what an ill plight the Priest supposes him, while he makes three Exsufflations upon his face, and uses an Exorcistical form for the ejecting of the foul Fiend.... And it is much if something might not appear affrightful to the Women in this approaching darkness. For though it be a gay thing for the Priest to be thought to have so much power over the Stygian Fiend, as to Exorcize him out of the Infant; yet it may be a sad consideration with some melancholick women laden with Superstition, to think they are never brought to bed, but they are delivered of a Devil and Child at once.
Sufflation appears in Roman Catholic anti-Protestant polemic, as well. The relative antiquity of the practice, and its strong endorsement by the Protestants' favorite Father, Saint Augustine, made it a natural element in Catholic arguments that contrasted the Protestant with the ancient and Apostolic church. A true church, according to Roman Catholic apologists, would be:
A Church that held the exorcismes exsufflations and renunciations, which are made in baptisme, for sacred Ceremonies, and of Apostolicall tradition.... A Church which in the Ceremonies of baptisme, vsed oyle, salte, waxe, lights, exorcismes, the signe of the Crose, the word Epheta and other thinges that accompanie it; to testifie ... by exorcismes, that baptisme puts vs out of the Diuells possession.
This was argued on the grounds that some of these ceremonies were demonstrably ancient, and all of them might be.
Sundry Ceremonies vsed in baptisme, and other Sacraments, as Exorcismes, Exsufflations, Christening, and the like mentioned by S. Augustine and by diuers other ancient Fathers ..., these being practised by the Primitiue Church (which is graunted to be the true Church) and compared to the customes of Protestants, and vs, in our Churches, will easily disclose, which of the two, they or we, do more imitate, or impugne the true Church of antiquity.
To which a Protestant reply was that sufflation was not ancient enough, and could not be proved to be apostolic:
It was plain then there was no clear Tradition in the Question, possibly there might be a custome in some Churches postnate to the times of the Apostles, but nothing that was obligatory, no Tradition Apostolicall. But this was a suppletory device ready at hand when ever they needed it; and S. Austin confuted the Pelagians, in the Question of Original sinne, by the custome of exorcisme and insufflation, which S. Austin said came from the Apostles by Tradition, which yet was then, and is now so impossible to be prov'd, that he that shall affirm it, shall gaine only the reputation of a bold man and a confident.
Sufflation was judged by Protestant critics to be irrational, mysterious, and obscure, an increasingly important factor by the close of the seventeenth century and the dawn of the Enlightenment:
Mystery prevail'd very little in the first Hundred or Century of Years after Christ; but in the second and third, it began to establish it self by Ceremonies. To Baptism were then added the tasting of Milk and Honey, Anointing, the Sign of the Cross, a white Garment, &c. ... But in later times there was no end of Lights, Exorcisms, Exsufflations, and many other Extravagancies of Jewish, or Heathen Original ... for there is nothing like these in the Writings of the Apostles, but they are all plainly contain'd in the Books of the Gentiles, and was the Substance of their Worship.
It was said to be a human invention, imposed by the arbitrary whim of a tyrannical prelate against the primitive Gospel freedom of the church:
... taking it into his head that there ought to be a trine-immersion in baptism; another the signation of the cross; another an unction with oil; another milk and honey, and imposition of hands immediately after it; another insufflation or breathing upon the person's face to exorcise the Devil... Thus, I say, that inundation of abominable corruptions, which at present overwhelms both the Greek and Romish Churches, gradually came in at this very breech which you are now zealously maintaining, namely, the Bishop's Power to decree rites and ceremonies in the Church.
To all of which, Roman Catholic apologists replied that insufflation was not only ancient and Apostolic, but had been practiced by Christ himself:
"When he had said this he breathed upon them, and said to them, Receive the Holy Ghost...." When the Pastors of our Church use the Insufflation or Breathing upon any, for the like mystical Signification, you cry aloud, Superstition, Superstition, an apish mimical action, &c.
### Prospects
Though liturgical sufflation is almost gone, at least from the Western churches, its revival is not inconceivable. Liturgical renewal movements always seem to look to the 'classic' catechumenate of the fourth and fifth centuries for inspiration. Insufflation has indeed been re-introduced into the Catholic "new catechumenate." But many ceremonies dating from that or the medieval period have been re-imported even into Protestant rites during the last couple of decades. Perhaps even more likely is a revival in the context of the growth of the African and Asian church, in which locally and culturally meaningful ceremonies have often revolutionized practice, and in which, often, the exorcistic function of baptism has enjoyed a new vitality. For example, a pure insufflation is apparently practiced in the Independent Church of the Philippines, and Spinks mentions a pre-baptismal ceremony used by the Christian Workers' Fellowship of Sri Lanka, in which the candidates are struck with a cane and their faces are breathed upon. It is not clear whether the latter represents a revival of historical sufflation, or a wholly new ceremony derived from local custom.
## Significance and associations
There were apparently at least three kinds of association that particularly influenced how liturgical sufflation came to be understood: Biblical antecedents; liturgical setting; and extra-liturgical (cultural) analogs.
### Biblical antecedents
Three Biblical passages recur repeatedly with reference to insufflation properly speaking, all of them referring to some kind of life-giving divine breath. The first and most commonly cited is Genesis 2:7 (echoed by Wisdom 15:11 and Job 33:4), in which God first creates man and then breathes into him the breath of life, in order to give him (as the passage was later interpreted) a human soul. The second passage, Ezekiel 37:9, reinterprets the Genesis passage prophetically, in foreseeing God resurrecting the dead bones of exiled Israel by means of his life-giving breath. And finally, in John 20:22, Christ is represented as conveying the Paraclete to his disciples, and so initiating the commissioned church, by breathing on them, here too, very possibly, with implicit reference to the original creation. The two passages were certainly so connected in later Christian exegesis: the same breath that created man re-created him.
signifies, To blow into, Gen. 2. 7. This sheweth mans soul not to be of the earth, as his body was, but of nothing, by the insufflation of God, and so differing from the spirit of beasts, Eccl. 3. 21. This word is used also, when Christ to make men new creatures, inspired his Apostles with the holy Ghost, Joh. 20. 21.
The Lord God, saith the Text, formed man of the dust of the ground, and breathed into his Nostrils the breath of life, and man became a living Soul. His Body made of Earth, but his Soul the Breath of God.... We must not understand it grosly; for so Breath is not attributable unto God, who is a simple and perfect Spirit; but ... as a figurative expression of God's communicating unto Man that inward Principle, whereby he lives and acts, not only in common with, but in a degree above other Animals.... The Learned P. Fagius takes notice of three things in the Text of Moses, which do conclude the Immortality of the Soul of Man. I. Insufflatio illa Dei: This Inspiration from God spoken of: For he that breaths into another, contributes unto him aliquid de suo somewhat of his own: And therefore, saith he, when our B. Saviour would communicate his Spirit to his Disciples, he did it with Insufflation, breathing on them, thereby to signifie, se Divinum & de suo quiddam illis contribuere .
The associations with creation, rebirth, initiation, and revivification created by these interconnected passages of Scripture suited insufflation for a role in baptism as it has been most commonly regarded: as figuring the waters of creation (over which the Spirit brooded); as figuring the womb of rebirth; and as figuring (in Saint Paul's metaphor) the tomb, into which the Christian joins Christ in descending, and from which the Christian likewise joins Christ in ascending, dead to the old life but made alive again in Christ.
There are also Biblical antecedents for exsufflation, properly speaking, that is, exorcistic blowing, especially the numerous Old Testament passages in which "the breath of God" is the vehicle or symbol not of life but of death and destruction--an expression of the wrath of God: "by the breath of God they perish / and by the blast of his anger they are consumed" (Job 4:9, RSV). The same power is attributed metaphorically to Christ, "The lawless one will be revealed, and the Lord Jesus will slay him with the breath of his mouth" (2 Thessalonians 2:8, RSV). Even less obvious passages could be associated with liturgical exsufflation. Jesse of Amiens, for example, interprets Psalm 34 (Vulg. 35):5 as descriptive of the fate of exsufflated devils: ""Let them be like chaff before the wind, with the angel of the Lord driving them on!" And the apocryphal Acts of Thomas describes a baptismal ceremony which, though it does not explicitly contain a breathing ceremony, appears to imply one, "Let the gift come by which, breathing upon thine enemies, thou didst make them draw back and fall headlong, and let it dwell in this oil, over which we name thy holy name."
God's breath can be fiery, consuming all it touches: "I will blow upon you with the fire of my wrath" (Ezekiel 21:31, RSV). Some of the interpretations of exsufflation may reflect this. Cyril of Jerusalem, for example, when he discusses exsufflation in his catechetical sermons, interprets the liturgical practice in terms of fire:
The breathing of the saints and the invocation of the name of God, like fiercest flame, scorch and drive out evil spirits.
Fire remains a theme in later liturgical exorcisms, for devils, as Nicetas is reported to have said, "are purged by exorcisms as by fire": "we come against you, devil, with spiritual words and fiery speech; we ignite the hiding places in which you are concealed."
### Liturgical context
More importantly, perhaps, fire is physically and symbolically associated with sufflation because of the traditional placement of baptism within the Paschal vigil--a setting heavy with symbolism of light and fire: the blessing of the Paschal candle, the lighting of the "new fire," and the singing of the exultet and the lumen christi. The intimate connection between divine breath and divine fire appears in its most visually arresting form during the benediction of the font, in which, according to most orders, the candle is dipped in the font while the priest declares the power of the Holy Spirit to have descended into the water: the sufflation of the font in most cases directly precedes or accompanies the immersion of the candle. Their close association can again be illustrated from Wulfstan's baptismal homilies:
By the breath that the priest breathes into the font when he blesses it, the devil is straightway driven out from it. And when the priest dips the consecrated candle in the water, then that water forthwith becomes imbued with the Holy Ghost.
Similar considerations bind sufflation closely to imagery of light and darkness, specifically of the movement of the baptizand from the kingdom of darkness into the kingdom of light (a very common theme), and to the sign of the cross (a very common action), among others that could be mentioned. On light-dark imagery, for example, consider John the Deacon:
The exsufflated person is exorcised so that ... having been delivered from the power of darkness, he might be translated into the kingdom ... of God.
So also Augustine ("The church exsufflates and exorcises that the power of darkness might be cast out from them"), and Isidore ("The power of the devil is ... exsufflated in them, so that ... being delivered from the power of darkness, might be translated unto the kingdom of their Lord").
And as regards signation (the sign of the cross), in Western texts from as early as the Gelasian Sacramentary, the one gesture almost always precedes (or precedes and follows) the other, and their significance is often complementary if not identical. In Raban Maur's discussion of the baptismal liturgy, for example, the exsufflation is said to expel the devil, the signing to keep him from coming back. The two signs are frequently combined, the blowing done in the form of a cross, e.g. in the Syrian rite described by James of Edessa, in the modern Coptic rite, in the late ninth-century Ordo Romanus XXXI, in Wulfstan's Anglo-Saxon homilies and their Continental sources, in the tenth-century Ambrosian rites for catechumen and font, in the eleventh-century North Italian catechumenal rites, in the twelfth- through fifteenth-century English pontificals, in the Sarum Missal, and in the thirteenth-century Roman pontifical.
# Extra-liturgical (hagiographic and magical) use
## Patristic period
There are hints in some of the Church Fathers that Christians had a habit of breathing (or hissing) at evil spirits as a recognized act of revulsion or repulsion, even apart from the ceremonies of the church. Tertullian is perhaps the best witness. He seems to be talking about an extra-liturgical casting out of demons by means of exsufflation and signing when he declares that the pagan gods, "by our touch and by our breath" are driven from the bodies of men, and are thus "carried away by the thought and vision of the fire ." He is talking about an ordinary gesture of aversion when he asks a Christian incense-dealer (regarded as hypocritical because he sells incense for the pagan altars), "with what mouth, I ask, will he spit and blow before the fuming altars for which he himself provided? with what constancy will he exorcise his foster children?" And his remarks to his wife about the dangers of mixed marriage suggest that exsufflation was a distinctively Christian practice: " shall you escape notice when you sign your bed or your body? when you blow away some impurity? When even by night you rise to pray?"
If such a custom did exist, it would clarify certain remarks by other Fathers, which might otherwise seem merely metaphorical. Eusebius, for example, says of the saints that they were men "who though they only breathed and spoke, were able to scatter the counsels of evil demons." Irenaeus describes the right response to Gnostic doctrine as "reviling" (καταφυσησαντασ; literally 'exsufflantes'). Cyril of Jerusalem, speaking of resisting temptation, not of baptism, says that "the mere breathing of the exorcist becomes as a fire to that unseen foe." And Augustine's remarks about blowing on images of the emperor suggest that the significance of the gesture was well enough established to be actionable: "Of the great crime of lese majesty ... is he held guilty, according to the laws of this world, who blows upon an image ... of the emperor." Even as late as Bede, we may suspect that "exsufflate" in the sense of "revile" or "cast off" may be a living metaphor.
## Hagiography
The extremely influential Life of Saint Martin by Sulpicius Severus, seems to have set in motion a hagiographic tradition in which saints cast out demons or repel tempting devils by blowing at them. Of Saint Pachomius, for example, it is said that "defending his brow with the sign of the cross, he blew upon and immediately he fled...; blowing upon him, he said, 'depart from me, devil.'" And of Saint Goswin that "a demon stood before Saint Goswin saying 'surely you see that I am Christ...' and...therefore Saint Goswin exsufflated vigorously, saying 'depart foe...,' and immediately...the devil vanished." Saint Justina is reported to have similarly unmasked a series of increasingly subtle and powerful demons, finally melting the prince of demons himself: "blowing upon the devil, she immediately melted him like wax and...felt herself freed from all temptation." And Saint Felix is said to have destroyed idols and uprooted (pagan) sacred trees by like means.
The breath of the saints was credited with healing, as well as exorcistic, powers from an early period. Gregory of Nyssa says of Gregory Thaumaturgus ('Gregory the magician') that he needed to resort to "no finicking and laborious" magic, but "there sufficed, for both the casting out of demons and the healing of bodily ailments, the breath of his mouth." Similar powers are attributed to the Irish saints: kindling lamps, curing dumbness. This theme, too, persists in later hagiographic and quasi-hagiographic texts, appearing, for example in the Estoire del saint graal as the agency by which a madman is miraculously restored. Among English texts, Felix's Life of Saint Guthlac relates that in order to give relief to a boy afflicted by madness, he "washed him in the water of the sacred font and, breathing into his face the breath of healing , drove away from him all the power of the evil spirit," illustrating the difficulty of distinguishing healing from exorcism in an era in which madness was attributed to demonic possession. The miracle that Bishop John performed, according to Bede, on behalf of Herebald, is another example, since it involved a sufflation that was seemingly exorcistic, catechetical, and curative simultaneously.
## Magic and folk medicine
It is difficult to draw a clear line between religious and magical uses of exsufflation: between legends of saints and legends of sorcerers, between magical and liturgical ceremonies, or indeed between beliefs and fictions. The religious use may in fact derive at least in part from magic, and certainly many folkloristic and magical uses (as commonly) were heavily influenced by liturgical ritual. Tertullian's remarks to his wife about Christian practices recognize this fact, since they conclude, "will you not seem to be doing magic?" i.e., in the eyes of a non-believer.
Celsus (according to Origen) reports the use of exufflation by Egyptian magicians. Plotinus seems to attack its use by Roman ones. One of Lucian's tall tales mentions a Chaldean pest-control sorcerer who causes toads and snakes to vanish by blowing on them.
But it is possible to regard Jesus himself as a magician in at least one popular event in the apocryphal infancy gospels, in which he is portrayed as using sufflation in order simultaneously to heal his brother of a snakebite and kill the snake; also in a rarer episode in which Jesus raises a boy from the dead by breathing on him. Christianized healing magic, if that is what it is, appears also in Syria, where ceremonial breathing became formalized as part of the rite of visitation of the sick. Ephraem Syrus advises that "if medicine fails you when you are sick, the 'visitors' will help, will pray for health, and one of them will breathe in your mouth, the other will sign you ."
Whether it be originally Christian or originally pagan, similar methods of healing have been reported persisting till modern times: in Westphalia, the healing of a wound by triple signing and triple cruciform sufflation, or by exsufflation accompanied by a rhyming charm; and in Holland the alleviation of toothache by similar means. According to Drechsler, "Illnesses were blown away by the breath. If a child had bumped himself, one would blow three times on the place and it would 'fly away.'" Burns, and conditions that in some fashion resemble burns, such as fevers, boils, sore throats and rashes, are naturally the most common objects of blowing among modern folk-remedies, for example the Shetland cure that requires blowing on a burn three times while reciting the charm "Here come I to cure a burnt sore. / If the dead knew what the living endure, / The burnt sore would burn no more." But everything from jaundice, convulsions, and colic to bad luck and evil spells can apparently be alleviated by a bit of blowing. Wolters points out that exorcistic blowing was still (in 1935) found in the custom of blowing over bread that is about to be eaten. Moreover,
A Syrian blows over his child to avert the evil eye. Some stillblow three times over a strange spoon before using it, and in Alaska the medicineman blows into the nose and mouth of a patient to drive out the daemon of disease.
Finally, in one American example of superstition clearly derived from liturgical use, it is said that if at the baptism of a baby one turns at the door and blows three times, one can successfully prevent the devil from ever coming between the baby and the altar. | Insufflation
Insufflation (Latin insufflatio "blowing on or into") is the practice of inhaling substances into a body cavity. Insufflation has limited medical use, but is a common route of administration with many respiratory drugs used to treat conditions in the lungs (asthma or emphasyma) and paranasal sinus (allergy) .
The technique is common for many recreational drugs and is also used for some entheogens. Nasal insufflation is commonly used for many psychoactive drugs because it causes a much faster onset than orally and bioavailability is usually, but not always, higher than orally. This bioavailability occurs due to the quick absorption of chemical molecules into the bloodstream through the soft tissue in the mucous membrane of the sinus cavity.
# Medical uses
## As a medical procedure
Inert, nontoxic gases, such as carbon dioxide, are often insufflated into a body cavity, in order to expand the cavity and increase workroom, or reduce obstruction during investigative surgery.
## As a method of administering drugs
Insufflation can also be synonymous with inhalation. Psychoactive substances are often inhaled nasally for the purpose of intranasal absorption through the mucous membrane, which is often more rapid, or more complete, than gastrointestinal absorption. For a substance to be effective when insufflated, it must be water soluble so it can be absorbed into the mucous membranes. This practice is commonly referred to as "snorting", "huffing", "railing", or "blowing".
Commonly insufflated psychoactive substances include:
- Cocaine - benzoylmethyl ecgonine - a strong stimulant
- Ketamine - dissociative anesthetic
- Heroin/Morphine - powerful opiates
- Opioids - a class of narcotics, typically semi-synthetic (e.g. Oxycodone and Hydromorphone) or completely synthetic (e.g. Meperidine)
- Phencyclidine - dissociative anesthetic, more commonly known by the acronym PCP or slang term angel dust
- Amphetamines - d-methamphetamine and d,l-amphetamine (speed)
- Ritalin - methylphenidate, a stimulant closely related to amphetamine, but often reported to have effects similar to that of cocaine when insufflated
- MDMA/ecstasy - 3,4-methylenedioxy-N-methylamphetamine - an entactogen commonly associated with and used at raves
- Zolpidem (Ambien) - (Ambien CR) - a sedative hypnotic that can have various hallucinogenic effects with certain people and/or at high doses
- Tobacco Snuff - contains nicotine, a mild, but extremely addictive stimulant
Various other drugs can be snorted so long as they are water soluble, though the substances listed are insufflated regularly.
Note: some psychoactive substances such as benzodiazepines (valium, oxazepam, clonazepam) are water soluble to a small degree (about 350ml/1000mg). Though this means they will be somewhat effective when insufflated, they will not be as readily absorbed into the mucous membrane as highly soluble substances such as amphetamines and opiates. Even despite this, many benzodiazepines are still occasionally insufflated.
# Liturgical use
In religious and magical use, insufflation and exsufflation (they are frequently indistinguishable and are considered together here) are ritual acts of blowing, breathing, hissing, or puffing that signify variously expulsion or renunciation of evil or of the devil (the evil one), or infilling or blessing with good (especially, in religious use, with the Spirit or grace of God).
In historical Christian practice, such blowing appears most prominently in the liturgy, and is connected almost exclusively with baptism and other ceremonies of Christian initiation, achieving its greatest popularity during periods in which such ceremonies were given a heavily prophylactic or exorcistic significance, and were viewed as essential to the defeat of the devil or to the removal of the taint of original sin.[1]
An act or acts of ritual blowing occur in the liturgies of catechumenate and baptism from a very early period and flourished there, surviving into the modern Roman Catholic, Greek Orthodox, Maronite, and Coptic rites.[2] Catholic liturgy post Vatican-II (the so-called 'novus ordo' 1969) has largely done away with insufflation (except in a special rite for the consecration of chrism on Maundy Thursday),[3] and Protestant liturgies typically abandoned it very early on, but the Tridentine Catholic liturgy retained both an insufflation of the baptismal water and (like the present-day Orthodox and Maronite rites)[4] an exsufflation of the candidate for baptism, right up to the nineteen-sixties:
[THE INSUFFLATION] He breathes thrice upon the waters in the form of a cross, saying: Do You with Your mouth bless these pure waters: that besides their natural virtue of cleansing the body, they may also be effectual for purifying the soul.[5]
THE EXSUFFLATION. The priest breathes three times on the child in the form of a cross, saying: Go out of him...you unclean spirit and give place to the Holy Spirit, the Paraclete.[6]
## Insufflation vs. exsufflation
From an early period, too, as illustrated here, the act had broadly speaking two distinct but not always distinguishable meanings: it signified on the one hand the derisive repudiation or exorcism of the devil; and, on the other, purification and consecration by and inspiration with the Holy Spirit. The former is sometimes called "exsufflation" and the latter "insufflation" (i.e., "blowing out" and "blowing in") but the ancient and medieval texts (followed by modern scholarhip) only occasionally honor this distinction. For example, the texts use not only Latin "insufflare" ('blow in') and "exsufflare" ('blow out') (or their Greek or vernacular equivalents), but also the simplex "sufflare" ('blow'), "halare" ('breathe'), "inspirare," "exspirare," etc.[7]
Typical is the 8th-century Libellus de mysterio baptismatis of Magnus of Sens, one of a number of responses to a questionnaire about baptism circulated by Charlemagne. In discussing insufflation as a means of exorcising catechumens, he unhesitatingly combines under that heading a variety of mostly exsufflation-like functions: "Those who are to be baptised are insufflated by the priest of God, so that the Prince of Sinners [i.e. the devil] may be put to flight from out of them, and that entry for the Lord Christ might be prepared, and that by his insufflation they might be made worthy to receive the Holy Spirit."[8] This double role appears as early as Cyril of Jerusalem's 4th-century Mystagogic Catacheses: as Yarnold says, "Cyril attributes both negative and positive effects [to insufflation].... The rite of breathing on the [baptismal] candidate has the negative effect of blowing away the devil (exsufflation) and the positive effect of breathing in grace (insufflation)."[9]
## History
### Early period
What might neutrally be called "sufflation" is found in some of the earliest liturgies dealing with the protracted process of initiation known as the "catechumenate," which saw its heyday in the fourth and fifth centuries. The earliest extant liturgical use is possibly that of the Apostolic Tradition attributed to Hippolytus of Rome, perhaps from the fourth century, and therefore contemporary with Cyril in the east:[10]
Those who are to be baptized should ... be gathered in one place.... And [the bishop] should lay his hands on them and exorcize all alien spirits, that they may flee out of them and ever return into them. And when he has finished exorcizing them, he shall breathe on their faces; and when he has signed their foreheads, ears, and noses, he shall raise them up.[11]
### Distribution, geographical and functional
The practice entered the baptismal liturgy proper only as the catechumenate, rendered vestigial by the growth of routine infant baptism, was absorbed into the rite of baptism. Both exsufflation and insufflation are well established by the time of Augustine and in later centuries are found widely. By the Western high Middle Ages of the twelfth century, sufflation was geographically widespread, and had been applied not only to sufflating catechumens and baptizands,[12] but also to exorcism of readmitted heretics;[13] to admission of pagans to the catechumenate;[14] to renunciation of the devil on the part of catechumens;[15] to consecration and/or exorcism of the baptismal font and water;[16] to consecration or exorcism of ashes;[17] and to the consecration of the chrism or holy oil.[18]
### Medieval period
Most of these variations persist in one branch or another of the hybrid Romano-Germanic rite that can be traced from fifth-century Rome through the western Middle Ages to the Council of Trent, and beyond that into modern (Tridentine) Roman Catholicism. As the 'national' rites such as the Ambrosian tradition in northern Italy and the Spanish Mozarabic rite faded away or were absorbed into international practice, it was this hybrid Roman-Gallican standard that came to dominate western Christendom, including Anglo-Saxon and medieval England, from the time of Charlemagne, and partly through his doing, through the high and late Middle Ages and into the modern period. Roman practice around the year 500 is reflected in a letter by a somewhat mysterious "John the Deacon" to a correspondent named Senarius. The letter discusses the exsufflation of catechumens at length.[19] The Stowe Missal, Irish in origin but largely Gallican in form, contains a prebaptismal sufflation of unclear significance.[20] The other Gallican rites are largely devoid of sufflation, though the so-called Missale Gothicum contains a triple exsufflation of baptismal water,[21] and a prebaptismal insufflation of catechumens is found in the hybrid Bobbio Missal[22] and the tenth-century Fulda sacramentary, alongside the more common baptismal exsufflation.[23] The eleventh-century North-Italian baptismal ritual in the Ambrosian Library MS. T.27.Sup. makes heavy use of the practice, requiring both insufflation and triple exsufflation of the baptismal candidates in modum crucis, and insufflation of the font as well.[24] The "Hadrianum" version of the Gregorian Sacramentary, sent to Charlemagne from Rome and augmented probably by Benedict of Aniane, contains an insufflation of the baptismal font,[25] as does the mid-tenth-century Ordo Romanus L,[26] the basis of the later Roman pontifical. Ordo Romanus L also contains a triple exsufflation of the candidates for baptism, immediately preceding the baptism itself.[27]
Most of the numerous Carolingian expositions of baptism treat sufflation to some extent.[28] One anonymous ninth-century catechism is unusual in distinguishing explicitly between the exsufflation of catechumens and the insufflation of baptismal water,[29] but most of the tracts and florilegia, when they treat both, do so without referring one to the other; most confine themselves to exsufflation and are usually content to quote extracts from authorities, especially Isidore and Alcuin.[30] Particularly popular was Isidore's lapidary remark in the Etymologies to the effect that it is not the human being ("God's creature") that is exsufflated, but the prince of sinners to whom that person is subjected by being born in sin,[31] a remark that echoed Augustine's arguments against the Pelagians to the effect that it was not the human infant (God's image) that was attacked in sufflation, but the infant's possessor, the devil. Particularly influential was Alcuin's brief treatment of the subject, the so-called "Primo paganus," which in turn depended heavily on John the Deacon.[32] The "Primo paganus" formed the basis of Charlemagne's famous circular questionnaire on baptism, part of his effort to harmonize liturgical practice across his empire; and many of the seventeen extant direct or indirect responses to the questionnaire are happy to echo Alcuin, making the process a little circular and the texts a little repetitious.[33] The burden of Alcuin's remarks, in fact, appears above in the quotation from the Libellus of Magnus of Sens, one of the respondents.[34] The questionnaire assumed that exsufflation of or on the part of the candidate for baptism was generally practiced--it merely asks what meaning is attached to the practice: "concerning the renunciation of Satan and all his works and pomps, what is the renunciation? and what are the works of the devil and his pomps? why is he breathed upon? ('cur exsufflatur?') why is he exorcised?"[35] Most of the respondents answered that it was so that, with the devil sent fleeing, the entry of the Holy Spirit might be prepared for.
On the other side of the Channel, in Anglo-Saxon England, sufflation is mentioned in Bishop Wulfstan's collection of Carolingian baptismal expositions, the Incipit de baptisma, and in the two vernacular (Old English) homilies based on it, the Quando volueris and the Sermo de baptismate. The Incipit de baptisma reads: "On his face let the sign of the cross be made by exsufflation, so that, the devil having been put to flight, entry for our Lord Christ might be prepared."[36] Among English liturgical texts proper, the tenth-century Leofric Pontifical (and Sacramentary) dictates an insufflation of baptizands, a triple insufflation of the baptismal water, and an 'exhalation' of holy oil.[37] In the eleventh century, the Salisbury Pontifical (BL Cotton MS Tiberius C.1) and the Pontifical of Thomas of Canterbury require insufflation of the font; the Missal of Robert of Jumièges (Canterbury) has an erased rubric where it may have done likewise, as well as having an illegible rubric where it probably directed the exsufflation of catechumens, and retaining the old ordo ad caticuminum ex pagano faciendum, complete with its sufflation ceremony; and an Engish Ordo Romanus (BL Cotton MS Vitellius E.12) contains a triple exsufflation of baptizands.[38] Various twelfth-century texts include signing and triple exsufflation of the holy oil (Sarum), triple exsufflation of baptizands (the Ely, Magdalene, and Winton Pontificals), and insufflation of the font "in modum crucis" (Ely and Magdalene, followed by most later texts).[39] Such are the origins of the late medieval sufflation rites, which were in turn retained in regularized form in post-Tridentine Catholicism.
### Sufflation in Protestantism
Sufflation did not last long in any of the churches arising from the magisterial or radical reformations. Martin Luther's first attempt at a baptismal liturgy, the Tauffbuchlin (Taufbüchlein) of 1523 (reprinted 1524 and 1525) did retain many ceremonies from the late Medieval ritual as it was known in Germany, including a triple exsufflation of baptizands. But in an epilogue, Luther listed this ceremony among the adiaphora--i.e., the inessential features that added nothing to the meaning of the sacrament:
The least importance attaches to these external things, namely breathing under the eyes, signing with the cross, placing salt in the mouth, putting spittle and clay on the ears and nose, anointing with oil the breast and shoulders, and signing the top of the head with chrism, vesting in the christening robe, and giving a burning candle into the hand, and whatever else ... men have added to embellish baptism. For ... they are not the kind of devices that the devil shuns.[40]
The Lutheran Strassbourg Taufbüchlein of June 1524, composed by Diobald Schwartz, assistant to Cathedral preacher Martin Zell, on the basis of the medieval rite used in Strassbourg combined with elements of Luther's 1523 rite, also retains baptismal exsufflation;[41] so does Andreas Osiander in Nuremberg, in the same year.[42]
But thereafter the practice vanished from Lutheranism, and indeed from Protestantism generally. Luther's revised edition of 1526 and its successors omit exsufflation altogether, as do the Luther-influenced early reformed rites of England (Thomas Cranmer's Prayer Book of 1549) and Sweden (the Manual of Olavus Petri), despite the former's conservative basis in the medieval Sarum ritual and the latter's strong interest in exorcism as an essential part of the baptismal ritual.[43]
Similarly in the Swiss Reformation (the Zwinglian/Reformed tradition), only the very earliest rites retain sufflation, namely the ceremony published by Leo Jud, pastor of St. Peter's in Zurich, in the same year (1523) as Luther's first baptismal manual.[44]
### Sufflation in Protestant-Roman Catholic debate
Though sufflation does not appear in Protestant practice, it definitely appears in Protestant polemic, where it is usually treated as an un-Scriptural and superstitious (i.e., in the Protestant view, a typically Roman Catholic) practice, and even one reeking of enchantment or witchcraft. It appears as such, for example in the work of Henry More (the 'Cambridge Platonist') on evil. His argument essentially reverses that of Augustine. Augustine had said to the Pelagians (to paraphrase): "you see that we exorcize and exsufflate infants before baptising them; therefore they must be tainted with sin and possessed by the devil since birth." More replies, in effect, "Infants cannot be devil-possessed sinners; therefore, ceremonial exorcism and exsufflation is presumptuous, frightening, and ridiculous," in a word "the most gross and fundamental Superstitions, that look like Magick or Sorcery":
The conjuring the Devil also out of the Infant that is to be baptized would seem a frightful thing to the Infant himself, if he understood in what an ill plight the Priest supposes him, while he makes three Exsufflations upon his face, and uses an Exorcistical form for the ejecting of the foul Fiend.... And it is much if something might not appear affrightful to the Women in this approaching darkness. For though it be a gay thing for the Priest to be thought to have so much power over the Stygian Fiend, as to Exorcize him out of the Infant; yet it may be a sad consideration with some melancholick women laden with Superstition, to think they are never brought to bed, but they are delivered of a Devil and Child at once.[45]
Sufflation appears in Roman Catholic anti-Protestant polemic, as well. The relative antiquity of the practice, and its strong endorsement by the Protestants' favorite Father, Saint Augustine, made it a natural element in Catholic arguments that contrasted the Protestant with the ancient and Apostolic church. A true church, according to Roman Catholic apologists, would be:
A Church that held the exorcismes exsufflations and renunciations, which are made in baptisme, for sacred Ceremonies, and of Apostolicall tradition.... A Church which in the Ceremonies of baptisme, vsed oyle, salte, waxe, lights, exorcismes, the signe of the Crose, the word Epheta and other thinges that accompanie it; to testifie ... by exorcismes, that baptisme puts vs out of the Diuells possession.[46]
This was argued on the grounds that some of these ceremonies were demonstrably ancient, and all of them might be.
Sundry Ceremonies vsed in baptisme, and other Sacraments, as Exorcismes, Exsufflations, Christening, and the like mentioned by S. Augustine and by diuers other ancient Fathers ..., these being practised by the Primitiue Church (which is graunted to be the true Church) and compared to the customes of Protestants, and vs, in our Churches, will easily disclose, which of the two, they or we, do more imitate, or impugne the true Church of antiquity.[47]
To which a Protestant reply was that sufflation was not ancient enough, and could not be proved to be apostolic:
It was plain then there was no clear Tradition in the Question, possibly there might be a custome in some Churches postnate to the times of the Apostles, but nothing that was obligatory, no Tradition Apostolicall. But this was a suppletory device ready at hand when ever they needed it; and S. Austin confuted the Pelagians, in the Question of Original sinne, by the custome of exorcisme and insufflation, which S. Austin said came from the Apostles by Tradition, which yet was then, and is now so impossible to be prov'd, that he that shall affirm it, shall gaine only the reputation of a bold man and a confident.[48]
Sufflation was judged by Protestant critics to be irrational, mysterious, and obscure, an increasingly important factor by the close of the seventeenth century and the dawn of the Enlightenment:
Mystery prevail'd very little in the first Hundred or Century of Years after Christ; but in the second and third, it began to establish it self by Ceremonies. To Baptism were then added the tasting of Milk and Honey, Anointing, the Sign of the Cross, a white Garment, &c. ... But in later times there was no end of Lights, Exorcisms, Exsufflations, and many other Extravagancies of Jewish, or Heathen Original ... for there is nothing like these in the Writings of the Apostles, but they are all plainly contain'd in the Books of the Gentiles, and was the Substance of their Worship.[49]
It was said to be a human invention, imposed by the arbitrary whim of a tyrannical prelate against the primitive Gospel freedom of the church:
[Some bishop] ... taking it into his head that there ought to be a trine-immersion in baptism; another the signation of the cross; another an unction with oil; another milk and honey, and imposition of hands immediately after it; another insufflation or breathing upon the person's face to exorcise the Devil... Thus, I say, that inundation of abominable corruptions, which at present overwhelms both the Greek and Romish Churches, gradually came in at this very breech which you are now zealously maintaining, namely, the Bishop's Power to decree rites and ceremonies in the Church.[50]
To all of which, Roman Catholic apologists replied that insufflation was not only ancient and Apostolic, but had been practiced by Christ himself:
"When he [Christ] had said this he breathed upon them, and said to them, Receive the Holy Ghost...." When the Pastors of our Church use the Insufflation or Breathing upon any, for the like mystical Signification, you cry aloud, Superstition, Superstition, an apish mimical action, &c.[51]
### Prospects
Though liturgical sufflation is almost gone, at least from the Western churches, its revival is not inconceivable. Liturgical renewal movements always seem to look to the 'classic' catechumenate of the fourth and fifth centuries for inspiration. Insufflation has indeed been re-introduced into the Catholic "new catechumenate." But many ceremonies dating from that or the medieval period have been re-imported even into Protestant rites during the last couple of decades. Perhaps even more likely is a revival in the context of the growth of the African and Asian church, in which locally and culturally meaningful ceremonies have often revolutionized practice, and in which, often, the exorcistic function of baptism has enjoyed a new vitality. For example, a pure insufflation is apparently practiced in the Independent Church of the Philippines,[52] and Spinks mentions a pre-baptismal ceremony used by the Christian Workers' Fellowship of Sri Lanka, in which the candidates are struck with a cane and their faces are breathed upon.[53] It is not clear whether the latter represents a revival of historical sufflation, or a wholly new ceremony derived from local custom.
## Significance and associations
There were apparently at least three kinds of association that particularly influenced how liturgical sufflation came to be understood: Biblical antecedents; liturgical setting; and extra-liturgical (cultural) analogs.
### Biblical antecedents
Three Biblical passages recur repeatedly with reference to insufflation properly speaking, all of them referring to some kind of life-giving divine breath. The first and most commonly cited is Genesis 2:7 (echoed by Wisdom 15:11 and Job 33:4), in which God first creates man and then breathes into him the breath of life, in order to give him (as the passage was later interpreted) a human soul.[54] The second passage, Ezekiel 37:9, reinterprets the Genesis passage prophetically, in foreseeing God resurrecting the dead bones of exiled Israel by means of his life-giving breath.[55] And finally, in John 20:22, Christ is represented as conveying the Paraclete to his disciples, and so initiating the commissioned church, by breathing on them, here too, very possibly, with implicit reference to the original creation.[56] The two passages were certainly so connected in later Christian exegesis: the same breath that created man re-created him.
[Insufflation] signifies, To blow into, Gen. 2. 7. This sheweth mans soul not to be of the earth, as his body was, but of nothing, by the insufflation of God, and so differing from the spirit of beasts, Eccl. 3. 21. This word is used also, when Christ to make men new creatures, inspired his Apostles with the holy Ghost, Joh. 20. 21.[57]
The Lord God, saith the Text, formed man of the dust of the ground, and breathed into his Nostrils the breath of life, and man became a living Soul. His Body made of Earth, but his Soul the Breath of God.... We must not understand it grosly; for so Breath is not attributable unto God, who is a simple and perfect Spirit; but ... as a figurative expression of God's communicating unto Man that inward Principle, whereby he lives and acts, not only in common with, but in a degree above other Animals.... The Learned P. Fagius takes notice of three things in the Text of Moses, which do conclude the Immortality of the Soul of Man. I. Insufflatio illa Dei: This Inspiration from God spoken of: For he that breaths into another, contributes unto him aliquid de suo somewhat of his own: And therefore, saith he, when our B. Saviour would communicate his Spirit to his Disciples, he did it with Insufflation, breathing on them, thereby to signifie, se Divinum & de suo quiddam illis contribuere [i.e., that he was himself divine and was infusing something of his own into them].[58]
The associations with creation, rebirth, initiation, and revivification created by these interconnected passages of Scripture suited insufflation for a role in baptism as it has been most commonly regarded: as figuring the waters of creation (over which the Spirit brooded); as figuring the womb of rebirth; and as figuring (in Saint Paul's metaphor) the tomb, into which the Christian joins Christ in descending, and from which the Christian likewise joins Christ in ascending, dead to the old life but made alive again in Christ.[59]
There are also Biblical antecedents for exsufflation, properly speaking, that is, exorcistic blowing, especially the numerous Old Testament passages in which "the breath of God" is the vehicle or symbol not of life but of death and destruction--an expression of the wrath of God: "by the breath of God they perish / and by the blast of his anger they are consumed" (Job 4:9, RSV).[60] The same power is attributed metaphorically to Christ, "The lawless one will be revealed, and the Lord Jesus will slay him with the breath of his mouth" (2 Thessalonians 2:8, RSV). Even less obvious passages could be associated with liturgical exsufflation. Jesse of Amiens, for example, interprets Psalm 34 (Vulg. 35):5 as descriptive of the fate of exsufflated devils: ""Let them be like chaff before the wind, with the angel of the Lord driving them on!"[61] And the apocryphal Acts of Thomas describes a baptismal ceremony which, though it does not explicitly contain a breathing ceremony, appears to imply one, "Let the gift come by which, breathing upon thine enemies, thou didst make them draw back and fall headlong, and let it dwell in this oil, over which we name thy holy name."[62]
God's breath can be fiery, consuming all it touches: "I will blow upon you with the fire of my wrath" (Ezekiel 21:31, RSV).[63] Some of the interpretations of exsufflation may reflect this. Cyril of Jerusalem, for example, when he discusses exsufflation in his catechetical sermons, interprets the liturgical practice in terms of fire:
The breathing of the saints and the invocation of the name of God, like fiercest flame, scorch and drive out evil spirits.[64]
Fire remains a theme in later liturgical exorcisms, for devils, as Nicetas is reported to have said, "are purged by exorcisms as by fire":[65] "we come against you, devil, with spiritual words and fiery speech; we ignite the hiding places in which you are concealed."[66]
### Liturgical context
More importantly, perhaps, fire is physically and symbolically associated with sufflation because of the traditional placement of baptism within the Paschal vigil--a setting heavy with symbolism of light and fire: the blessing of the Paschal candle, the lighting of the "new fire," and the singing of the exultet and the lumen christi. The intimate connection between divine breath and divine fire appears in its most visually arresting form during the benediction of the font, in which, according to most orders, the candle is dipped in the font while the priest declares the power of the Holy Spirit to have descended into the water: the sufflation of the font in most cases directly precedes or accompanies the immersion of the candle.[67] Their close association can again be illustrated from Wulfstan's baptismal homilies:
By the breath that the priest breathes into the font when he blesses it, the devil is straightway driven out from it. And when the priest dips the consecrated candle in the water, then that water forthwith becomes imbued with the Holy Ghost.[68]
Similar considerations bind sufflation closely to imagery of light and darkness, specifically of the movement of the baptizand from the kingdom of darkness into the kingdom of light (a very common theme), and to the sign of the cross (a very common action), among others that could be mentioned. On light-dark imagery, for example, consider John the Deacon:
The exsufflated person is exorcised so that ... having been delivered from the power of darkness, he might be translated into the kingdom ... of God.[69]
So also Augustine ("The church exsufflates and exorcises [infants] that the power of darkness might be cast out from them"[70]), and Isidore ("The power of the devil is ... exsufflated in them, so that ... being delivered from the power of darkness, [they] might be translated unto the kingdom of their Lord"[71]).
And as regards signation (the sign of the cross), in Western texts from as early as the Gelasian Sacramentary, the one gesture almost always precedes (or precedes and follows) the other,[72] and their significance is often complementary if not identical. In Raban Maur's discussion of the baptismal liturgy, for example, the exsufflation is said to expel the devil, the signing to keep him from coming back.[73] The two signs are frequently combined, the blowing done in the form of a cross, e.g. in the Syrian rite described by James of Edessa,[74] in the modern Coptic rite,[75] in the late ninth-century Ordo Romanus XXXI,[76] in Wulfstan's Anglo-Saxon homilies and their Continental sources,[77] in the tenth-century Ambrosian rites for catechumen and font,[78] in the eleventh-century North Italian catechumenal rites,[79] in the twelfth- through fifteenth-century English pontificals,[80] in the Sarum Missal,[81] and in the thirteenth-century Roman pontifical.[82]
# Extra-liturgical (hagiographic and magical) use
## Patristic period
There are hints in some of the Church Fathers that Christians had a habit of breathing (or hissing) at evil spirits as a recognized act of revulsion or repulsion, even apart from the ceremonies of the church. Tertullian is perhaps the best witness. He seems to be talking about an extra-liturgical casting out of demons by means of exsufflation and signing when he declares that the pagan gods, "by our touch and by our breath" are driven from the bodies of men, and are thus "carried away by the thought and vision of the fire [of judgment]."[83] He is talking about an ordinary gesture of aversion when he asks a Christian incense-dealer (regarded as hypocritical because he sells incense for the pagan altars), "with what mouth, I ask, will he spit and blow before the fuming altars for which he himself provided? with what constancy will he [thus] exorcise his foster children?"[84] And his remarks to his wife about the dangers of mixed marriage suggest that exsufflation was a distinctively Christian practice: "[If you marry again, to a non-Christian,] shall you escape notice when you sign your bed or your body? when you blow away some impurity? When even by night you rise to pray?"[85]
If such a custom did exist, it would clarify certain remarks by other Fathers, which might otherwise seem merely metaphorical. Eusebius, for example, says of the saints that they were men "who though they only breathed and spoke, were able to scatter the counsels of evil demons."[86] Irenaeus describes the right response to Gnostic doctrine as "reviling" (καταφυσησαντασ; literally 'exsufflantes').[87] Cyril of Jerusalem, speaking of resisting temptation, not of baptism, says that "the mere breathing of the exorcist becomes as a fire to that unseen foe."[88] And Augustine's remarks about blowing on images of the emperor suggest that the significance of the gesture was well enough established to be actionable: "Of the great crime of lese majesty ... is he held guilty, according to the laws of this world, who blows upon an image ... of the emperor."[89] Even as late as Bede, we may suspect that "exsufflate" in the sense of "revile" or "cast off" may be a living metaphor.[90]
## Hagiography
The extremely influential Life of Saint Martin by Sulpicius Severus, seems to have set in motion a hagiographic tradition in which saints cast out demons or repel tempting devils by blowing at them.[91] Of Saint Pachomius, for example, it is said that "defending his brow with the sign of the cross, he blew upon [the demon] and immediately he fled...; blowing upon him, he said, 'depart from me, devil.'"[92] And of Saint Goswin that "a demon stood before Saint Goswin saying 'surely you see that I am Christ...' and...therefore Saint Goswin exsufflated vigorously, saying 'depart foe...,' and immediately...the devil vanished."[93] Saint Justina is reported to have similarly unmasked a series of increasingly subtle and powerful demons, finally melting the prince of demons himself: "blowing upon the devil, she immediately melted him like wax and...felt herself freed from all temptation."[94] And Saint Felix is said to have destroyed idols and uprooted (pagan) sacred trees by like means.[95]
The breath of the saints was credited with healing, as well as exorcistic, powers from an early period. Gregory of Nyssa says of Gregory Thaumaturgus ('Gregory the magician') that he needed to resort to "no finicking and laborious" magic, but "there sufficed, for both the casting out of demons and the healing of bodily ailments, the breath of his mouth."[96] Similar powers are attributed to the Irish saints: kindling lamps, curing dumbness.[97] This theme, too, persists in later hagiographic and quasi-hagiographic texts, appearing, for example in the Estoire del saint graal as the agency by which a madman is miraculously restored. Among English texts, Felix's Life of Saint Guthlac relates that in order to give relief to a boy afflicted by madness, he "washed him in the water of the sacred font and, breathing into his face the breath of healing [or 'spirit of salvation'], drove away from him all the power of the evil spirit,"[98] illustrating the difficulty of distinguishing healing from exorcism in an era in which madness was attributed to demonic possession. The miracle that Bishop John performed, according to Bede, on behalf of Herebald, is another example, since it involved a sufflation that was seemingly exorcistic, catechetical, and curative simultaneously.[99]
## Magic and folk medicine
It is difficult to draw a clear line between religious and magical uses of exsufflation: between legends of saints and legends of sorcerers, between magical and liturgical ceremonies, or indeed between beliefs and fictions. The religious use may in fact derive at least in part from magic, and certainly many folkloristic and magical uses (as commonly) were heavily influenced by liturgical ritual. Tertullian's remarks to his wife about Christian practices recognize this fact, since they conclude, "will you not seem to be doing magic?" i.e., in the eyes of a non-believer.[100]
Celsus (according to Origen) reports the use of exufflation by Egyptian magicians.[101] Plotinus seems to attack its use by Roman ones.[102] One of Lucian's tall tales mentions a Chaldean pest-control sorcerer who causes toads and snakes to vanish by blowing on them.[103]
But it is possible to regard Jesus himself as a magician in at least one popular event in the apocryphal infancy gospels, in which he is portrayed as using sufflation in order simultaneously to heal his brother of a snakebite and kill the snake;[104] also in a rarer episode in which Jesus raises a boy from the dead by breathing on him.[105] Christianized healing magic, if that is what it is, appears also in Syria, where ceremonial breathing became formalized as part of the rite of visitation of the sick. Ephraem Syrus advises that "if medicine fails you when you are sick, the 'visitors' will help, will pray for health, and one of them will breathe in your mouth, the other will sign you [with the sign of the cross]."[106]
Whether it be originally Christian or originally pagan, similar methods of healing have been reported persisting till modern times: in Westphalia, the healing of a wound by triple signing and triple cruciform sufflation, or by exsufflation accompanied by a rhyming charm; and in Holland the alleviation of toothache by similar means.[107] According to Drechsler, "Illnesses were blown away by the breath. If a child had bumped himself, one would blow three times on the place and it would 'fly away.'"[108] Burns, and conditions that in some fashion resemble burns, such as fevers, boils, sore throats and rashes, are naturally the most common objects of blowing among modern folk-remedies,[109] for example the Shetland cure that requires blowing on a burn three times while reciting the charm "Here come I to cure a burnt sore. / If the dead knew what the living endure, / The burnt sore would burn no more."[110] But everything from jaundice, convulsions, and colic to bad luck and evil spells can apparently be alleviated by a bit of blowing.[111] Wolters points out that exorcistic blowing was still (in 1935) found in the custom of blowing over bread that is about to be eaten.[112] Moreover,
A Syrian blows over his child to avert the evil eye. Some stillblow three times over a strange spoon before using it, and in Alaska the medicineman blows into the nose and mouth of a patient to drive out the daemon of disease.[113]
Finally, in one American example of superstition clearly derived from liturgical use, it is said that if at the baptism of a baby one turns at the door and blows three times, one can successfully prevent the devil from ever coming between the baby and the altar.[114] | https://www.wikidoc.org/index.php/Insufflate | |
fe8712128ae76a72ac421587c3404aad82e1d48d | wikidoc | Insulin pump | Insulin pump
An insulin pump is a medical device used for administering insulin in the treatment of diabetes mellitus, also known as continuous subcutaneous insulin infusion therapy.
The device includes:
- the pump itself (including controls, processing module, and batteries)
- a disposable reservoir for insulin (inside the pump)
- a disposable infusion set, including a cannula for subcutaneuos insertion (under the skin) and a tubing system to interface the insulin reservoir to the cannula.
An insulin pump is an alternative to multiple daily injections of insulin by insulin syringe or an insulin pen and allows for intensive insulin therapy when used in conjunction with blood glucose monitoring and carb counting.
# Setting up
In order to use an insulin pump, the reservoir must first be filled with insulin. Some pumps are designed to be used with prefilled cartridges that are replaced when empty. Most, however, must be filled with insulin of the user's choice (usually Novolog, Humalog, or Apidra). Setting up includes:
- Opening a new (sterile) empty pump reservoir of the manufacturer's design;
- Withdrawing the plunger;
- Inserting the needle into a vial of insulin;
- Injecting the air from the reservoir into the vial to prevent a vacuum forming in the vial as insulin is withdrawn;
- Drawing insulin into the reservoir with the plunger, and then removing the needle;
- Squirting out any air bubbles from the reservoir, and then removing the plunger;
- Attaching the reservoir to the infusion set tubing;
- Installing the assembly into the pump and priming the tubing (pushing insulin and any air bubbles through the tubing) - it is essential that this is done with the pump disconnected from the body to prevent accidental insulin delivery;
- Attaching to the infusion "site" (and priming the cannula if a new set has been inserted).
# Dosing
An insulin pump allows the replacement of slow-acting insulin for basal needs with a continuous infusion of rapid-acting insulin.
The insulin pump delivers a single type of fast-acting insulin in two ways:
- a bolus dose that is pumped to cover food eaten or to correct a high blood glucose level.
- a basal dose that is pumped continuously at an adjustable basal rate to deliver insulin needed between meals and at night.
## Bolus Shaping
An insulin pump user has the ability to influence the profile of the rapid-acting insulin by shaping the bolus. While each user must experiment with bolus shapes to determine what is best for any given food, they can improve control of blood sugar by adapting the bolus shape to their needs.
A standard bolus is an infusion of insulin pumped completely at the onset of the bolus. It is most similar to an injection. By pumping with a "spike" shape, the expected action is the fastest possible bolus for that type of insulin. The standard bolus is most appropriate when eating high carb low protein low fat meals because it will return blood sugar to normal levels quickly.
An extended bolus is a slow infusion of insulin spread out over time. By pumping with a "square wave" shape, the bolus avoids a high initial dose of insulin that may enter the blood and cause low blood sugar before digestion can facilitate sugar entering the blood. The extended bolus also extends the action of insulin well beyond that of the insulin alone. The extended bolus is appropriate when covering high fat high protein meals such as steak, which will be raising blood sugar for many hours past the onset of the bolus. The extended bolus is also useful for those with slow digestion (such as with gastroparesis or Coeliac disease).
A combination bolus is the combination of a standard bolus spike with an extended bolus square wave. This shape provides a large dose of insulin up front, and then also extends the tail of the insulin action. The combination bolus is appropriate for high carb high fat meals such as pizza, pasta with heavy cream sauce, and chocolate cake.
A super bolus is a method of increasing the spike of the standard bolus. Since the action of the bolus insulin in the blood stream will extend for several hours, the basal insulin could be stopped or reduced during this time. This facilitates the "borrowing" of the basal insulin and including it into the bolus spike to deliver the same total insulin with faster action than can be achieved with spike and basal rate together. The super bolus is useful for certain foods (like sugary breakfast cereals) which cause a large post-prandial peak of blood sugar. It attacks the blood sugar peak with the fastest delivery of insulin that can be practically achieved by pumping.
## Bolus Timing
Since the pump user is responsible to manually start a bolus, this provides an opportunity for the user to pre-bolus to improve upon the insulin pump's capability to prevent post-prandial hypoglycemia. A pre-bolus is simply a bolus of insulin given before it is actually needed to cover carbohydrates eaten.
There are two situations where a pre-bolus is helpful:
- A pre-bolus of insulin will mitigate a spike in blood sugar that results from eating high glycemic foods. Infused insulin analogs such as NovoLog and Humalog typically begin to impact blood sugar levels 15 or 20 minutes after infusion. As a result, easily digested sugars often hit the bloodstream much faster than infused insulin intended to cover them, and the blood sugar level spikes upward as a result. If the bolus were to be infused 20 minutes before eating, then the pre-bolused insulin will be hitting the bloodstream simultaneously with the digested sugars to control the magnitude of the spike.
- A pre-bolus of insulin can also combine a meal bolus and a correction bolus when the blood sugar is above the target range before a meal. The timing of the bolus is a controllable variable to bring down the blood sugar level before eating again causes it to increase.
Both the blood sugar level as well as the type of food eaten has an impact on the ideal time to pre-bolus with the pump. New insulin analogs are "fast" enough to be given right before a meal, but this is ideal only when starting with a blood glucose value that is within range and the food to be eaten is of moderate glycemic index. If a time period of 15 or 20 minutes is considered to be a "time increment," then the pre-bolus time can be estimated by multiple increments. The time period is increased by one increment when blood glucose in high or when glycemic index is high. Time increments can also double, cancel, or go negative as the situation calls for as shown in the table below. Note however that an extended bolus allowed from the newer insulin pumps may be more convenient than a delayed standard bolus for a situation with low BG and low glycemic food to slow down the action of insulin.
## Basal Rate Patterns
The pattern for delivering basal insulin throughout the day can also be customized with a pattern to suit the pump user.
- A reduction of basal at night to prevent low blood sugar in infants and toddlers.
- An increase of basal at night to counteract high blood sugar levels due to growth hormone in teenagers.
- A pre-dawn increase to prevent high blood sugar due to the dawn effect in adults and teens.
- In a proactive plan before regularly scheduled exercise times such as morning gym for elementary school children or after school basketball practice for high school children.
## Basal Rate Determination
Basal insulin requirements will vary between individuals and periods of the day. The basal rate for a particular time period is determined by fasting while periodically evaluating the blood sugar level. Neither food nor bolus insulin must be taken for 4 hours prior to or during the evaluation period. If the blood sugar level changes dramatically during evaluation, then the basal rate can be adjusted to increase or decrease insulin delivery to keep the blood sugar level approximately steady.
For instance, to determine an individual's morning basal requirement, they must skip breakfast. On waking, they would test their blood glucose level periodically until lunch. Changes in blood glucose level are compensated with adjustments in the morning basal rate. The process is repeated over several days, varying the fasting period, until a 24-hour basal profile has been built up which keeps fasting blood sugar levels relatively steady. Once the basal rate is matched to the fasting basal insulin need, the pump user will then gain the flexibility to skip or postpone meals such as sleeping late on the weekends or working overtime on a weekday.
Many factors can change insulin requirements and require an adjustment to the basal rate:
- continued beta cell death following diagnosis of type 1 diabetes (honeymoon period)
- growth spurts particularly during puberty
- weight gain or loss
- any drug treatment that affects insulin sensitivity (e.g. corticosteroids)
- eating, sleeping, or exercise routine changes
- whenever the control over hyperglycemia is degrading
- and according to the seasons.
A pump user should be educated by their diabetes care professional about basal rate determination before beginning pump therapy.
## Temporary Basal Rates
Since the basal insulin is provided as a rapid-acting insulin, the basal insulin can be immediately increased or decreased as needed with a temporary basal rate. Examples when this is helpful include:
- During a long car drive, when more insulin is needed due to inactivity.
- During and after spontaneous exercise or sports activities, when the body needs less insulin.
- During illness or stress, when basal demand increases due to insulin resistance.
- When blood ketones are present, when additional insulin is needed.
- During menses, when additional basal insulin is needed.
# Advantages of pumping insulin
- The use of rapid-acting insulin for basal needs offers relative freedom from a structured meal and exercise regimen previously needed to control blood sugar with slow-acting insulin.
- Many pumpers feel that bolusing insulin from a pump is more convenient and discreet than injection.
- Insulin pumps also make it possible to deliver more precise amounts of insulin than can be injected using a syringe. This supports tighter control over blood sugar and Hemoglobin A1c levels, reducing the chance of long-term complications associated with diabetes. This is predicted to result in a long term cost savings relative to multiple daily injections.
# Disadvantages of pumping insulin
- Insulin pumps, cartridges, and infusion sets are more expensive than syringes used for insulin injection.
- Since the insulin pump needs to be worn most of the time, pump users need strategies to participate in activities that may damage the pump, such as rough sports and activities in the water. Some users may find that wearing the pump all the time (together with the infusion set tubing) is uncomfortable or unwieldy.
- An episode of diabetic ketoacidosis may occur if the pump user does not receive sufficient fast acting insulin for many hours. This can happen if the pump battery is discharged, if the insulin resevoir runs empty, the tubing becomes loose and insulin leaks rather than being injected, or if the cannula becomes bent or kinked in the body, preventing delivery. Therefore pump users typically monitor their blood sugars more frequently to evaluate the effectiveness of insulin delivery.
# Acceptability
Use of insulin pumps is increasing throughout the world because:
- it provides an easier means to deliver multiple insulin injections for those using intensive insulin therapy. This is especially true for children and others who are uncomfortable with needles (although the pump user still has to inject an infusion set every few days, and poke fingers for blood glucose tests many times a day).
- acceptance among doctors and insurance companies due to the benefits contributing to reducing the incidence of long-term complications. It's also interesting to note that because of differences in health insurance and public funding, the US has about 150,000 pump users. In the UK, NICE have now ruled that if a Type 1 diabetic patient's doctor agrees that they should be using an insulin pump, they should apply to the NHS and they will fund it, this does not apply to Type 2 diabetes . Therefore numbers are increasing but are still less than the USA, there are around 1100 pump users in the UK by comparison.
- improvements in blood glucose monitoring. New meters require smaller drops of blood, and the corresponding lancet poke in the fingers is smaller and less painful. These meters also support alternate site testing for the most routine tests for practically painless testing. This compensates for the need for pump users to test blood sugar more frequently.
- techniques learned to adapt their pump use to sports, exercise, and water sports. Expert help is becoming common in user groups and books. The pump can be effectively combined with partial basal insulin from the pump and partial basal insulin from a long-acting insulin such as Lantus and Levemir. This is becoming known as the Untethered Regimen.
# Recent developments
New insulin pumps are becoming "smart" as new features are added to their design. These simplify the tasks involved in delivering an insulin bolus.
- insulin on board: Based on the time and quantity of the last bolus, the pump software keeps track of the insulin remaining in the bloodstream and displays it on the screen. This supports the process of performing a new bolus before the effects of the last bolus are complete, and thereby helps prevent the user from overcompensating for high blood sugar with unnecessary correction boluses.
- bolus calculators: Pump software helps by calculating the dose for the next insulin bolus. The user enters the grams of carbohydrates to be consumed, and the bolus "wizard" calculates the number of units of insulin needed. It adjusts for the most recent blood glucose level and the insulin on board, and then suggests the best insulin dose to the user to approve and bolus.
- custom alarms: The pump can monitor for activities during specific times of day and then alarm the user if an expected activity did not occur. Examples include a missed lunch bolus, a missed blood glucose test at 10am, a new blood glucose test 15 minutes after a low blood glucose test, etc. The alarms can be customized to support each user.
- touch bolus: For persons with visual impairments, this button on the pump can be used to bolus for insulin without using the display. This works with a system of beeps to confirm the bolus parameters to the pump user.
- interface to personal computers: New pumps interface to personal computers for managing and documenting pumps delivery programs and to upload data from the pump. This simplifies record keeping and can be interfaced with diabetes management software.
- integration with blood glucose meters: Blood glucose data can be manually entered into the pump for supporting the bolus wizard for calculation of the next insulin bolus. Some pumps are supporting an interface from the insulin pump to a blood glucose meter.
The Cozmo pump works with the CozMonitor (using Freestyle test strips) attached to the back of the pump. The pump receives glucose readings from this attached meter via infrared (IR).
The Medtronic Diabetes Minimed Paradigm series of insulin pumps allow for radio frequency (RF) communication. This enables the pump to receive data from a BD or Ascentia blood glucose meter. The RF link also supports a continuous blood glucose sensor known as the "Guardian" which provides the blood glucose value every 5 minutes for display right on the pump screen.
The Insulet Omnipod has a separate electronic display with a built-in meter that uses Freestyle test strips.
- The Cozmo pump works with the CozMonitor (using Freestyle test strips) attached to the back of the pump. The pump receives glucose readings from this attached meter via infrared (IR).
- The Medtronic Diabetes Minimed Paradigm series of insulin pumps allow for radio frequency (RF) communication. This enables the pump to receive data from a BD or Ascentia blood glucose meter. The RF link also supports a continuous blood glucose sensor known as the "Guardian" which provides the blood glucose value every 5 minutes for display right on the pump screen.
- The Insulet Omnipod has a separate electronic display with a built-in meter that uses Freestyle test strips.
- An RF remote control: allows a discrete bolus when the pump is concealed or inaccessible.
- tubeless pod: The Omnipod pump can be attached directly to the skin by its infusion set, eliminating the tube from the pump.
# Current insulin pump manufacturers
# Future developments
- When insulin pump technology is combined with a continuous blood glucose monitoring system, the technology seems promising for real-time control of the blood sugar level. Currently there are no mature algorithms to automatically control the insulin delivery based on feedback of the blood glucose level. When the loop is closed, the system may function as an artificial pancreas.
- Insulin pumps are being used for infusing pramlintide (brand name Symlin, or synthetic amylin) with insulin for improved post-prandial glycemic control compared to insulin alone.
- An insulin pump that can be surgically implanted inside the body will be available soon by Medtronic. It is the approximate size of a hockey puck, and communicates via RF to an external control. It is refilled by injection through the skin, and holds approximately 2 weeks of insulin.
- A Wristop may soon function as a remote control for an insulin pump.
# Bibliography
- Chapter 6 of "Understanding Diabetes" a.k.a. "The Pink Panther Book" by H. Peter Chase
- Pumping Insulin, by John Walsh and Ruth Roberts
- Smart Pumping, by Howard Wolpert
- Think Like A Pancreas, by Gary Scheiner
- "Strike The Spike! Strategies for Combatting After-Meal Highs:" an instructional presentation by Gary Scheiner | Insulin pump
An insulin pump is a medical device used for administering insulin in the treatment of diabetes mellitus, also known as continuous subcutaneous insulin infusion therapy.
The device includes:
- the pump itself (including controls, processing module, and batteries)
- a disposable reservoir for insulin (inside the pump)
- a disposable infusion set, including a cannula for subcutaneuos insertion (under the skin) and a tubing system to interface the insulin reservoir to the cannula.
An insulin pump is an alternative to multiple daily injections of insulin by insulin syringe or an insulin pen and allows for intensive insulin therapy when used in conjunction with blood glucose monitoring and carb counting.
# Setting up
In order to use an insulin pump, the reservoir must first be filled with insulin. Some pumps are designed to be used with prefilled cartridges that are replaced when empty. Most, however, must be filled with insulin of the user's choice (usually Novolog, Humalog, or Apidra). Setting up includes:
- Opening a new (sterile) empty pump reservoir of the manufacturer's design;
- Withdrawing the plunger;
- Inserting the needle into a vial of insulin;
- Injecting the air from the reservoir into the vial to prevent a vacuum forming in the vial as insulin is withdrawn;
- Drawing insulin into the reservoir with the plunger, and then removing the needle;
- Squirting out any air bubbles from the reservoir, and then removing the plunger;
- Attaching the reservoir to the infusion set tubing;
- Installing the assembly into the pump and priming the tubing (pushing insulin and any air bubbles through the tubing) - it is essential that this is done with the pump disconnected from the body to prevent accidental insulin delivery;
- Attaching to the infusion "site" (and priming the cannula if a new set has been inserted).
# Dosing
An insulin pump allows the replacement of slow-acting insulin for basal needs with a continuous infusion of rapid-acting insulin.
The insulin pump delivers a single type of fast-acting insulin in two ways:
- a bolus dose that is pumped to cover food eaten or to correct a high blood glucose level.
- a basal dose that is pumped continuously at an adjustable basal rate to deliver insulin needed between meals and at night.
## Bolus Shaping
An insulin pump user has the ability to influence the profile of the rapid-acting insulin by shaping the bolus. While each user must experiment with bolus shapes to determine what is best for any given food, they can improve control of blood sugar by adapting the bolus shape to their needs.
A standard bolus is an infusion of insulin pumped completely at the onset of the bolus. It is most similar to an injection. By pumping with a "spike" shape, the expected action is the fastest possible bolus for that type of insulin. The standard bolus is most appropriate when eating high carb low protein low fat meals because it will return blood sugar to normal levels quickly.
An extended bolus is a slow infusion of insulin spread out over time. By pumping with a "square wave" shape, the bolus avoids a high initial dose of insulin that may enter the blood and cause low blood sugar before digestion can facilitate sugar entering the blood. The extended bolus also extends the action of insulin well beyond that of the insulin alone. The extended bolus is appropriate when covering high fat high protein meals such as steak, which will be raising blood sugar for many hours past the onset of the bolus. The extended bolus is also useful for those with slow digestion (such as with gastroparesis or Coeliac disease).
A combination bolus is the combination of a standard bolus spike with an extended bolus square wave. This shape provides a large dose of insulin up front, and then also extends the tail of the insulin action. The combination bolus is appropriate for high carb high fat meals such as pizza, pasta with heavy cream sauce, and chocolate cake.
A super bolus is a method of increasing the spike of the standard bolus. Since the action of the bolus insulin in the blood stream will extend for several hours, the basal insulin could be stopped or reduced during this time. This facilitates the "borrowing" of the basal insulin and including it into the bolus spike to deliver the same total insulin with faster action than can be achieved with spike and basal rate together. The super bolus is useful for certain foods (like sugary breakfast cereals) which cause a large post-prandial peak of blood sugar. It attacks the blood sugar peak with the fastest delivery of insulin that can be practically achieved by pumping.
## Bolus Timing
Since the pump user is responsible to manually start a bolus, this provides an opportunity for the user to pre-bolus to improve upon the insulin pump's capability to prevent post-prandial hypoglycemia. A pre-bolus is simply a bolus of insulin given before it is actually needed to cover carbohydrates eaten.
There are two situations where a pre-bolus is helpful:
- A pre-bolus of insulin will mitigate a spike in blood sugar that results from eating high glycemic foods. Infused insulin analogs such as NovoLog and Humalog typically begin to impact blood sugar levels 15 or 20 minutes after infusion. As a result, easily digested sugars often hit the bloodstream much faster than infused insulin intended to cover them, and the blood sugar level spikes upward as a result. If the bolus were to be infused 20 minutes before eating, then the pre-bolused insulin will be hitting the bloodstream simultaneously with the digested sugars to control the magnitude of the spike.
- A pre-bolus of insulin can also combine a meal bolus and a correction bolus when the blood sugar is above the target range before a meal. The timing of the bolus is a controllable variable to bring down the blood sugar level before eating again causes it to increase.
Both the blood sugar level as well as the type of food eaten has an impact on the ideal time to pre-bolus with the pump. New insulin analogs are "fast" enough to be given right before a meal, but this is ideal only when starting with a blood glucose value that is within range and the food to be eaten is of moderate glycemic index. If a time period of 15 or 20 minutes is considered to be a "time increment," then the pre-bolus time can be estimated by multiple increments. The time period is increased by one increment when blood glucose in high or when glycemic index is high. Time increments can also double, cancel, or go negative as the situation calls for as shown in the table below. Note however that an extended bolus allowed from the newer insulin pumps may be more convenient than a delayed standard bolus for a situation with low BG and low glycemic food to slow down the action of insulin.
## Basal Rate Patterns
The pattern for delivering basal insulin throughout the day can also be customized with a pattern to suit the pump user.
- A reduction of basal at night to prevent low blood sugar in infants and toddlers.
- An increase of basal at night to counteract high blood sugar levels due to growth hormone in teenagers.
- A pre-dawn increase to prevent high blood sugar due to the dawn effect in adults and teens.
- In a proactive plan before regularly scheduled exercise times such as morning gym for elementary school children or after school basketball practice for high school children.
## Basal Rate Determination
Basal insulin requirements will vary between individuals and periods of the day. The basal rate for a particular time period is determined by fasting while periodically evaluating the blood sugar level. Neither food nor bolus insulin must be taken for 4 hours prior to or during the evaluation period. If the blood sugar level changes dramatically during evaluation, then the basal rate can be adjusted to increase or decrease insulin delivery to keep the blood sugar level approximately steady.
For instance, to determine an individual's morning basal requirement, they must skip breakfast. On waking, they would test their blood glucose level periodically until lunch. Changes in blood glucose level are compensated with adjustments in the morning basal rate. The process is repeated over several days, varying the fasting period, until a 24-hour basal profile has been built up which keeps fasting blood sugar levels relatively steady. Once the basal rate is matched to the fasting basal insulin need, the pump user will then gain the flexibility to skip or postpone meals such as sleeping late on the weekends or working overtime on a weekday.
Many factors can change insulin requirements and require an adjustment to the basal rate:
- continued beta cell death following diagnosis of type 1 diabetes (honeymoon period)
- growth spurts particularly during puberty
- weight gain or loss
- any drug treatment that affects insulin sensitivity (e.g. corticosteroids)
- eating, sleeping, or exercise routine changes
- whenever the control over hyperglycemia is degrading
- and according to the seasons.
A pump user should be educated by their diabetes care professional about basal rate determination before beginning pump therapy.
## Temporary Basal Rates
Since the basal insulin is provided as a rapid-acting insulin, the basal insulin can be immediately increased or decreased as needed with a temporary basal rate. Examples when this is helpful include:
- During a long car drive, when more insulin is needed due to inactivity.
- During and after spontaneous exercise or sports activities, when the body needs less insulin.
- During illness or stress, when basal demand increases due to insulin resistance.
- When blood ketones are present, when additional insulin is needed.
- During menses, when additional basal insulin is needed.
# Advantages of pumping insulin
- The use of rapid-acting insulin for basal needs offers relative freedom from a structured meal and exercise regimen previously needed to control blood sugar with slow-acting insulin.
- Many pumpers feel that bolusing insulin from a pump is more convenient and discreet than injection.
- Insulin pumps also make it possible to deliver more precise amounts of insulin than can be injected using a syringe. This supports tighter control over blood sugar and Hemoglobin A1c levels, reducing the chance of long-term complications associated with diabetes. This is predicted to result in a long term cost savings relative to multiple daily injections.[1]
# Disadvantages of pumping insulin
- Insulin pumps, cartridges, and infusion sets are more expensive than syringes used for insulin injection.
- Since the insulin pump needs to be worn most of the time, pump users need strategies to participate in activities that may damage the pump, such as rough sports and activities in the water. Some users may find that wearing the pump all the time (together with the infusion set tubing) is uncomfortable or unwieldy.
- An episode of diabetic ketoacidosis may occur if the pump user does not receive sufficient fast acting insulin for many hours. This can happen if the pump battery is discharged, if the insulin resevoir runs empty, the tubing becomes loose and insulin leaks rather than being injected, or if the cannula becomes bent or kinked in the body, preventing delivery. Therefore pump users typically monitor their blood sugars more frequently to evaluate the effectiveness of insulin delivery.
# Acceptability
Use of insulin pumps is increasing throughout the world because:
- it provides an easier means to deliver multiple insulin injections for those using intensive insulin therapy. This is especially true for children and others who are uncomfortable with needles (although the pump user still has to inject an infusion set every few days, and poke fingers for blood glucose tests many times a day).
- acceptance among doctors and insurance companies due to the benefits contributing to reducing the incidence of long-term complications. It's also interesting to note that because of differences in health insurance and public funding, the US has about 150,000 pump users. In the UK, NICE have now ruled that if a Type 1 diabetic patient's doctor agrees that they should be using an insulin pump, they should apply to the NHS and they will fund it, this does not apply to Type 2 diabetes http://www.nice.org.uk/guidance/TA57. Therefore numbers are increasing but are still less than the USA, there are around 1100 pump users in the UK by comparison.
- improvements in blood glucose monitoring. New meters require smaller drops of blood, and the corresponding lancet poke in the fingers is smaller and less painful. These meters also support alternate site testing for the most routine tests for practically painless testing. This compensates for the need for pump users to test blood sugar more frequently.
- techniques learned to adapt their pump use to sports, exercise, and water sports. Expert help is becoming common in user groups and books. The pump can be effectively combined with partial basal insulin from the pump and partial basal insulin from a long-acting insulin such as Lantus and Levemir. This is becoming known as the Untethered Regimen.
# Recent developments
New insulin pumps are becoming "smart" as new features are added to their design. These simplify the tasks involved in delivering an insulin bolus.
- insulin on board: Based on the time and quantity of the last bolus, the pump software keeps track of the insulin remaining in the bloodstream and displays it on the screen. This supports the process of performing a new bolus before the effects of the last bolus are complete, and thereby helps prevent the user from overcompensating for high blood sugar with unnecessary correction boluses.
- bolus calculators: Pump software helps by calculating the dose for the next insulin bolus. The user enters the grams of carbohydrates to be consumed, and the bolus "wizard" calculates the number of units of insulin needed. It adjusts for the most recent blood glucose level and the insulin on board, and then suggests the best insulin dose to the user to approve and bolus.
- custom alarms: The pump can monitor for activities during specific times of day and then alarm the user if an expected activity did not occur. Examples include a missed lunch bolus, a missed blood glucose test at 10am, a new blood glucose test 15 minutes after a low blood glucose test, etc. The alarms can be customized to support each user.
- touch bolus: For persons with visual impairments, this button on the pump can be used to bolus for insulin without using the display. This works with a system of beeps to confirm the bolus parameters to the pump user.
- interface to personal computers: New pumps interface to personal computers for managing and documenting pumps delivery programs and to upload data from the pump. This simplifies record keeping and can be interfaced with diabetes management software.
- integration with blood glucose meters: Blood glucose data can be manually entered into the pump for supporting the bolus wizard for calculation of the next insulin bolus. Some pumps are supporting an interface from the insulin pump to a blood glucose meter.
The Cozmo pump works with the CozMonitor (using Freestyle test strips) attached to the back of the pump. The pump receives glucose readings from this attached meter via infrared (IR).
The Medtronic Diabetes Minimed Paradigm series of insulin pumps allow for radio frequency (RF) communication. This enables the pump to receive data from a BD or Ascentia blood glucose meter. The RF link also supports a continuous blood glucose sensor known as the "Guardian" which provides the blood glucose value every 5 minutes for display right on the pump screen.
The Insulet Omnipod has a separate electronic display with a built-in meter that uses Freestyle test strips.
- The Cozmo pump works with the CozMonitor (using Freestyle test strips) attached to the back of the pump. The pump receives glucose readings from this attached meter via infrared (IR).
- The Medtronic Diabetes Minimed Paradigm series of insulin pumps allow for radio frequency (RF) communication. This enables the pump to receive data from a BD or Ascentia blood glucose meter. The RF link also supports a continuous blood glucose sensor known as the "Guardian" which provides the blood glucose value every 5 minutes for display right on the pump screen.
- The Insulet Omnipod has a separate electronic display with a built-in meter that uses Freestyle test strips.
- An RF remote control: allows a discrete bolus when the pump is concealed or inaccessible.
- tubeless pod: The Omnipod pump can be attached directly to the skin by its infusion set, eliminating the tube from the pump.
# Current insulin pump manufacturers
- http://www.animascorp.com/
- http://www.medtronicdiabetes.com/
- http://www.disetronic-usa.com/
- http://www.cozmore.com/
- http://www.niprodiabetes.com/home.html
- http://www.myomnipod.com/
# Future developments
- When insulin pump technology is combined with a continuous blood glucose monitoring system, the technology seems promising for real-time control of the blood sugar level. Currently there are no mature algorithms to automatically control the insulin delivery based on feedback of the blood glucose level. When the loop is closed, the system may function as an artificial pancreas.
- Insulin pumps are being used for infusing pramlintide (brand name Symlin, or synthetic amylin) with insulin for improved post-prandial glycemic control compared to insulin alone.
- An insulin pump that can be surgically implanted inside the body will be available soon by Medtronic. It is the approximate size of a hockey puck, and communicates via RF to an external control. It is refilled by injection through the skin, and holds approximately 2 weeks of insulin.
- A Wristop may soon function as a remote control for an insulin pump.
# Bibliography
- Chapter 6 of "Understanding Diabetes" a.k.a. "The Pink Panther Book" by H. Peter Chase
- Pumping Insulin, by John Walsh and Ruth Roberts
- Smart Pumping, by Howard Wolpert
- Think Like A Pancreas, by Gary Scheiner
- "Strike The Spike! Strategies for Combatting After-Meal Highs:" an instructional presentation by Gary Scheiner
# External links
- American Diabetes Association guide to insulin pumps
- A pump users' support group for adults
- A pump users' support group for kids
- National Diabetes Information Clearinghouse
cs:Inzulínová pumpa
de:Insulinpumpe
he:משאבת אינסולין
nl:Insulinepomp
no:Insulinpumpe
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Insulin_pump | |
1e9655754de2dadfd763ae47aebd82708c7b8f13 | wikidoc | Lateral horn | Lateral horn
# Overview
In the thoracic region, the postero-lateral part of the anterior column projects lateralward as a triangular field, which is named the lateral column (lateral cornu, lateral horn).
# Nerve Cells in the Lateral Column
These form a column (the intermedioloateral cell column) which is best marked where the lateral gray column is differentiated, viz., in the thoracic region; but it can be traced throughout the entire length of the medulla spinalis in the form of groups of small cells which are situated in the anterior part of the formatio reticularis. The intermediolateral cell column exists at vertebral levels T1 - L2 and mediates the entire sympathetic innervation of the body. Preganglionic, myelinated GVA fibers from viscera course through prevertebral and paravertebral (sympathetic) ganglia, white rami and dorsal roots to synapse with cells of the intermediolateral cell column. These cells then give rise to preganglionic GVE fibers which will pass through ventral spinal roots, white rami, and into paravertebral ganglia where some will synapse, thus sending unmyelinated, postganglionic fibers through gray rami and into peripheral nerves. Those fibers that do not synapse in the paravertebral ganglia will eventually synapse at prevertebral ganglia near target viscera. Postganglionic neurons in the prevertebral ganglia send postganglionic fibers to target tissues.
In the upper part of the cervical region and lower part of the medulla oblongata as well as in the third and fourth sacral segments this column is again differentiated.
In the medulla it is known as the lateral nucleus.
The cells of this column are fusiform or star-shaped, and of a medium size: the axons of some of them pass into the anterior nerve roots, by which they are carried to the sympathetic nerves: they constitute the white rami and are sympathetic or visceral efferent fibers; they are also known as preganglionic fibers of the sympathetic system; the axons of others pass into the anterior and lateral funiculi, where they become longitudinal. | Lateral horn
Template:Infobox Anatomy
# Overview
In the thoracic region, the postero-lateral part of the anterior column projects lateralward as a triangular field, which is named the lateral column (lateral cornu, lateral horn).
# Nerve Cells in the Lateral Column
These form a column (the intermedioloateral cell column) which is best marked where the lateral gray column is differentiated, viz., in the thoracic region; but it can be traced throughout the entire length of the medulla spinalis in the form of groups of small cells which are situated in the anterior part of the formatio reticularis. The intermediolateral cell column exists at vertebral levels T1 - L2 and mediates the entire sympathetic innervation of the body. Preganglionic, myelinated GVA fibers from viscera course through prevertebral and paravertebral (sympathetic) ganglia, white rami and dorsal roots to synapse with cells of the intermediolateral cell column. These cells then give rise to preganglionic GVE fibers which will pass through ventral spinal roots, white rami, and into paravertebral ganglia where some will synapse, thus sending unmyelinated, postganglionic fibers through gray rami and into peripheral nerves. Those fibers that do not synapse in the paravertebral ganglia will eventually synapse at prevertebral ganglia near target viscera. Postganglionic neurons in the prevertebral ganglia send postganglionic fibers to target tissues.
In the upper part of the cervical region and lower part of the medulla oblongata as well as in the third and fourth sacral segments this column is again differentiated.
In the medulla it is known as the lateral nucleus.
The cells of this column are fusiform or star-shaped, and of a medium size: the axons of some of them pass into the anterior nerve roots, by which they are carried to the sympathetic nerves: they constitute the white rami and are sympathetic or visceral efferent fibers; they are also known as preganglionic fibers of the sympathetic system; the axons of others pass into the anterior and lateral funiculi, where they become longitudinal.
Template:Gray's
Template:Spinal cord
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Intermediolateral_cell_column | |
8c9818dc088fc929e8782dc200d93c2ad75c84c6 | wikidoc | Invagination | Invagination
Invagination means to fold inward or to sheath. In biology, this can refer to a number of processes.
(1) Invagination is the morphogenetic processes by which an embryo takes form, and is the initial step of gastrulation, the massive reorganization of the embryo from a simple spherical ball of cells, the blastula, into a multi-layered organism, with differentiated germ layers: endoderm, mesoderm, and ectoderm. More localized invaginations also occur later in embryonic development, to form coelom, etc.
(2) Invagination is the formation of a cleavage furrow during cytokinesis in animal cells.
(3) Invagination in some bacteria (also called a mesosome) is a tightly-folded region of the cell membrane containing all the membrane-bound proteins required for respiration and photosynthesis. It can also be associated with the nucleoid.
(4) The inner membrane of a mitochondrion invaginates to form cristae, thus providing a much greater surface area to accommodate the protein complexes and other participants that produce ATP.
In development biology, dosal part of cells can inergrate adjacent cells into invagination. No matter what cell it is.
de:Invagination | Invagination
Invagination means to fold inward or to sheath. In biology, this can refer to a number of processes.
(1) Invagination is the morphogenetic processes by which an embryo takes form, and is the initial step of gastrulation, the massive reorganization of the embryo from a simple spherical ball of cells, the blastula, into a multi-layered organism, with differentiated germ layers: endoderm, mesoderm, and ectoderm. More localized invaginations also occur later in embryonic development, to form coelom, etc.
(2) Invagination is the formation of a cleavage furrow during cytokinesis in animal cells.
(3) Invagination in some bacteria (also called a mesosome) is a tightly-folded region of the cell membrane containing all the membrane-bound proteins required for respiration and photosynthesis. It can also be associated with the nucleoid.
(4) The inner membrane of a mitochondrion invaginates to form cristae, thus providing a much greater surface area to accommodate the protein complexes and other participants that produce ATP.
In development biology, dosal part of cells can inergrate adjacent cells into invagination. No matter what cell it is.
de:Invagination
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Invaginated | |
3c83e1ecba5ed9031ede90a5c5a23539b68c1498 | wikidoc | Iodine value | Iodine value
The iodine value (or "iodine adsorption value" or "iodine number") in chemistry is the mass of iodine in grams that is consumed by 100 grams of a chemical substance. An iodine solution is yellow/brown in color and any chemical group in the substance that reacts with iodine will make the color disappear at a precise concentration. The amount of iodine solution thus required to keep the solution yellow/brown is a measure of the amount of iodine sensitive reactive groups.
One application of the iodine number is the determination of saturation of fatty acids as double bonds in fatty acids also react with iodine compounds. The higher the iodine number, the more unsaturated fatty acid bonds are present in a fat. In a typical procedure the acid is treated with an excess of the Hanus solution which is a solution of iodobromine (BrI). Unreacted iodobromine is reacted with potassium iodide which converts it to iodine. The iodine concentration is then determined by titration with sodium thiosulfate.
Standard methods for analysis are for example ASTM D1959-97 and DIN 53241.
For a simple analysis, 0.2 grams of the fat is mixed with 20cm3 Wij's solution and 10cm3 1,1,1-trichloroethane. It is then left in the dark for 30mins. Next, 15cm3 of 10% potassium iodide solution and 10cm3 of deionised water is added. This is then titrated against 0.1M sodium thiosulphate (VI) solution.
1cm3 of 0.1M sodium thiosulphate solution = 0.01269g of iodine. The difference between a control titration and the titration with the fat present multiplied by this factor gives the mass of iodine absorbed by the oil. | Iodine value
The iodine value (or "iodine adsorption value" or "iodine number") in chemistry is the mass of iodine in grams that is consumed by 100 grams of a chemical substance. An iodine solution is yellow/brown in color and any chemical group in the substance that reacts with iodine will make the color disappear at a precise concentration. The amount of iodine solution thus required to keep the solution yellow/brown is a measure of the amount of iodine sensitive reactive groups.
One application of the iodine number is the determination of saturation of fatty acids as double bonds in fatty acids also react with iodine compounds. The higher the iodine number, the more unsaturated fatty acid bonds are present in a fat. [1] In a typical procedure the acid is treated with an excess of the Hanus solution which is a solution of iodobromine (BrI). Unreacted iodobromine is reacted with potassium iodide which converts it to iodine. The iodine concentration is then determined by titration with sodium thiosulfate.
Standard methods for analysis are for example ASTM D1959-97 and DIN 53241.
For a simple analysis, 0.2 grams of the fat is mixed with 20cm3 Wij's solution and 10cm3 1,1,1-trichloroethane. It is then left in the dark for 30mins. Next, 15cm3 of 10% potassium iodide solution and 10cm3 of deionised water is added. This is then titrated against 0.1M sodium thiosulphate (VI) solution.
1cm3 of 0.1M sodium thiosulphate solution = 0.01269g of iodine. The difference between a control titration and the titration with the fat present multiplied by this factor gives the mass of iodine absorbed by the oil. | https://www.wikidoc.org/index.php/Iodine_number | |
03c7e6710e246986b3cbb7b6f9c6cb9ff228b7e2 | wikidoc | Ionic liquid | Ionic liquid
# Overview
An ionic liquid is a liquid that contains essentially only ions. Some ionic liquids, such as ethylammonium nitrate are in a dynamic equilibrium where at any time more than 99.99% of the liquid is made up of ionic rather than molecular species. In the broad sense, the term includes all molten salts, for instance, sodium chloride at temperatures higher than 800 °C. Today, however, the term "ionic liquid" is commonly used for salts whose melting point is relatively low (below 100 °C). In particular, the salts that are liquid at room temperature are called room-temperature ionic liquids, or RTILs. There also exist mixtures of substances which have low melting points, called Deep eutectic solvent, or DES, that have many similarities with ionic liquids.
# History
The date of discovery, as well as discoverer, of the "first" ionic liquid is disputed. Ethanolammonium nitrate (m.p. 52-55 °C) was reported in 1888 by Gabriel. However, one of the earlier known truly room temperature ionic liquids was + - (m.p. 12 °C), the synthesis of which was published in 1914. Much later, series of ionic liquids based on mixtures of 1,3-dialkylimidazolium or 1-alkylpyridinium halides and trihalogenoaluminates, initially developed for use as electrolytes, were to follow.
An important property of the imidazolium halogenoaluminate salts was that they were tuneable – viscosity, melting point and the acidity of the melt could be adjusted by changing the alkyl substituents and the ratio of imidazolium or pyridinium halide to halogenoaluminate.
A major drawback was their moisture sensitivity and, though to a somewhat lesser extent, their acidity/basicity, the latter which can sometimes be used to an advantage. In 1992, Wilkes and Zawarotko reported the preparation of ionic liquids with alternative, 'neutral', weakly coordinating anions such as hexafluorophosphate (-) and tetrafluoroborate ()-, allowing a much wider range of applications for ionic liquids. It was not until recently that a class of new, air- and moisture stable, neutral ionic liquids, was available that the field attracted significant interest from the wider scientific community.
More recently, people have been moving away from - and - since they are highly toxic, and towards new anions such as bistriflimide - or even away from halogenated compounds completely. Moves towards less toxic cations have also been growing, with compounds like ammonium salts (such as choline) being just as flexible a scaffold as imidazole.
# Characteristics
Ionic liquids are electrically conductive and have extremely low vapor pressure. (Their noticeable odours are likely due to impurities.) Their other properties are diverse. Many have low combustibility, excellent thermal stability, a wide liquid range, and favorable solvating properties for diverse compounds. Many classes of chemical reactions, such as Diels-Alder reactions and Friedel-Crafts reactions, can be performed using ionic liquids as solvents. Recent work has shown that ionic liquids can serve as solvents for biocatalysis . The miscibility of ionic liquids with water or organic solvents varies with sidechain lengths on the cation and with choice of anion. They can be functionalized to act as acids, bases or ligands, and have been used as precursor salts in the preparation of stable carbenes. Because of their distinctive properties, ionic liquids are attracting increasing attention in many fields, including organic chemistry, electrochemistry, catalysis, physical chemistry, and engineering; see for instance magnetic ionic liquid.
Despite their extremely low vapor pressures, some ionic liquids can be distilled under vacuum conditions at temperatures near 300 °C. Some ionic liquids (such as 1-butyl-3-methylimidazolium nitrate) generate flammable gases on thermal decomposition. Thermal stability and melting point depend on the components of the liquid. Thermal stability of various RTILs are available. The thermal stability of a task-specific ionic liquid, protonated betaine bis(trifluoromethanesulfonyl)imide is of about 534 K and N-Butyl-N-Methyl pyrrolidinium bis(trifluoromethanesulfonyl)imide was thermally stable up to 640 K
The solubility of different species in imidazolium ionic liquids depends mainly on polarity and hydrogen bonding ability. Simple aliphatic compounds are generally only sparingly soluble in ionic liquids, whereas olefins show somewhat greater solubility, and aldehydes can be completely miscible. This can be exploited in biphasic catalysis, such as hydrogenation and hydrocarbonylation processes, allowing for relatively easy separation of products and/or unreacted substrate(s). Gas solubility follows the same trend, with carbon dioxide gas showing exceptional solubility in many ionic liquids, carbon monoxide being less soluble in ionic liquids than in many popular organic solvents, and hydrogen being only slightly soluble (similar to the solubility in water) and probably varying relatively little between the more popular ionic liquids. (Different analytical techniques have yielded somewhat different absolute solubility values.)
# Room temperature ionic liquids
Room temperature ionic liquids consist of bulky and asymmetric organic cations such as 1-alkyl-3-methylimidazolium, 1-alkylpyridinium, N-methyl-N-alkylpyrrolidinium and ammonium ions. A wide range of anions is employed, from simple halides, which generally inflect high melting points, to inorganic anions such as tetrafluoroborate and hexafluorophosphate and to large organic anions like bistriflimide, triflate or tosylate. There are also many interesting examples of uses of ionic liquids with simple non-halogenated organic anions such as formate, alkylsulfate, alkylphosphate or glycolate. As an example, the melting point of 1-butyl-3-methylimidazolium tetrafluoroborate or with an imidazole skeleton is about -80 °C, and it is a colorless liquid with high viscosity at room temperature.
It has been pointed out that in many synthetic processes using transition metal catalyst, metal nanoparticles play an important role as the actual catalyst or as a catalyst reservoir. It also been shown that ionic liquids (ILs) are an appealing medium for the formation and stabilization of catalytically active transition metal nanoparticles.
More importantly, ILs can be made that incorporate co-ordinating groups,, for example, with nitrile groups on either the cation or anion (CN-IL). In various C-C coupling reactions catalyzed by palladium catalyst, it has been found the palladium nanoparticles are better stabilized in CN-IL compared to non-functionalized ionic liquids; thus enhanced catalytic activity and recyclability are realized.
# Low temperature ionic liquids
Low temperature ionic liquids (below 130 kelvins) have been proposed as the fluid base for an extremely large diameter spinning liquid mirror telescope to be based on the earth's moon. Low temperature is advantageous in imaging long wave infrared light which is the form of light (extremely red-shifted) that arrives from the most distant parts of the visible universe. Such a liquid base would be covered by a thin metallic film that forms the reflective surface. A low volatility is important for use in the vacuum conditions present on the moon.
# Food science
Ionic liquids have been used in food science. Cl for instance is able to completely dissolve freeze dried banana pulp and the solution with an additional 15% DMSO lends itself to Carbon-13 NMR analysis. In this way the entire banana compositional makeup of starch, sucrose, glucose, and fructose can be monitored as a function of banana ripening.
# Applications
Nowadays ionic liquids find a number of industrial applications which vary greatly in character. A few of their industrial applications are briefly described below; more detailed information can be found in a recent review article.
## BASIL
The first major industrial application of ILs was the BASIL (Biphasic Acid Scavenging utilizing Ionic Liquids) process by BASF, in which a 1-alkylimidazole was used to scavenge the acid from an existing process. This then results in the formation of an IL which can easily be removed from the reaction mixture. But the easier removal of an unwanted side-product (as an IL rather than as a solid salt) is not the only advantage of the IL based process. By using an IL it was possible to increase the space/time yield of the reaction by a factor of 80,000. It should, however, be kept in mind that improvements of such scale are rare.
## Cellulose Processing
Occurring at a volume of some 700 billion tons, cellulose is the earth’s most widespread natural organic chemical and, thus, highly important as a bio-renewable resource. But even out of the 40 billion tons nature renews every year, only approx. 0.2 billion tons are used as feedstock for further processing. A more intensive exploitation of cellulose as a biorenewable feedstock has to date been prevented by the lack of a suitable solvent that can be used in chemical processes. Robin Rogers and co-workers at the University of Alabama have found that by means of ionic liquids, however, real solutions of cellulose can now be produced for the first time at technically useful concentrations . This new technology therefore opens up great potential for cellulose processing.
For example, making cellulosic fibers from so-called dissolving pulp currently involves the use, and subsequent disposal, of great volumes of various chemical auxiliaries, esp. carbon disulfide (CS2). Major volumes of waste water are also produced for process reasons and need to be disposed of. These processes can be greatly simplified by the use of ionic liquids, which serve as solvents and are nearly entirely recycled. The “Institut für Textilchemie und Chemiefasern” (ITCF) in Denkendorf and BASF are jointly investigating the properties of fibers spun from an ionic liquid solution of cellulose in a pilot plant setup.
## Eastman chemical’s DHF plant
Eastman operated an ionic liquid-based plant for the synthesis of 2,5-dihydrofuran from 1996 to 2004. However, the plant is now defunct because demand for the product has ceased.
## Dimersol - Difasol
The dimersol process is a traditional way to dimerise short chain alkenes into branched alkenes of higher molecular weight. Nobel laureate Yves Chauvin and Hélène Olivier-Bourbigou at IFP (France) have developed an ionic liquid-based add-on to this process called the Difasol process. However, while may be licensed it has as yet not been put into commercial practice.
## Petrochina
Petrochina have announced the implementation of an ionic liquid-based process called Ionikylation. This process, the alkylation of C4 olefins with iso-butane, is retrofitted into a 65,000 tonne per year alkylation plant, making it the biggest industrial application of ILs to date.
## Degussa paint additives
Ionic liquids can enhance the finish, appearance and drying properties of paints. Degussa are marketing such ILs under the name of TEGO Dispers. These products are also added to the Pliolite paint range.
## Air products - ILs as a transport medium for reactive gases
Air products make use of ILs as a medium to transport reactive gases in. Reactive gases such as trifluoroborane, phosphine or arsine, BF3, PH3 or AsH3, respectively, are stored in suitable ILs at sub-ambient pressure. This is a significant improvement over pressurised cylinders. The gases are easily withdrawn from the containers by applying a vacuum.
## Linde's IL 'piston'
Whereas Air Product’s Gasguard system relies on the solubility of some gases in ILs, Linde are exploiting other gases’ insolubility in ILs. As mentioned above, the solubility of Hydrogen in ILs is very low. Linde now make use of this insolubility by using a body of ionic liquid to compress Hydrogen in filling stations; and in so doing they reduced the number of moving parts from about 500 in a conventional piston pump engine down to 8.
## Nuclear industry
RTILs are extensively explored for various innovative applications in nuclear industry. It includes application of ionic liquid as extractant/diluent in solvent extraction systems, as alternate electrolyte media for the high temperature pyrochemical processing, etc. Fundamental studies on the extraction cum electrodeposition of fission products like uranium, palladium etc., from spent nuclear fuel using RTILs as extractants are reported. Reports on employing using Ionic liquids as non-aquoues electrolyte media for the recovery of uranium and useful fission products like palladium and rhodium from spent nuclear fuel are also available.Studies on the electrochemical behavior of uranium(VI) in ionic liquid, 1-butyl-3-methylimidazolium chloride and also the recovery of valuable fission products from tissue paper waste was studied in room temperature ionic liquids..
# Safety
Due to their non-volatility, effectively eliminating a major pathway for environmental release and contamination, ionic liquids have been considered as having a low impact on the environment and human health, and thus recognized as solvents for green chemistry. However, this is distinct from toxicity, and it remains to be seen how 'environmentally-friendly' ILs will be regarded once widely used by industry. Research into IL aquatic toxicity has shown them to be as toxic or more so than many current solvents already in use . A review paper on this aspect has been published in 2007. Available research also shows that mortality isn't necessarily the most important metric for measuring their impacts in aquatic environments, as sub-lethal concentrations have been shown to change organisms' life histories in meaningful ways. According to these researchers balancing between zero VOC emissions, and avoiding spills into waterways (via waste ponds/streams, etc.) should become a top priority. However, with the enormous diversity of substituents available to make useful ILs, it should be possible to design them with useful physical properties and less toxic chemical properties.
With regard to the safe disposal of ionic liquids, a 2007 paper has reported the use of ultrasound to degrade solutions of imidazolium-based ionic liquids with hydrogen peroxide and acetic acid to relatively innocuous compounds.
Despite their low vapor pressure many ionic liquids have also found to be combustible and therefore require careful handling . Brief exposure (5 to 7 seconds) to a flame torch will ignite these IL's and some of them are even completely consumed by combustion. | Ionic liquid
# Overview
An ionic liquid is a liquid that contains essentially only ions. Some ionic liquids, such as ethylammonium nitrate are in a dynamic equilibrium where at any time more than 99.99% of the liquid is made up of ionic rather than molecular species. In the broad sense, the term includes all molten salts, for instance, sodium chloride at temperatures higher than 800 °C. Today, however, the term "ionic liquid" is commonly used for salts whose melting point is relatively low (below 100 °C). In particular, the salts that are liquid at room temperature are called room-temperature ionic liquids, or RTILs. There also exist mixtures of substances which have low melting points, called Deep eutectic solvent, or DES, that have many similarities with ionic liquids.
# History
The date of discovery, as well as discoverer, of the "first" ionic liquid is disputed. Ethanolammonium nitrate (m.p. 52-55 °C) was reported in 1888 by Gabriel.[1] However, one of the earlier known truly room temperature ionic liquids was [EtNH3]+ [NO3]- (m.p. 12 °C), the synthesis of which was published in 1914.[2] Much later, series of ionic liquids based on mixtures of 1,3-dialkylimidazolium or 1-alkylpyridinium halides and trihalogenoaluminates, initially developed for use as electrolytes, were to follow.[3][4]
An important property of the imidazolium halogenoaluminate salts was that they were tuneable – viscosity, melting point and the acidity of the melt could be adjusted by changing the alkyl substituents and the ratio of imidazolium or pyridinium halide to halogenoaluminate.[5]
A major drawback was their moisture sensitivity and, though to a somewhat lesser extent, their acidity/basicity, the latter which can sometimes be used to an advantage. In 1992, Wilkes and Zawarotko reported the preparation of ionic liquids with alternative, 'neutral', weakly coordinating anions such as hexafluorophosphate ([PF6]-) and tetrafluoroborate ([BF4])-, allowing a much wider range of applications for ionic liquids.[6] It was not until recently that a class of new, air- and moisture stable, neutral ionic liquids, was available that the field attracted significant interest from the wider scientific community.
More recently, people have been moving away from [PF6]- and [BF4]- since they are highly toxic, and towards new anions such as bistriflimide [(CF3SO2)2N]- or even away from halogenated compounds completely. Moves towards less toxic cations have also been growing, with compounds like ammonium salts (such as choline) being just as flexible a scaffold as imidazole.
# Characteristics
Ionic liquids are electrically conductive and have extremely low vapor pressure. (Their noticeable odours are likely due to impurities.) Their other properties are diverse. Many have low combustibility, excellent thermal stability, a wide liquid range, and favorable solvating properties for diverse compounds. Many classes of chemical reactions, such as Diels-Alder reactions and Friedel-Crafts reactions, can be performed using ionic liquids as solvents. Recent work has shown that ionic liquids can serve as solvents for biocatalysis [7]. The miscibility of ionic liquids with water or organic solvents varies with sidechain lengths on the cation and with choice of anion. They can be functionalized to act as acids, bases or ligands, and have been used as precursor salts in the preparation of stable carbenes. Because of their distinctive properties, ionic liquids are attracting increasing attention in many fields, including organic chemistry, electrochemistry, catalysis, physical chemistry, and engineering; see for instance magnetic ionic liquid.
Despite their extremely low vapor pressures, some ionic liquids can be distilled under vacuum conditions at temperatures near 300 °C.[8] Some ionic liquids (such as 1-butyl-3-methylimidazolium nitrate) generate flammable gases on thermal decomposition. Thermal stability and melting point depend on the components of the liquid. Thermal stability of various RTILs are available. The thermal stability of a task-specific ionic liquid, protonated betaine bis(trifluoromethanesulfonyl)imide is of about 534 K and N-Butyl-N-Methyl pyrrolidinium bis(trifluoromethanesulfonyl)imide was thermally stable up to 640 K [9]
The solubility of different species in imidazolium ionic liquids depends mainly on polarity and hydrogen bonding ability. Simple aliphatic compounds are generally only sparingly soluble in ionic liquids, whereas olefins show somewhat greater solubility, and aldehydes can be completely miscible. This can be exploited in biphasic catalysis, such as hydrogenation and hydrocarbonylation processes, allowing for relatively easy separation of products and/or unreacted substrate(s). Gas solubility follows the same trend, with carbon dioxide gas showing exceptional solubility in many ionic liquids, carbon monoxide being less soluble in ionic liquids than in many popular organic solvents, and hydrogen being only slightly soluble (similar to the solubility in water) and probably varying relatively little between the more popular ionic liquids. (Different analytical techniques have yielded somewhat different absolute solubility values.)
# Room temperature ionic liquids
Room temperature ionic liquids consist of bulky and asymmetric organic cations such as 1-alkyl-3-methylimidazolium, 1-alkylpyridinium, N-methyl-N-alkylpyrrolidinium and ammonium ions. A wide range of anions is employed, from simple halides, which generally inflect high melting points, to inorganic anions such as tetrafluoroborate and hexafluorophosphate and to large organic anions like bistriflimide, triflate or tosylate. There are also many interesting examples of uses of ionic liquids with simple non-halogenated organic anions such as formate, alkylsulfate, alkylphosphate or glycolate. As an example, the melting point of 1-butyl-3-methylimidazolium tetrafluoroborate or [bmim][BF4] with an imidazole skeleton is about -80 °C, and it is a colorless liquid with high viscosity at room temperature.
It has been pointed out that in many synthetic processes using transition metal catalyst, metal nanoparticles play an important role as the actual catalyst or as a catalyst reservoir. It also been shown that ionic liquids (ILs) are an appealing medium for the formation and stabilization of catalytically active transition metal nanoparticles.
More importantly, ILs can be made that incorporate co-ordinating groups,[10], for example, with nitrile groups on either the cation or anion (CN-IL). In various C-C coupling reactions catalyzed by palladium catalyst, it has been found the palladium nanoparticles are better stabilized in CN-IL compared to non-functionalized ionic liquids; thus enhanced catalytic activity and recyclability are realized. [11]
# Low temperature ionic liquids
Low temperature ionic liquids (below 130 kelvins) have been proposed as the fluid base for an extremely large diameter spinning liquid mirror telescope to be based on the earth's moon.[12] Low temperature is advantageous in imaging long wave infrared light which is the form of light (extremely red-shifted) that arrives from the most distant parts of the visible universe. Such a liquid base would be covered by a thin metallic film that forms the reflective surface. A low volatility is important for use in the vacuum conditions present on the moon.
# Food science
Ionic liquids have been used in food science. [bmim]Cl for instance is able to completely dissolve freeze dried banana pulp and the solution with an additional 15% DMSO lends itself to Carbon-13 NMR analysis. In this way the entire banana compositional makeup of starch, sucrose, glucose, and fructose can be monitored as a function of banana ripening.[13]
# Applications
Nowadays ionic liquids find a number of industrial applications which vary greatly in character. A few of their industrial applications are briefly described below; more detailed information can be found in a recent review article.[14]
## BASIL
The first major industrial application of ILs was the BASIL (Biphasic Acid Scavenging utilizing Ionic Liquids) process by BASF, in which a 1-alkylimidazole was used to scavenge the acid from an existing process. This then results in the formation of an IL which can easily be removed from the reaction mixture.[15] But the easier removal of an unwanted side-product (as an IL rather than as a solid salt) is not the only advantage of the IL based process. By using an IL it was possible to increase the space/time yield of the reaction by a factor of 80,000. It should, however, be kept in mind that improvements of such scale are rare.[citation needed]
## Cellulose Processing
Occurring at a volume of some 700 billion tons, cellulose is the earth’s most widespread natural organic chemical and, thus, highly important as a bio-renewable resource. But even out of the 40 billion tons nature renews every year, only approx. 0.2 billion tons are used as feedstock for further processing. A more intensive exploitation of cellulose as a biorenewable feedstock has to date been prevented by the lack of a suitable solvent that can be used in chemical processes. Robin Rogers and co-workers at the University of Alabama have found that by means of ionic liquids, however, real solutions of cellulose can now be produced for the first time at technically useful concentrations [16]. This new technology therefore opens up great potential for cellulose processing.
For example, making cellulosic fibers from so-called dissolving pulp currently involves the use, and subsequent disposal, of great volumes of various chemical auxiliaries, esp. carbon disulfide (CS2). Major volumes of waste water are also produced for process reasons and need to be disposed of. These processes can be greatly simplified by the use of ionic liquids, which serve as solvents and are nearly entirely recycled. The “Institut für Textilchemie und Chemiefasern” (ITCF) in Denkendorf and BASF are jointly investigating the properties of fibers spun from an ionic liquid solution of cellulose in a pilot plant setup. [17]
## Eastman chemical’s DHF plant
Eastman operated an ionic liquid-based plant for the synthesis of 2,5-dihydrofuran from 1996 to 2004. However, the plant is now defunct because demand for the product has ceased.[citation needed]
## Dimersol - Difasol
The dimersol process is a traditional way to dimerise short chain alkenes into branched alkenes of higher molecular weight. Nobel laureate Yves Chauvin and Hélène Olivier-Bourbigou at IFP (France) have developed an ionic liquid-based add-on to this process called the Difasol process. However, while may be licensed it has as yet not been put into commercial practice.
## Petrochina
Petrochina have announced the implementation of an ionic liquid-based process called Ionikylation. This process, the alkylation of C4 olefins with iso-butane, is retrofitted into a 65,000 tonne per year alkylation plant, making it the biggest industrial application of ILs to date.
## Degussa paint additives
Ionic liquids can enhance the finish, appearance and drying properties of paints. Degussa are marketing such ILs under the name of TEGO Dispers. These products are also added to the Pliolite paint range.
## Air products - ILs as a transport medium for reactive gases
Air products make use of ILs as a medium to transport reactive gases in. Reactive gases such as trifluoroborane, phosphine or arsine, BF3, PH3 or AsH3, respectively, are stored in suitable ILs at sub-ambient pressure. This is a significant improvement over pressurised cylinders. The gases are easily withdrawn from the containers by applying a vacuum.
## Linde's IL 'piston'
Whereas Air Product’s Gasguard system relies on the solubility of some gases in ILs, Linde are exploiting other gases’ insolubility in ILs. As mentioned above, the solubility of Hydrogen in ILs is very low. Linde now make use of this insolubility by using a body of ionic liquid to compress Hydrogen in filling stations; and in so doing they reduced the number of moving parts from about 500 in a conventional piston pump engine down to 8.
## Nuclear industry
RTILs are extensively explored for various innovative applications in nuclear industry. It includes application of ionic liquid as extractant/diluent in solvent extraction systems, as alternate electrolyte media for the high temperature pyrochemical processing, etc. Fundamental studies on the extraction cum electrodeposition of fission products like uranium, palladium etc., from spent nuclear fuel using RTILs as extractants are reported. Reports on employing using Ionic liquids as non-aquoues electrolyte media for the recovery of uranium [18]and useful fission products like palladium [19] and rhodium [20] from spent nuclear fuel are also available.Studies on the electrochemical behavior of uranium(VI) in ionic liquid, 1-butyl-3-methylimidazolium chloride and also the recovery of valuable fission products from tissue paper waste was studied in room temperature ionic liquids.[21].
# Safety
Due to their non-volatility, effectively eliminating a major pathway for environmental release and contamination, ionic liquids have been considered as having a low impact on the environment and human health, and thus recognized as solvents for green chemistry. However, this is distinct from toxicity, and it remains to be seen how 'environmentally-friendly' ILs will be regarded once widely used by industry. Research into IL aquatic toxicity has shown them to be as toxic or more so than many current solvents already in use [22]. A review paper on this aspect has been published in 2007.[23] Available research also shows that mortality isn't necessarily the most important metric for measuring their impacts in aquatic environments, as sub-lethal concentrations have been shown to change organisms' life histories in meaningful ways. According to these researchers balancing between zero VOC emissions, and avoiding spills into waterways (via waste ponds/streams, etc.) should become a top priority. However, with the enormous diversity of substituents available to make useful ILs, it should be possible to design them with useful physical properties and less toxic chemical properties.
With regard to the safe disposal of ionic liquids, a 2007 paper has reported the use of ultrasound to degrade solutions of imidazolium-based ionic liquids with hydrogen peroxide and acetic acid to relatively innocuous compounds.[24]
Despite their low vapor pressure many ionic liquids have also found to be combustible and therefore require careful handling [25]. Brief exposure (5 to 7 seconds) to a flame torch will ignite these IL's and some of them are even completely consumed by combustion. | https://www.wikidoc.org/index.php/Ionic_liquid | |
9535b856e2943c7a5089a4b2f170a658dedbd45a | wikidoc | Ionic radius | Ionic radius
The ionic radius, rion, is a measure of the size of an ion in a crystal lattice. It is measured in either picometres (pm) or Angstrom (Å), with 1 Å = 100 pm. Typical values range from 30 pm (0.3 Å) to over 200 pm (2 Å).
The concept of ionic radius was developed independently by Goldschmidt and Pauling in the 1920s to summarize the data being generated by the (then) new technique of X-ray crystallography: it is Pauling's approach which proved to be the more influential. X-ray crystallography can readily give the length of the side of the unit cell of a crystal, but it is much more difficult (in most cases impossible, even with more modern techniques) to distinguish a boundary between two ions. For example, it can be readily determined that each side of the unit cell of sodium chloride is 564.02 pm in length, and that this length is twice the distance between the centre of a sodium ion and the centre of a chloride ion:
However, it is not apparent what proportion of this distance is due to the size of the sodium ion and what proportion is due to the size of the chloride ion. By comparing many different compounds, and with a certain amount of chemical intuition, Pauling decided to assign a radius of 140 pm to the oxide ion O2−, at which point he was able to calculate the radii of the other ions by subtraction.
A major review of crystallographic data led to the publication of a revised set of ionic radii in 1976, and these are preferred to Pauling's original values. Some sources have retained Pauling's reference of rion(O2−) = 140 pm, while other sources prefer to list "effective" ionic radii based on rion(O2−) = 126 pm. The latter values are thought to be a more accurate approximation to the "true" relative sizes of anions and cations in ionic crystals.
The ionic radius is not a fixed property of a given ion, but varies with coordination number, spin state and other parameters. Nevertheless, ionic radius values are sufficiently transferable to allow periodic trends to be recognised. As with other types of atomic radius, ionic radii increase on descending a group. Ionic size (for the same ion) also increases with increasing coordination number, and an ion in a high-spin state will be larger than the same ion in a low-spin state. Anions (negatively charged) are almost invariable larger than cations (positively charged), although the fluorides of some alkali metals are rare exceptions. In general, ionic radius decreases with increasing positive charge and increases with increasing negative charge.
An "anomalous" ionic radius in a crystal is often a sign of significant covalent character in the bonding. No bond is completely ionic, and some supposedly "ionic" compounds, especially of the transition metals, are particularly covalent in character. This is illustrated by the unit cell parameters for sodium and silver halides in the table. On the basis of the fluorides, one would say that Ag+ is larger than Na+, but on the basis of the chlorides and bromides the opposite appears to be true. This is because the greater covalent character of the bonds in AgCl and AgBr reduces the bond length and hence the apparent ionic radius of Ag+, an effect which is not present in the halides of the more electropositive sodium, nor in silver fluoride in which the fluoride ion is relatively unpolarizable. | Ionic radius
Template:Atomic radius
The ionic radius, rion, is a measure of the size of an ion in a crystal lattice. It is measured in either picometres (pm) or Angstrom (Å), with 1 Å = 100 pm. Typical values range from 30 pm (0.3 Å) to over 200 pm (2 Å).
The concept of ionic radius was developed independently by Goldschmidt and Pauling in the 1920s to summarize the data being generated by the (then) new technique of X-ray crystallography: it is Pauling's approach which proved to be the more influential. X-ray crystallography can readily give the length of the side of the unit cell of a crystal, but it is much more difficult (in most cases impossible, even with more modern techniques) to distinguish a boundary between two ions. For example, it can be readily determined that each side of the unit cell of sodium chloride is 564.02 pm in length, and that this length is twice the distance between the centre of a sodium ion and the centre of a chloride ion:
However, it is not apparent what proportion of this distance is due to the size of the sodium ion and what proportion is due to the size of the chloride ion. By comparing many different compounds, and with a certain amount of chemical intuition, Pauling decided to assign a radius of 140 pm to the oxide ion O2−, at which point he was able to calculate the radii of the other ions by subtraction.[1]
A major review of crystallographic data led to the publication of a revised set of ionic radii in 1976,[2] and these are preferred to Pauling's original values. Some sources have retained Pauling's reference of rion(O2−) = 140 pm, while other sources prefer to list "effective" ionic radii based on rion(O2−) = 126 pm. The latter values are thought to be a more accurate approximation to the "true" relative sizes of anions and cations in ionic crystals.
The ionic radius is not a fixed property of a given ion, but varies with coordination number, spin state and other parameters. Nevertheless, ionic radius values are sufficiently transferable to allow periodic trends to be recognised. As with other types of atomic radius, ionic radii increase on descending a group. Ionic size (for the same ion) also increases with increasing coordination number, and an ion in a high-spin state will be larger than the same ion in a low-spin state. Anions (negatively charged) are almost invariable larger than cations (positively charged), although the fluorides of some alkali metals are rare exceptions. In general, ionic radius decreases with increasing positive charge and increases with increasing negative charge.
An "anomalous" ionic radius in a crystal is often a sign of significant covalent character in the bonding. No bond is completely ionic, and some supposedly "ionic" compounds, especially of the transition metals, are particularly covalent in character. This is illustrated by the unit cell parameters for sodium and silver halides in the table. On the basis of the fluorides, one would say that Ag+ is larger than Na+, but on the basis of the chlorides and bromides the opposite appears to be true.[3] This is because the greater covalent character of the bonds in AgCl and AgBr reduces the bond length and hence the apparent ionic radius of Ag+, an effect which is not present in the halides of the more electropositive sodium, nor in silver fluoride in which the fluoride ion is relatively unpolarizable. | https://www.wikidoc.org/index.php/Ionic_radius | |
72cf7e312ea2a600ef87f4b996a9a01dbb31b5b1 | wikidoc | Isaac Newton | Isaac Newton
Sir Isaac Newton, FRS (Template:PronEng; 4 January 1643– 31 March 1727 ) was an English physicist, mathematician, astronomer, natural philosopher, alchemist and theologian. His Philosophiæ Naturalis Principia Mathematica, published in 1687, is considered to be the most influential book in the history of science. In this work, Newton described universal gravitation and the three laws of motion, laying the groundwork for classical mechanics, which dominated the scientific view of the physical universe for the next three centuries and is the basis for modern engineering. Newton showed that the motions of objects on Earth and of celestial bodies are governed by the same set of natural laws by demonstrating the consistency between Kepler's laws of planetary motion and his theory of gravitation, thus removing the last doubts about heliocentrism and advancing the scientific revolution.
In mechanics, Newton enunciated the principles of conservation of momentum and angular momentum. In optics, he invented the reflecting telescope and developed a theory of colour based on the observation that a prism decomposes white light into a visible spectrum. He also formulated an empirical law of cooling and studied the speed of sound.
In mathematics, Newton shares the credit with Gottfried Leibniz for the development of the differential and integral calculus. He also demonstrated the generalised binomial theorem, developed the so-called "Newton's method" for approximating the zeroes of a function, and contributed to the study of power series.
Newton was also highly religious (though unorthodox), producing more work on Biblical hermeneutics than the natural science he is remembered for today.
In a 2005 poll of the Royal Society asking who had the greater effect on the history of science, Newton was deemed much more influential than Albert Einstein.
# Biography
## Early years
Isaac Newton was born on 4 January 1643 at Woolsthorpe Manor in Woolsthorpe-by-Colsterworth, a hamlet in the county of Lincolnshire. At the time of Newton's birth, England had not adopted the latest papal calendar and therefore his date of birth was recorded as Christmas Day, 25 December 1642. Newton was born three months after the death of his father. Born prematurely, he was a small child; his mother Hannah Ayscough reportedly said that he could have fit inside a quart mug. When Newton was three, his mother remarried and went to live with her new husband, the Reverend Barnabus Smith, leaving her son in the care of his maternal grandmother, Margery Ayscough. The young Isaac disliked his stepfather and held some enmity towards his mother for marrying him, as revealed by this entry in a list of sins committed up to the age of 19: Threatening my father and mother Smith to burn them and the house over them.
According to E.T. Bell and H. Eves:
Newton began his schooling in the village schools and was later sent to The King's School, Grantham, where he became the top student in the school. At King's, he lodged with the local apothecary, William Clarke and eventually became engaged to the apothecary's stepdaughter, Anne Storer, before he went off to the University of Cambridge at the age of 19. As Newton became engrossed in his studies, the romance cooled and Miss Storer married someone else. It is said he kept a warm memory of this love, but Newton had no other recorded "sweet-hearts" and never married.
There are rumours that he remained a confirmed celibate. However, Bell and Eves' sources for this claim, William Stukeley and Mrs. Vincent (the former Miss Storer– actually named Katherine, not Anne), merely say that Newton entertained "a passion" for Storer while he lodged at the Clarke house.
From the age of about twelve until he was seventeen, Newton was educated at The King's School, Grantham (where his signature can still be seen upon a library window sill). He was removed from school, and by October 1659, he was to be found at Woolsthorpe-by-Colsterworth, where his mother, widowed by now for a second time, attempted to make a farmer of him. He was, by later reports of his contemporaries, thoroughly unhappy with the work. It appears to have been Henry Stokes, master at the King's School, who persuaded his mother to send him back to school so that he might complete his education. This he did at the age of eighteen, achieving an admirable final report.
In June 1661, he was admitted to Trinity College, Cambridge. According to John Stillwell, he entered Trinity as a sizar. At that time, the college's teachings were based on those of Aristotle, but Newton preferred to read the more advanced ideas of modern philosophers such as Descartes and astronomers such as Copernicus, Galileo, and Kepler. In 1665, he discovered the generalised binomial theorem and began to develop a mathematical theory that would later become calculus. Soon after Newton had obtained his degree in August of 1665, the University closed down as a precaution against the Great Plague. Although he had been undistinguished as a Cambridge student, Newton's private studies at his home in Woolsthorpe over the subsequent two years saw the development of his theories on calculus, optics and the law of gravitation.
## Middle years
### Mathematics
Most modern historians believe that Newton and Leibniz had developed calculus independently, using their own unique notations. According to Newton's inner circle, Newton had worked out his method years before Leibniz, yet he published almost nothing about it until 1693, and did not give a full account until 1704. Meanwhile, Leibniz began publishing a full account of his methods in 1684. Moreover, Leibniz's notation and "differential Method" were universally adopted on the Continent, and after 1820 or so, in the British Empire. Whereas Leibniz's notebooks show the advancement of the ideas from early stages until maturity, there is only the end product in Newton's known notes. Newton claimed that he had been reluctant to publish his calculus because he feared being mocked for it. Newton had a very close relationship with Swiss mathematician Nicolas Fatio de Duillier, who from the beginning was impressed by Newton's gravitational theory. In 1691 Duillier planned to prepare a new version of Newton's Philosophiae Naturalis Principia Mathematica, but never finished it. However, in 1694 the relationship between the two men changed. At the time, Duillier had also exchanged several letters with Leibniz.
Starting in 1699, other members of the Royal Society (of which Newton was a member) accused Leibniz of plagiarism, and the dispute broke out in full force in 1711. Newton's Royal Society proclaimed in a study that it was Newton who was the true discoverer and labeled Leibniz a fraud. This study was cast into doubt when it was later found that Newton himself wrote the study's concluding remarks on Leibniz. Thus began the bitter Newton v. Leibniz calculus controversy, which marred the lives of both Newton and Leibniz until the latter's death in 1716.
Newton is generally credited with the generalised binomial theorem, valid for any exponent. He discovered Newton's identities, Newton's method, classified cubic plane curves (polynomials of degree three in two variables), made substantial contributions to the theory of finite differences, and was the first to use fractional indices and to employ coordinate geometry to derive solutions to Diophantine equations. He approximated partial sums of the harmonic series by logarithms (a precursor to Euler's summation formula), and was the first to use power series with confidence and to revert power series. He also discovered a new formula for calculating pi.
He was elected Lucasian Professor of Mathematics in 1669. In that day, any fellow of Cambridge or Oxford had to be an ordained Anglican priest. However, the terms of the Lucasian professorship required that the holder not be active in the church (presumably so as to have more time for science). Newton argued that this should exempt him from the ordination requirement, and Charles II, whose permission was needed, accepted this argument. Thus a conflict between Newton's religious views and Anglican orthodoxy was averted.
### Optics
From 1670 to 1672, Newton lectured on optics. During this period he investigated the refraction of light, demonstrating that a prism could decompose white light into a spectrum of colours, and that a lens and a second prism could recompose the multicoloured spectrum into white light.
He also showed that the coloured light does not change its properties by separating out a coloured beam and shining it on various objects. Newton noted that regardless of whether it was reflected or scattered or transmitted, it stayed the same colour. Thus, he observed that colour is the result of objects interacting with already-coloured light rather than objects generating the colour themselves. This is known as Newton's theory of colour.
From this work he concluded that any refracting telescope would suffer from the dispersion of light into colours, and invented a reflecting telescope (today known as a Newtonian telescope) to bypass that problem. By grinding his own mirrors, using Newton's rings to judge the quality of the optics for his telescopes, he was able to produce a superior instrument to the refracting telescope, due primarily to the wider diameter of the mirror. In 1671 the Royal Society asked for a demonstration of his reflecting telescope. Their interest encouraged him to publish his notes On Colour, which he later expanded into his Opticks. When Robert Hooke criticised some of Newton's ideas, Newton was so offended that he withdrew from public debate. The two men remained enemies until Hooke's death.
Newton argued that light is composed of particles or corpuscles, which were refracted by accelerating toward the denser medium, but he had to associate them with waves to explain the diffraction of light (Opticks Bk. II, Props. XII-L). Later physicists instead favoured a purely wavelike explanation of light to account for diffraction. Today's quantum mechanics, photons and the idea of wave-particle duality bear only a minor resemblance to Newton's understanding of light.
In his Hypothesis of Light of 1675, Newton posited the existence of the ether to transmit forces between particles. The contact with the theosophist Henry More, revived his interest in alchemy. He replaced the ether with occult forces based on Hermetic ideas of attraction and repulsion between particles. John Maynard Keynes, who acquired many of Newton's writings on alchemy, stated that "Newton was not the first of the age of reason: he was the last of the magicians." Newton's interest in alchemy cannot be isolated from his contributions to science. (This was at a time when there was no clear distinction between alchemy and science.) Had he not relied on the occult idea of action at a distance, across a vacuum, he might not have developed his theory of gravity. (See also Isaac Newton's occult studies.)
In 1704 Newton published Opticks, in which he expounded his corpuscular theory of light. He considered light to be made up of extremely subtle corpuscles, that ordinary matter was made of grosser corpuscles and speculated that through a kind of alchemical transmutation "Are not gross Bodies and Light convertible into one another, ...and may not Bodies receive much of their Activity from the Particles of Light which enter their Composition?" Newton also constructed a primitive form of a frictional electrostatic generator, using a glass globe (Optics, 8th Query).
### Mechanics and gravitation
In 1677, Newton returned to his work on mechanics, i.e., gravitation and its effect on the orbits of planets, with reference to Kepler's laws of planetary motion, and consulting with Hooke and Flamsteed on the subject. He published his results in De motu corporum in gyrum (1684). This contained the beginnings of the laws of motion that would inform the Principia.
The Philosophiae Naturalis Principia Mathematica (now known as the Principia) was published on 5 July 1687 with encouragement and financial help from Edmond Halley. In this work Newton stated the three universal laws of motion that were not to be improved upon for more than two hundred years. He used the Latin word gravitas (weight) for the effect that would become known as gravity, and defined the law of universal gravitation. In the same work he presented the first analytical determination, based on Boyle's law, of the speed of sound in air. Newton's postulate of an invisible force able to act over vast distances led to him being criticised for introducing "occult agencies" into science.
With the Principia, Newton became internationally recognised. He acquired a circle of admirers, including the Swiss-born mathematician Nicolas Fatio de Duillier, with whom he formed an intense relationship that lasted until 1693. The end of this friendship led Newton to a nervous breakdown.Template:Unclear
## Later life
In the 1690s, Newton wrote a number of religious tracts dealing with the literal interpretation of the Bible. Henry More's belief in the universe and rejection of Cartesian dualism may have influenced Newton's religious ideas. A manuscript he sent to John Locke in which he disputed the existence of the Trinity was never published. Later works– The Chronology of Ancient Kingdoms Amended (1728) and Observations Upon the Prophecies of Daniel and the Apocalypse of St. John (1733)– were published after his death. He also devoted a great deal of time to alchemy (see above).
Newton was also a member of the Parliament of England from 1689 to 1690 and in 1701, but his only recorded comments were to complain about a cold draft in the chamber and request that the window be closed.
Newton moved to London to take up the post of warden of the Royal Mint in 1696, a position that he had obtained through the patronage of Charles Montagu, 1st Earl of Halifax, then Chancellor of the Exchequer. He took charge of England's great recoining, somewhat treading on the toes of Master Lucas (and securing the job of deputy comptroller of the temporary Chester branch for Edmond Halley). Newton became perhaps the best-known Master of the Mint upon Lucas' death in 1699, a position Newton held until his death. These appointments were intended as sinecures, but Newton took them seriously, retiring from his Cambridge duties in 1701, and exercising his power to reform the currency and punish clippers and counterfeiters. As Master of the Mint in 1717 Newton unofficially moved the Pound Sterling from the silver standard to the gold standard by creating a relationship between gold coins and the silver penny in the "Law of Queen Anne"; these were all great reforms at the time, adding considerably to the wealth and stability of England. It was his work at the Mint, rather than his earlier contributions to science, that earned him a knighthood from Queen Anne in 1705.
Newton was made President of the Royal Society in 1703 and an associate of the French Académie des Sciences. In his position at the Royal Society, Newton made an enemy of John Flamsteed, the Astronomer Royal, by prematurely publishing Flamsteed's star catalogue, which Newton had used in his studies.
Newton died in London on 31 March 1727 , and was buried in Westminster Abbey. His half-niece, Catherine Barton Conduitt, served as his hostess in social affairs at his house on Jermyn Street in London; he was her "very loving Uncle," according to his letter to her when she was recovering from smallpox. Although Newton, who had no children, had divested much of his estate onto relatives in his last years, he actually died intestate.
After his death, Newton's body was discovered to have had massive amounts of mercury in it, probably resulting from his alchemical pursuits. Mercury poisoning could explain Newton's eccentricity in late life.
# Religious views
Historian Stephen D. Snobelen says of Newton, "Isaac Newton was a heretic. But like Nicodemus, the secret disciple of Jesus, he never made a public declaration of his private faith - which the orthodox would have deemed extremely radical. He hid his faith so well that scholars are still unravelling his personal beliefs." Snobelen concludes that Newton was at least a Socinian sympathiser (he owned and had thoroughly read at least eight Socinian books), possibly an Arian and almost certainly an antitrinitarian. In an age notable for its religious intolerance there are few public expressions of Newton's radical views, most notably his refusal to take holy orders and his refusal, on his death bed, to take the sacrament when it was offered to him.
In a view disputed by Snobelen, T.C. Pfizenmaier argues that Newton held the Eastern Orthodox view of the Trinity rather than the Western one held by Roman Catholics, Anglicans, and most Protestants. In his own day, he was also accused of being a Rosicrucian (as were many in the Royal Society and in the court of Charles II).
Although the laws of motion and universal gravitation became Newton's best-known discoveries, he warned against using them to view the universe as a mere machine, as if akin to a great clock. He said, "Gravity explains the motions of the planets, but it cannot explain who set the planets in motion. God governs all things and knows all that is or can be done."
His scientific fame notwithstanding, Newton's studies of the Bible and of the early Church Fathers were also noteworthy. Newton wrote works on textual criticism, most notably An Historical Account of Two Notable Corruptions of Scripture. He also placed the crucifixion of Jesus Christ at 3 April, AD 33, which agrees with one traditionally accepted date. He also attempted, unsuccessfully, to find hidden messages within the Bible.
In his own lifetime, Newton wrote more on religion than he did on natural science. He believed in a rationally immanent world, but he rejected the hylozoism implicit in Leibniz and Baruch Spinoza. Thus, the ordered and dynamically informed universe could be understood, and must be understood, by an active reason, but this universe, to be perfect and ordained, had to be regular.
## Newton's effect on religious thought
Newton and Robert Boyle’s mechanical philosophy was promoted by rationalist pamphleteers as a viable alternative to the pantheists and enthusiasts, and was accepted hesitantly by orthodox preachers as well as dissident preachers like the latitudinarians. Thus, the clarity and simplicity of science was seen as a way to combat the emotional and metaphysical superlatives of both superstitious enthusiasm and the threat of atheism, and, at the same time, the second wave of English deists used Newton's discoveries to demonstrate the possibility of a "Natural Religion."
The attacks made against pre-Enlightenment "magical thinking," and the mystical elements of Christianity, were given their foundation with Boyle’s mechanical conception of the universe. Newton gave Boyle’s ideas their completion through mathematical proofs and, perhaps more importantly, was very successful in popularising them. Newton refashioned the world governed by an interventionist God into a world crafted by a God that designs along rational and universal principles. These principles were available for all people to discover, allowed people to pursue their own aims fruitfully in this life, not the next, and to perfect themselves with their own rational powers.
Newton saw God as the master creator whose existence could not be denied in the face of the grandeur of all creation. But the unforeseen theological consequence of his conception of God, as Leibniz pointed out, was that God was now entirely removed from the world’s affairs, since the need for intervention would only evidence some imperfection in God’s creation, something impossible for a perfect and omnipotent creator. Leibniz's theodicy cleared God from the responsibility for "l'origine du mal" by making God removed from participation in his creation. The understanding of the world was now brought down to the level of simple human reason, and humans, as Odo Marquard argued, became responsible for the correction and elimination of evil.
On the other hand, latitudinarian and Newtonian ideas taken too far resulted in the millenarians, a religious faction dedicated to the concept of a mechanical universe, but finding in it the same enthusiasm and mysticism that the Enlightenment had fought so hard to extinguish.
## Views of the end of the world
In a manuscript he wrote in 1704 in which he describes his attempts to extract scientific information from the Bible, he estimated that the world would end no earlier than 2060. In predicting this he said, "This I mention not to assert when the time of the end shall be, but to put a stop to the rash conjectures of fanciful men who are frequently predicting the time of the end, and by doing so bring the sacred prophesies into discredit as often as their predictions fail."
# Newton and the counterfeiters
As warden of the Royal Mint, Newton estimated that 20% of the coins taken in during The Great Recoinage were counterfeit. Counterfeiting was high treason, punishable by being hanged, drawn and quartered. Despite this, convictions of the most flagrant criminals could be extremely difficult to achieve; however, Newton proved to be equal to the task.
Disguised as an habitué of bars and taverns, he gathered much of that evidence himself. For all the barriers placed to prosecution, and separating the branches of government, English law still had ancient and formidable customs of authority. Newton was made a justice of the peace and between June 1698 and Christmas 1699 conducted some 200 cross-examinations of witnesses, informers and suspects. Newton won his convictions and in February 1699, he had ten prisoners waiting to be executed.
Possibly Newton's greatest triumph as the king's attorney was against William Chaloner. One of Chaloner's schemes was to set up phony conspiracies of Catholics and then turn in the hapless conspirators whom he entrapped. Chaloner made himself rich enough to posture as a gentleman. Petitioning Parliament, Chaloner accused the Mint of providing tools to counterfeiters (a charge also made by others). He proposed that he be allowed to inspect the Mint's processes in order to improve them. He petitioned Parliament to adopt his plans for a coinage that could not be counterfeited, while at the same time striking false coins. Newton was outraged, and went about the work to uncover anything about Chaloner. During his studies, he found that Chaloner was engaged in counterfeiting. He immediately put Chaloner on trial, but Chaloner had friends in high places and, to Newton's horror, Chaloner walked free. Newton put him on trial a second time with conclusive evidence. Chaloner was convicted of high treason and hanged, drawn and quartered on 23 March 1699 at Tyburn gallows.
# Enlightenment philosophers
Enlightenment philosophers chose a short history of scientific predecessors—Galileo, Boyle, and Newton principally—as the guides and guarantors of their applications of the singular concept of Nature and Natural Law to every physical and social field of the day. In this respect, the lessons of history and the social structures built upon it could be discarded.
It was Newton’s conception of the universe based upon Natural and rationally understandable laws that became the seed for Enlightenment ideology. Locke and Voltaire applied concepts of Natural Law to political systems advocating intrinsic rights; the physiocrats and Adam Smith applied Natural conceptions of psychology and self-interest to economic systems and the sociologists criticised the current social order for trying to fit history into Natural models of progress. Monboddo and Samuel Clarke resisted elements of Newton's work, but eventually rationalised it to conform with their strong religious views of nature.
# Newton's laws of motion
The famous three laws of motion:
Newton's First Law (also known as the Law of Inertia) states that an object at rest tends to stay at rest and that an object in uniform motion tends to stay in uniform motion unless acted upon by a net external force.
Newton's Second Law states that an applied force, \scriptstyle{\vec{F}}, on an object equals the rate of change of its momentum, \scriptstyle{\vec{p}}, with time. Mathematically, this is expressed as
Because this relation only holds when the mass is constant, that is, when \scriptstyle{dm/dt=0}, the first term vanishes, and the equation can be written it the iconic form
where
This equation states that a force \scriptstyle{\vec{F}} applied to an object of mass m causes it to accelerate at a rate \scriptstyle{\vec{a}}.
This equality requires a consistent set of units for measuring mass, length, and time. One such set is the SI system, where mass is in kilograms, length in metres, and time in seconds. This leads to force being in newtons, named in his honour, and acceleration in metres per second per second. The English analogous system is slugs, feet, and seconds.
Newton's Third Law states that for every action there is an equal and opposite reaction. This means that any force exerted onto an object has a counterpart force that is exerted in the opposite direction back onto the first object. The most common example is of two ice skaters pushing against each other and sliding apart in opposite directions. Another example is the recoil of a firearm, in which the force propelling the bullet is exerted equally back onto the gun and is felt by the shooter. Since the objects in question do not necessarily have the same mass, the resulting acceleration of the two objects can be different (as in the case of firearm recoil).
# Newton's apple
A popular story claims that Newton was inspired to formulate his theory of universal gravitation by the fall of an apple from a tree. Cartoons have gone further to suggest the apple actually hit Newton's head, and that its impact somehow made him aware of the force of gravity. John Conduitt, Newton's assistant at the Royal Mint and husband of Newton's niece, described the event when he wrote about Newton's life:
The question was not whether gravity existed, but whether it extended so far from Earth that it could also be the force holding the moon to its orbit. Newton showed that if the force decreased as the inverse square of the distance, one could indeed calculate the Moon's orbital period, and get good agreement. He guessed the same force was responsible for other orbital motions, and hence named it "universal gravitation".
A contemporary writer, William Stukeley, recorded in his Memoirs of Sir Isaac Newton's Life a conversation with Newton in Kensington on 15 April 1726, in which Newton recalled "when formerly, the notion of gravitation came into his mind. It was occasioned by the fall of an apple, as he sat in contemplative mood. Why should that apple always descend perpendicularly to the ground, thought he to himself. Why should it not go sideways or upwards, but constantly to the earth's centre." In similar terms, Voltaire wrote in his Essay on Epic Poetry (1727), "Sir Isaac Newton walking in his gardens, had the first thought of his system of gravitation, upon seeing an apple falling from a tree." These accounts are probably exaggerations of Newton's own tale about sitting by a window in his home (Woolsthorpe Manor) and watching an apple fall from a tree.
Various trees are claimed to be "the" apple tree which Newton describes. The King's School, Grantham, claims that the tree was purchased by the school, uprooted and transported to the headmaster's garden some years later, the staff of the National Trust-owned Woolsthorpe Manor dispute this, and claim that a tree present in their gardens is the one described by Newton. A descendant of the original tree can be seen growing outside the main gate of Trinity College, Cambridge, below the room Newton lived in when he studied there. The National Fruit Collection at Brogdale can supply grafts from their tree (ref 1948-729), which appears identical to Flower of Kent, a coarse-fleshed cooking variety.
# Writings by Newton
- Method of Fluxions (1671)
- Of Natures Obvious Laws & Processes in Vegetation (unpublished, c. 1671–75)
- De Motu Corporum in Gyrum (1684)
- Philosophiae Naturalis Principia Mathematica (1687)
- Opticks (1704)
- Reports as Master of the Mint (1701–25)
- Arithmetica Universalis (1707)
- The System of the World, Optical Lectures, The Chronology of Ancient Kingdoms, (Amended) and De mundi systemate (published posthumously in 1728)
- Observations on Daniel and The Apocalypse of St. John (1733)
- An Historical Account of Two Notable Corruptions of Scripture (1754)
# Fame
French mathematician Joseph-Louis Lagrange often said that Newton was the greatest genius who ever lived, and once added that he was also "the most fortunate, for we cannot find more than once a system of the world to establish." English poet Alexander Pope was moved by Newton's accomplishments to write the famous epitaph:
Newton himself was rather more modest of his own achievements, famously writing in a letter to Robert Hooke in February 1676
Historians generally think the above quote was an attack on Hooke (who was short and hunchbacked), rather than– or in addition to– a statement of modesty. The two were in a dispute over optical discoveries at the time. The latter interpretation also fits with many of his other disputes over his discoveries– such as the question of who discovered calculus as discussed above.
And then in a memoir later
# Newton in popular culture
Newton is an important character in The Baroque Cycle by Neal Stephenson. A major theme of these novels is the emergence of modern science, with Newton's work in the Principia being prominent. Newton's interest in alchemy and the dispute over the discovery of calculus are prominent plot points, and there is a (fictional) debate on metaphysics between Newton and Gottfried Leibniz moderated by Caroline of Ansbach. The development of an economy based on money and credit is also a major theme, with Newton's time with the Royal Mint and intrigues against counterfeit leading to a Trial of the Pyx. | Isaac Newton
Template:Infobox Scientist
Sir Isaac Newton, FRS (Template:PronEng; 4 January 1643– 31 March 1727 [OS: 25 December 1642– 20 March 1726])[1] was an English physicist, mathematician, astronomer, natural philosopher, alchemist and theologian. His Philosophiæ Naturalis Principia Mathematica, published in 1687, is considered to be the most influential book in the history of science. In this work, Newton described universal gravitation and the three laws of motion, laying the groundwork for classical mechanics, which dominated the scientific view of the physical universe for the next three centuries and is the basis for modern engineering. Newton showed that the motions of objects on Earth and of celestial bodies are governed by the same set of natural laws by demonstrating the consistency between Kepler's laws of planetary motion and his theory of gravitation, thus removing the last doubts about heliocentrism and advancing the scientific revolution.
In mechanics, Newton enunciated the principles of conservation of momentum and angular momentum. In optics, he invented the reflecting telescope and developed a theory of colour based on the observation that a prism decomposes white light into a visible spectrum. He also formulated an empirical law of cooling and studied the speed of sound.
In mathematics, Newton shares the credit with Gottfried Leibniz for the development of the differential and integral calculus. He also demonstrated the generalised binomial theorem, developed the so-called "Newton's method" for approximating the zeroes of a function, and contributed to the study of power series.
Newton was also highly religious (though unorthodox), producing more work on Biblical hermeneutics than the natural science he is remembered for today.
In a 2005 poll of the Royal Society asking who had the greater effect on the history of science, Newton was deemed much more influential than Albert Einstein.[2]
# Biography
Template:IsaacNewtonSegments
## Early years
Isaac Newton was born on 4 January 1643 [OS: 25 December 1642][1] at Woolsthorpe Manor in Woolsthorpe-by-Colsterworth, a hamlet in the county of Lincolnshire. At the time of Newton's birth, England had not adopted the latest papal calendar and therefore his date of birth was recorded as Christmas Day, 25 December 1642. Newton was born three months after the death of his father. Born prematurely, he was a small child; his mother Hannah Ayscough reportedly said that he could have fit inside a quart mug. When Newton was three, his mother remarried and went to live with her new husband, the Reverend Barnabus Smith, leaving her son in the care of his maternal grandmother, Margery Ayscough. The young Isaac disliked his stepfather and held some enmity towards his mother for marrying him, as revealed by this entry in a list of sins committed up to the age of 19: Threatening my father and mother Smith to burn them and the house over them.[3]
According to E.T. Bell and H. Eves:
Newton began his schooling in the village schools and was later sent to The King's School, Grantham, where he became the top student in the school. At King's, he lodged with the local apothecary, William Clarke and eventually became engaged to the apothecary's stepdaughter, Anne Storer, before he went off to the University of Cambridge at the age of 19. As Newton became engrossed in his studies, the romance cooled and Miss Storer married someone else. It is said he kept a warm memory of this love, but Newton had no other recorded "sweet-hearts" and never married.[4]
There are rumours that he remained a confirmed celibate.[5] However, Bell and Eves' sources for this claim, William Stukeley and Mrs. Vincent (the former Miss Storer– actually named Katherine, not Anne), merely say that Newton entertained "a passion" for Storer while he lodged at the Clarke house.
From the age of about twelve until he was seventeen, Newton was educated at The King's School, Grantham (where his signature can still be seen upon a library window sill). He was removed from school, and by October 1659, he was to be found at Woolsthorpe-by-Colsterworth, where his mother, widowed by now for a second time, attempted to make a farmer of him. He was, by later reports of his contemporaries, thoroughly unhappy with the work. It appears to have been Henry Stokes, master at the King's School, who persuaded his mother to send him back to school so that he might complete his education. This he did at the age of eighteen, achieving an admirable final report.
In June 1661, he was admitted to Trinity College, Cambridge. According to John Stillwell, he entered Trinity as a sizar[6]. At that time, the college's teachings were based on those of Aristotle, but Newton preferred to read the more advanced ideas of modern philosophers such as Descartes and astronomers such as Copernicus, Galileo, and Kepler. In 1665, he discovered the generalised binomial theorem and began to develop a mathematical theory that would later become calculus. Soon after Newton had obtained his degree in August of 1665, the University closed down as a precaution against the Great Plague. Although he had been undistinguished as a Cambridge student,[7] Newton's private studies at his home in Woolsthorpe over the subsequent two years saw the development of his theories on calculus, optics and the law of gravitation.
## Middle years
### Mathematics
Most modern historians believe that Newton and Leibniz had developed calculus independently, using their own unique notations. According to Newton's inner circle, Newton had worked out his method years before Leibniz, yet he published almost nothing about it until 1693, and did not give a full account until 1704. Meanwhile, Leibniz began publishing a full account of his methods in 1684. Moreover, Leibniz's notation and "differential Method" were universally adopted on the Continent, and after 1820 or so, in the British Empire. Whereas Leibniz's notebooks show the advancement of the ideas from early stages until maturity, there is only the end product in Newton's known notes. Newton claimed that he had been reluctant to publish his calculus because he feared being mocked for it. Newton had a very close relationship with Swiss mathematician Nicolas Fatio de Duillier, who from the beginning was impressed by Newton's gravitational theory. In 1691 Duillier planned to prepare a new version of Newton's Philosophiae Naturalis Principia Mathematica, but never finished it. However, in 1694 the relationship between the two men changed. At the time, Duillier had also exchanged several letters with Leibniz.
Starting in 1699, other members of the Royal Society (of which Newton was a member) accused Leibniz of plagiarism, and the dispute broke out in full force in 1711. Newton's Royal Society proclaimed in a study that it was Newton who was the true discoverer and labeled Leibniz a fraud. This study was cast into doubt when it was later found that Newton himself wrote the study's concluding remarks on Leibniz. Thus began the bitter Newton v. Leibniz calculus controversy, which marred the lives of both Newton and Leibniz until the latter's death in 1716.
Newton is generally credited with the generalised binomial theorem, valid for any exponent. He discovered Newton's identities, Newton's method, classified cubic plane curves (polynomials of degree three in two variables), made substantial contributions to the theory of finite differences, and was the first to use fractional indices and to employ coordinate geometry to derive solutions to Diophantine equations. He approximated partial sums of the harmonic series by logarithms (a precursor to Euler's summation formula), and was the first to use power series with confidence and to revert power series. He also discovered a new formula for calculating pi.
He was elected Lucasian Professor of Mathematics in 1669. In that day, any fellow of Cambridge or Oxford had to be an ordained Anglican priest. However, the terms of the Lucasian professorship required that the holder not be active in the church (presumably so as to have more time for science). Newton argued that this should exempt him from the ordination requirement, and Charles II, whose permission was needed, accepted this argument. Thus a conflict between Newton's religious views and Anglican orthodoxy was averted.
### Optics
From 1670 to 1672, Newton lectured on optics. During this period he investigated the refraction of light, demonstrating that a prism could decompose white light into a spectrum of colours, and that a lens and a second prism could recompose the multicoloured spectrum into white light.
He also showed that the coloured light does not change its properties by separating out a coloured beam and shining it on various objects. Newton noted that regardless of whether it was reflected or scattered or transmitted, it stayed the same colour. Thus, he observed that colour is the result of objects interacting with already-coloured light rather than objects generating the colour themselves. This is known as Newton's theory of colour.
From this work he concluded that any refracting telescope would suffer from the dispersion of light into colours, and invented a reflecting telescope (today known as a Newtonian telescope) to bypass that problem. By grinding his own mirrors, using Newton's rings to judge the quality of the optics for his telescopes, he was able to produce a superior instrument to the refracting telescope, due primarily to the wider diameter of the mirror. In 1671 the Royal Society asked for a demonstration of his reflecting telescope. Their interest encouraged him to publish his notes On Colour, which he later expanded into his Opticks. When Robert Hooke criticised some of Newton's ideas, Newton was so offended that he withdrew from public debate. The two men remained enemies until Hooke's death.
Newton argued that light is composed of particles or corpuscles, which were refracted by accelerating toward the denser medium, but he had to associate them with waves to explain the diffraction of light (Opticks Bk. II, Props. XII-L). Later physicists instead favoured a purely wavelike explanation of light to account for diffraction. Today's quantum mechanics, photons and the idea of wave-particle duality bear only a minor resemblance to Newton's understanding of light.
In his Hypothesis of Light of 1675, Newton posited the existence of the ether to transmit forces between particles. The contact with the theosophist Henry More, revived his interest in alchemy. He replaced the ether with occult forces based on Hermetic ideas of attraction and repulsion between particles. John Maynard Keynes, who acquired many of Newton's writings on alchemy, stated that "Newton was not the first of the age of reason: he was the last of the magicians."[8] Newton's interest in alchemy cannot be isolated from his contributions to science.[9] (This was at a time when there was no clear distinction between alchemy and science.) Had he not relied on the occult idea of action at a distance, across a vacuum, he might not have developed his theory of gravity. (See also Isaac Newton's occult studies.)
In 1704 Newton published Opticks, in which he expounded his corpuscular theory of light. He considered light to be made up of extremely subtle corpuscles, that ordinary matter was made of grosser corpuscles and speculated that through a kind of alchemical transmutation "Are not gross Bodies and Light convertible into one another, ...and may not Bodies receive much of their Activity from the Particles of Light which enter their Composition?"[10] Newton also constructed a primitive form of a frictional electrostatic generator, using a glass globe (Optics, 8th Query).
### Mechanics and gravitation
In 1677, Newton returned to his work on mechanics, i.e., gravitation and its effect on the orbits of planets, with reference to Kepler's laws of planetary motion, and consulting with Hooke and Flamsteed on the subject. He published his results in De motu corporum in gyrum (1684). This contained the beginnings of the laws of motion that would inform the Principia.
The Philosophiae Naturalis Principia Mathematica (now known as the Principia) was published on 5 July 1687 with encouragement and financial help from Edmond Halley. In this work Newton stated the three universal laws of motion that were not to be improved upon for more than two hundred years. He used the Latin word gravitas (weight) for the effect that would become known as gravity, and defined the law of universal gravitation. In the same work he presented the first analytical determination, based on Boyle's law, of the speed of sound in air. Newton's postulate of an invisible force able to act over vast distances led to him being criticised for introducing "occult agencies" into science.[11]
With the Principia, Newton became internationally recognised. He acquired a circle of admirers, including the Swiss-born mathematician Nicolas Fatio de Duillier, with whom he formed an intense relationship that lasted until 1693. The end of this friendship led Newton to a nervous breakdown.Template:Unclear[citation needed]
## Later life
In the 1690s, Newton wrote a number of religious tracts dealing with the literal interpretation of the Bible. Henry More's belief in the universe and rejection of Cartesian dualism may have influenced Newton's religious ideas. A manuscript he sent to John Locke in which he disputed the existence of the Trinity was never published. Later works– The Chronology of Ancient Kingdoms Amended (1728) and Observations Upon the Prophecies of Daniel and the Apocalypse of St. John (1733)– were published after his death. He also devoted a great deal of time to alchemy (see above).
Newton was also a member of the Parliament of England from 1689 to 1690 and in 1701, but his only recorded comments were to complain about a cold draft in the chamber and request that the window be closed.
Newton moved to London to take up the post of warden of the Royal Mint in 1696, a position that he had obtained through the patronage of Charles Montagu, 1st Earl of Halifax, then Chancellor of the Exchequer. He took charge of England's great recoining, somewhat treading on the toes of Master Lucas (and securing the job of deputy comptroller of the temporary Chester branch for Edmond Halley). Newton became perhaps the best-known Master of the Mint upon Lucas' death in 1699, a position Newton held until his death. These appointments were intended as sinecures, but Newton took them seriously, retiring from his Cambridge duties in 1701, and exercising his power to reform the currency and punish clippers and counterfeiters. As Master of the Mint in 1717 Newton unofficially moved the Pound Sterling from the silver standard to the gold standard by creating a relationship between gold coins and the silver penny in the "Law of Queen Anne"; these were all great reforms at the time, adding considerably to the wealth and stability of England. It was his work at the Mint, rather than his earlier contributions to science, that earned him a knighthood from Queen Anne in 1705.
Newton was made President of the Royal Society in 1703 and an associate of the French Académie des Sciences. In his position at the Royal Society, Newton made an enemy of John Flamsteed, the Astronomer Royal, by prematurely publishing Flamsteed's star catalogue, which Newton had used in his studies.
Newton died in London on 31 March 1727 [OS: 20 March 1726][1], and was buried in Westminster Abbey. His half-niece, Catherine Barton Conduitt,[12] served as his hostess in social affairs at his house on Jermyn Street in London; he was her "very loving Uncle,"[13] according to his letter to her when she was recovering from smallpox. Although Newton, who had no children, had divested much of his estate onto relatives in his last years, he actually died intestate.
After his death, Newton's body was discovered to have had massive amounts of mercury in it, probably resulting from his alchemical pursuits. Mercury poisoning could explain Newton's eccentricity in late life.[14]
# Religious views
Historian Stephen D. Snobelen says of Newton, "Isaac Newton was a heretic. But like Nicodemus, the secret disciple of Jesus, he never made a public declaration of his private faith - which the orthodox would have deemed extremely radical. He hid his faith so well that scholars are still unravelling his personal beliefs."[15] Snobelen concludes that Newton was at least a Socinian sympathiser (he owned and had thoroughly read at least eight Socinian books), possibly an Arian and almost certainly an antitrinitarian.[15] In an age notable for its religious intolerance there are few public expressions of Newton's radical views, most notably his refusal to take holy orders and his refusal, on his death bed, to take the sacrament when it was offered to him.[15]
In a view disputed by Snobelen,[15] T.C. Pfizenmaier argues that Newton held the Eastern Orthodox view of the Trinity rather than the Western one held by Roman Catholics, Anglicans, and most Protestants.[16] In his own day, he was also accused of being a Rosicrucian (as were many in the Royal Society and in the court of Charles II).[17]
Although the laws of motion and universal gravitation became Newton's best-known discoveries, he warned against using them to view the universe as a mere machine, as if akin to a great clock. He said, "Gravity explains the motions of the planets, but it cannot explain who set the planets in motion. God governs all things and knows all that is or can be done."[18]
His scientific fame notwithstanding, Newton's studies of the Bible and of the early Church Fathers were also noteworthy. Newton wrote works on textual criticism, most notably An Historical Account of Two Notable Corruptions of Scripture. He also placed the crucifixion of Jesus Christ at 3 April, AD 33, which agrees with one traditionally accepted date.[19] He also attempted, unsuccessfully, to find hidden messages within the Bible.
In his own lifetime, Newton wrote more on religion than he did on natural science. He believed in a rationally immanent world, but he rejected the hylozoism implicit in Leibniz and Baruch Spinoza. Thus, the ordered and dynamically informed universe could be understood, and must be understood, by an active reason, but this universe, to be perfect and ordained, had to be regular.
## Newton's effect on religious thought
Newton and Robert Boyle’s mechanical philosophy was promoted by rationalist pamphleteers as a viable alternative to the pantheists and enthusiasts, and was accepted hesitantly by orthodox preachers as well as dissident preachers like the latitudinarians.[20] Thus, the clarity and simplicity of science was seen as a way to combat the emotional and metaphysical superlatives of both superstitious enthusiasm and the threat of atheism,[21] and, at the same time, the second wave of English deists used Newton's discoveries to demonstrate the possibility of a "Natural Religion."
The attacks made against pre-Enlightenment "magical thinking," and the mystical elements of Christianity, were given their foundation with Boyle’s mechanical conception of the universe. Newton gave Boyle’s ideas their completion through mathematical proofs and, perhaps more importantly, was very successful in popularising them.[22] Newton refashioned the world governed by an interventionist God into a world crafted by a God that designs along rational and universal principles.[23] These principles were available for all people to discover, allowed people to pursue their own aims fruitfully in this life, not the next, and to perfect themselves with their own rational powers.[24]
Newton saw God as the master creator whose existence could not be denied in the face of the grandeur of all creation.[25][26][27] But the unforeseen theological consequence of his conception of God, as Leibniz pointed out, was that God was now entirely removed from the world’s affairs, since the need for intervention would only evidence some imperfection in God’s creation, something impossible for a perfect and omnipotent creator.[28] Leibniz's theodicy cleared God from the responsibility for "l'origine du mal" by making God removed from participation in his creation. The understanding of the world was now brought down to the level of simple human reason, and humans, as Odo Marquard argued, became responsible for the correction and elimination of evil.[29]
On the other hand, latitudinarian and Newtonian ideas taken too far resulted in the millenarians, a religious faction dedicated to the concept of a mechanical universe, but finding in it the same enthusiasm and mysticism that the Enlightenment had fought so hard to extinguish.[30]
## Views of the end of the world
In a manuscript he wrote in 1704 in which he describes his attempts to extract scientific information from the Bible, he estimated that the world would end no earlier than 2060. In predicting this he said, "This I mention not to assert when the time of the end shall be, but to put a stop to the rash conjectures of fanciful men who are frequently predicting the time of the end, and by doing so bring the sacred prophesies into discredit as often as their predictions fail."[31]
# Newton and the counterfeiters
As warden of the Royal Mint, Newton estimated that 20% of the coins taken in during The Great Recoinage were counterfeit. Counterfeiting was high treason, punishable by being hanged, drawn and quartered. Despite this, convictions of the most flagrant criminals could be extremely difficult to achieve; however, Newton proved to be equal to the task.
Disguised as an habitué of bars and taverns, he gathered much of that evidence himself. For all the barriers placed to prosecution, and separating the branches of government, English law still had ancient and formidable customs of authority. Newton was made a justice of the peace and between June 1698 and Christmas 1699 conducted some 200 cross-examinations of witnesses, informers and suspects. Newton won his convictions and in February 1699, he had ten prisoners waiting to be executed.
Possibly Newton's greatest triumph as the king's attorney was against William Chaloner. One of Chaloner's schemes was to set up phony conspiracies of Catholics and then turn in the hapless conspirators whom he entrapped. Chaloner made himself rich enough to posture as a gentleman. Petitioning Parliament, Chaloner accused the Mint of providing tools to counterfeiters (a charge also made by others). He proposed that he be allowed to inspect the Mint's processes in order to improve them. He petitioned Parliament to adopt his plans for a coinage that could not be counterfeited, while at the same time striking false coins. Newton was outraged, and went about the work to uncover anything about Chaloner. During his studies, he found that Chaloner was engaged in counterfeiting. He immediately put Chaloner on trial, but Chaloner had friends in high places and, to Newton's horror, Chaloner walked free. Newton put him on trial a second time with conclusive evidence. Chaloner was convicted of high treason and hanged, drawn and quartered on 23 March 1699 at Tyburn gallows.[32]
# Enlightenment philosophers
Enlightenment philosophers chose a short history of scientific predecessors—Galileo, Boyle, and Newton principally—as the guides and guarantors of their applications of the singular concept of Nature and Natural Law to every physical and social field of the day. In this respect, the lessons of history and the social structures built upon it could be discarded.[33]
It was Newton’s conception of the universe based upon Natural and rationally understandable laws that became the seed for Enlightenment ideology. Locke and Voltaire applied concepts of Natural Law to political systems advocating intrinsic rights; the physiocrats and Adam Smith applied Natural conceptions of psychology and self-interest to economic systems and the sociologists criticised the current social order for trying to fit history into Natural models of progress. Monboddo and Samuel Clarke resisted elements of Newton's work, but eventually rationalised it to conform with their strong religious views of nature.
# Newton's laws of motion
Template:Classical mechanics
The famous three laws of motion:
Newton's First Law (also known as the Law of Inertia) states that an object at rest tends to stay at rest and that an object in uniform motion tends to stay in uniform motion unless acted upon by a net external force.
Newton's Second Law states that an applied force, <math>\scriptstyle{\vec{F}}</math>, on an object equals the rate of change of its momentum, <math>\scriptstyle{\vec{p}}</math>, with time. Mathematically, this is expressed as
Because this relation only holds when the mass is constant, that is, when <math>\scriptstyle{dm/dt=0}</math>, the first term vanishes, and the equation can be written it the iconic form
where
This equation states that a force <math>\scriptstyle{\vec{F}}</math> applied to an object of mass <math>m</math> causes it to accelerate at a rate <math>\scriptstyle{\vec{a}}</math>.
This equality requires a consistent set of units for measuring mass, length, and time. One such set is the SI system, where mass is in kilograms, length in metres, and time in seconds. This leads to force being in newtons, named in his honour, and acceleration in metres per second per second. The English analogous system is slugs, feet, and seconds.
Newton's Third Law states that for every action there is an equal and opposite reaction. This means that any force exerted onto an object has a counterpart force that is exerted in the opposite direction back onto the first object. The most common example is of two ice skaters pushing against each other and sliding apart in opposite directions. Another example is the recoil of a firearm, in which the force propelling the bullet is exerted equally back onto the gun and is felt by the shooter. Since the objects in question do not necessarily have the same mass, the resulting acceleration of the two objects can be different (as in the case of firearm recoil).
# Newton's apple
Template:Double image stack
A popular story claims that Newton was inspired to formulate his theory of universal gravitation by the fall of an apple from a tree. Cartoons have gone further to suggest the apple actually hit Newton's head, and that its impact somehow made him aware of the force of gravity. John Conduitt, Newton's assistant at the Royal Mint and husband of Newton's niece, described the event when he wrote about Newton's life:
The question was not whether gravity existed, but whether it extended so far from Earth that it could also be the force holding the moon to its orbit. Newton showed that if the force decreased as the inverse square of the distance, one could indeed calculate the Moon's orbital period, and get good agreement. He guessed the same force was responsible for other orbital motions, and hence named it "universal gravitation".
A contemporary writer, William Stukeley, recorded in his Memoirs of Sir Isaac Newton's Life a conversation with Newton in Kensington on 15 April 1726, in which Newton recalled "when formerly, the notion of gravitation came into his mind. It was occasioned by the fall of an apple, as he sat in contemplative mood. Why should that apple always descend perpendicularly to the ground, thought he to himself. Why should it not go sideways or upwards, but constantly to the earth's centre." In similar terms, Voltaire wrote in his Essay on Epic Poetry (1727), "Sir Isaac Newton walking in his gardens, had the first thought of his system of gravitation, upon seeing an apple falling from a tree." These accounts are probably exaggerations of Newton's own tale about sitting by a window in his home (Woolsthorpe Manor) and watching an apple fall from a tree.
Various trees are claimed to be "the" apple tree which Newton describes. The King's School, Grantham, claims that the tree was purchased by the school, uprooted and transported to the headmaster's garden some years later, the staff of the [now] National Trust-owned Woolsthorpe Manor dispute this, and claim that a tree present in their gardens is the one described by Newton. A descendant of the original tree can be seen growing outside the main gate of Trinity College, Cambridge, below the room Newton lived in when he studied there. The National Fruit Collection at Brogdale[36] can supply grafts from their tree (ref 1948-729), which appears identical to Flower of Kent, a coarse-fleshed cooking variety.
# Writings by Newton
- Method of Fluxions (1671)
- Of Natures Obvious Laws & Processes in Vegetation (unpublished, c. 1671–75)[37]
- De Motu Corporum in Gyrum (1684)
- Philosophiae Naturalis Principia Mathematica (1687)
- Opticks (1704)
- Reports as Master of the Mint (1701–25)
- Arithmetica Universalis (1707)
- The System of the World, Optical Lectures, The Chronology of Ancient Kingdoms, (Amended) and De mundi systemate (published posthumously in 1728)
- Observations on Daniel and The Apocalypse of St. John (1733)
- An Historical Account of Two Notable Corruptions of Scripture (1754)
# Fame
French mathematician Joseph-Louis Lagrange often said that Newton was the greatest genius who ever lived, and once added that he was also "the most fortunate, for we cannot find more than once a system of the world to establish."[38] English poet Alexander Pope was moved by Newton's accomplishments to write the famous epitaph:
Newton himself was rather more modest of his own achievements, famously writing in a letter to Robert Hooke in February 1676
Historians generally think the above quote was an attack on Hooke (who was short and hunchbacked), rather than– or in addition to– a statement of modesty. The two were in a dispute over optical discoveries at the time. The latter interpretation also fits with many of his other disputes over his discoveries– such as the question of who discovered calculus as discussed above.
And then in a memoir later
# Newton in popular culture
Newton is an important character in The Baroque Cycle by Neal Stephenson. A major theme of these novels is the emergence of modern science, with Newton's work in the Principia being prominent. Newton's interest in alchemy and the dispute over the discovery of calculus are prominent plot points, and there is a (fictional) debate on metaphysics between Newton and Gottfried Leibniz moderated by Caroline of Ansbach. The development of an economy based on money and credit is also a major theme, with Newton's time with the Royal Mint and intrigues against counterfeit leading to a Trial of the Pyx. | https://www.wikidoc.org/index.php/Isaac_Newton | |
a3bb2ea04f652a55fd70ad41ec5be22a42a5c89e | wikidoc | Isoquinoline | Isoquinoline
Isoquinoline, also known as benzopyridine or 2-benzanine, is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline derivatives. Isoquinoline is the structural backbone in naturally occurring alkaloids including papaverine and morphine. The isoquinoline ring in these natural compound derives from the aromatic amino acid tyrosine.
# Properties
Isoquinoline is a colorless hygroscopic liquid at room temperature with a penetrating, unpleasant odor. Impure samples can appear brownish, as is typical for nitrogen heterocycles. It crystallizes platelets that have a low solubility in water but dissolve well in ethanol, acetone, ethyl ether, carbon disulfide, and other common organic solvents. It is also soluble in dilute acids as the protonated derivative.
Being an analog of pyridine, isoquinoline is a weak base, with a pKb of 8.6. It protonates to form salts upon treatment with strong acids, such as HCl. It forms adducts with Lewis acids, such as BF3.
# Production
Isoquinolone was first isolated from coal tar in 1885 by Hoogewerf and van Dorp. They isolated it by fractional crystallization of the acid sulfate. Weissgerber developed a more rapid route in 1914 by selective extraction of coal tar, exploiting the fact that isoquinoline is more basic than quinoline. Isoquinoline can then be isolated from the mixture by fractional crystallization of the acid sulphate.
Although isoquinoline derivatives can be synthesized by several methods, relatively few direct methods deliver the unsubstituted isoquinoline. The Pomeranz-Fritsch reaction provides an efficient method for the preparation of isoquinoline:
- The Pomeranz-Fritsch reaction uses a benzaldehyde and aminoacetoaldehyde diethyl acetal, which in an acid medium react to form isoquinoline. Alternatively, benzylamine and a glyoxal acetal can be used, to produce the same result.
File:Pomeranz-fritsch.gif
The following methods are useful for the preparation of various isoquinoline derivatives:
- In the Bischler-Napieralski reaction an β-phenylethylamine is acylated and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or phosphorus pentoxide. The resulting 1-substituted-3,4-dihydroisoquinoline can then be dehydrogenated using palladium. The following Bischler-Napieralski reaction produces papaverine.
- The Pictet-Gams and Pictet-Spengler syntheses are both variations on the Bischler-Napieralski reaction. The differences are as follows:
- The Pictet-Gams reaction avoids the final dehydrogenation step of the Bischler-Napieralski reaction by constructing a β-phenylethylamine with a hydroxy group in the side chain. This reaction results in a 1-alkyl-isoquinoline.
- The Pictet-Spengler reaction combines a β-phenylethylamine and an aldehyde in an acid medium, which cyclizes the imine in a reaction of the Mannich type. This produces the tetrahydroisoquinoline instead of the dihydroisoquinoline.
- Intramolecular aza Wittig reactions also afford isoquinolines.
# Applications of derivatives
Isoquinolines find many applicatons, including (but not limited to):
- anesthetics; dimethisoquin is one example (shown below).
File:Dimethisoquin.gif
- antihypertension agents, such as quinapril, quinapirilat, and debrisoquine (all derived from 1,2,3,4-tetrahydroisoquinoline).
- antifungal agents, such as 2,2'Hexadecamethylenediisoquinolinium dichloride, which is also used as a topical antiseptic. This derivative, shown below, is prepared by N-alkylation of isoquinoline with the appropriate dihalide.
File:Antifungal ex.gif
- disinfectants, like N-laurylisoquinolinium bromide (shown below), which is prepared by simple N-alkylation of isoquinoline.
File:N-laurylisoquin.gif
- vasodilators, a well-known example, papaverine, shown below.
File:Papaverine.gif
Bisbenzylisoquinolinium compounds are compounds similar in structure to tubocurarine. They have two isoquinolinium structures, linked by a carbon chain, containing two ester linkages.
# Isoquinolines and the human body
Parkinson's disease, a slowly progressing movement disorder, is thought to be caused by certain neurotoxins. A neurotoxin called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the precursor to MPP+, was found and linked to Parkinson's disease in the 1980's. The active neurotoxins destroy dopaminergic neurons, leading to parkinsonism and Parkinson's disease. Several tetrahydroisoquinoline derivatives have been found to have the same neurochemical properties as MPTP. These derivatives may act as neurotoxin precursors to active neurotoxins.
# Other uses
Isoquinolines are used in the manufacture of dyes, paints, insecticides and antifungals. It is also used as a solvent for the extraction of resins an terpenes, and as a corrosion inhibitor. | Isoquinoline
Template:Chembox new
Isoquinoline, also known as benzo[c]pyridine or 2-benzanine, is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline derivatives. Isoquinoline is the structural backbone in naturally occurring alkaloids including papaverine and morphine. The isoquinoline ring in these natural compound derives from the aromatic amino acid tyrosine.
# Properties
Isoquinoline is a colorless hygroscopic liquid at room temperature with a penetrating, unpleasant odor. Impure samples can appear brownish, as is typical for nitrogen heterocycles. It crystallizes platelets that have a low solubility in water but dissolve well in ethanol, acetone, ethyl ether, carbon disulfide, and other common organic solvents. It is also soluble in dilute acids as the protonated derivative.
Being an analog of pyridine, isoquinoline is a weak base, with a pKb of 8.6. It protonates to form salts upon treatment with strong acids, such as HCl. It forms adducts with Lewis acids, such as BF3.
# Production
Isoquinolone was first isolated from coal tar in 1885 by Hoogewerf and van Dorp. They isolated it by fractional crystallization of the acid sulfate. Weissgerber developed a more rapid route in 1914 by selective extraction of coal tar, exploiting the fact that isoquinoline is more basic than quinoline. Isoquinoline can then be isolated from the mixture by fractional crystallization of the acid sulphate.
Although isoquinoline derivatives can be synthesized by several methods, relatively few direct methods deliver the unsubstituted isoquinoline. The Pomeranz-Fritsch reaction provides an efficient method for the preparation of isoquinoline:
- The Pomeranz-Fritsch reaction uses a benzaldehyde and aminoacetoaldehyde diethyl acetal, which in an acid medium react to form isoquinoline. Alternatively, benzylamine and a glyoxal acetal can be used, to produce the same result.
File:Pomeranz-fritsch.gif
The following methods are useful for the preparation of various isoquinoline derivatives:
- In the Bischler-Napieralski reaction an β-phenylethylamine is acylated and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or phosphorus pentoxide. The resulting 1-substituted-3,4-dihydroisoquinoline can then be dehydrogenated using palladium. The following Bischler-Napieralski reaction produces papaverine.
- The Pictet-Gams and Pictet-Spengler syntheses are both variations on the Bischler-Napieralski reaction. The differences are as follows:
- The Pictet-Gams reaction avoids the final dehydrogenation step of the Bischler-Napieralski reaction by constructing a β-phenylethylamine with a hydroxy group in the side chain. This reaction results in a 1-alkyl-isoquinoline.
- The Pictet-Spengler reaction combines a β-phenylethylamine and an aldehyde in an acid medium, which cyclizes the imine in a reaction of the Mannich type. This produces the tetrahydroisoquinoline instead of the dihydroisoquinoline.
- Intramolecular aza Wittig reactions also afford isoquinolines.
# Applications of derivatives
Isoquinolines find many applicatons, including (but not limited to):
- anesthetics; dimethisoquin is one example (shown below).
File:Dimethisoquin.gif
- antihypertension agents, such as quinapril, quinapirilat, and debrisoquine (all derived from 1,2,3,4-tetrahydroisoquinoline).
- antifungal agents, such as 2,2'Hexadecamethylenediisoquinolinium dichloride, which is also used as a topical antiseptic. This derivative, shown below, is prepared by N-alkylation of isoquinoline with the appropriate dihalide.
File:Antifungal ex.gif
- disinfectants, like N-laurylisoquinolinium bromide (shown below), which is prepared by simple N-alkylation of isoquinoline.
File:N-laurylisoquin.gif
- vasodilators, a well-known example, papaverine, shown below.
File:Papaverine.gif
Bisbenzylisoquinolinium compounds are compounds similar in structure to tubocurarine. They have two isoquinolinium structures, linked by a carbon chain, containing two ester linkages.
# Isoquinolines and the human body
Parkinson's disease, a slowly progressing movement disorder, is thought to be caused by certain neurotoxins. A neurotoxin called MPTP (1[N]-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the precursor to MPP+, was found and linked to Parkinson's disease in the 1980's. The active neurotoxins destroy dopaminergic neurons, leading to parkinsonism and Parkinson's disease. Several tetrahydroisoquinoline derivatives have been found to have the same neurochemical properties as MPTP. These derivatives may act as neurotoxin precursors to active neurotoxins.
# Other uses
Isoquinolines are used in the manufacture of dyes, paints, insecticides and antifungals. It is also used as a solvent for the extraction of resins an terpenes, and as a corrosion inhibitor. | https://www.wikidoc.org/index.php/Isoquinoline | |
2526558693463e3a11ec996cddf537bb0ba8505c | wikidoc | Itraconazole | Itraconazole
- Congestive Heart Failure, Cardiac Effects and Drug Interactions
- blastomycosis, pulmonary and extrapulmonary
- histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and
- aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.
- Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly.
- Itraconazole capsules are also indicated for the treatment of the following fungal infectionsin non-immunocompromised patients:
- onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and
- onychomycosis of the fingernail due to dermatophytes (tinea unguium).
Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.
# Description of Clinical Studies
- Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.
- Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.
- Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.
- Analyses were conducted on data from an open-label, "single-patient-use" protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 mg to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.
- Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given itraconazole capsules) in which patients with onychomycosis of the toenails received 200 mg of itraconazole capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).
- Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given itraconazole capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of itraconazole capsules b.i.d., followed by a 3-week period without itraconazole, which was followed by a second 1-week pulse of 200 mg of itraconazole capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed.
# Dosing Information
- Itraconazole capsules should be taken with a full meal to ensure maximal absorption. Itraconazole capsules must be swallowed whole.
- Itraconazole capsules is a different preparation than itraconazole oral solution and should not be used interchangeably.
- The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses.
- A daily dose of 200 mg to 400 mg is recommended.
- In life-threatening situations, a loading dose should be used.
- Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (400 mg/day) be given for the first 3 days of treatment.
- Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.
- Itraconazole capsules and itraconazole oral solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.
- Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.
- Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without itraconazole.
- Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population (see CLINICAL PHARMACOLOGY, SPECIAL POPULATIONS and PRECAUTIONS).
- Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population.
- Allergic bronchopulmonary aspergillosis
- Candidal vulvovaginitis
- Candidal vulvovaginitis - HIV infection
- Chromoblastomycosis
- Chromoblastomycosi
- Coccidioidomycosis
- Coccidioidomycosis; Prophylaxis - HIV infection
- Coccidioidomycosis - HIV infection
- Cryptococcal meningitis - HIV infection
- CryptococcosisView
- Febrile neutropenia, Empiric antifungal therapy
- histoplasmosis, Central Nervous System - HIV infection
- histoplasmosis; Prophylaxis - HIV infection
- Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.
- Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole. Plasma concentrations increase for the following drugs: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effect and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia.
- Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.
- Itraconazole is contraindicated for patients who have shown hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing itraconazole to patients with hypersensitivity to other azoles.
- Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole is contraindicated.
- Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Itraconazole capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.
- For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of itraconazole capsules, discontinue administration.
- Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.
- Itraconazole has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.
- Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and felodipine or nisoldipine is contraindicated.
- Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections.
# Interaction Potential
- Itraconazole has a potential for clinically important drug interactions. Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS, DRUG INTERACTIONS.
# Interchangeability
- Itraconazole capsules and itraconazole oral solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.
# PRECAUTIONS
- Itraconazole capsules should be administered after a full meal.
- Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a non-diet cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown.
- Rare cases of serious hepatotoxicity have been observed with itraconazole treatment, including some cases within the first week. It is recommended that liver function monitoring be considered in all patients receiving itraconazole. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.
- If neuropathy occurs that may be attributable to itraconazole capsules, the treatment should be discontinued.
- Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
- Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of itraconazole use should be reassessed.
- Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients.
- Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain.
- Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks.
- The following adverse events led to temporary or permanent discontinuation of therapy.
- The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%.
- Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug.
- The following adverse events led to temporary or permanent discontinuation of therapy.
- The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%.
- There is limited information on the use of itraconazole during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with itraconazole has not been established.
- Itraconazole is mainly metabolized through CYP3A4. Other drugs that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other drugs that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust dosages.
- Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from itraconazole capsules. It is recommended that these drugs be used with caution when coadministered with itraconazole capsules:
- It is recommended that itraconazole capsules be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity.
- It is recommended that acid neutralizing medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of itraconazole capsules.
- Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
- Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Examples include:
- Antibacterials: isoniazid, rifabutin (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), rifampicin
Anticonvulsants: carbamazepine, (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), phenobarbital, phenytoin
- Antivirals: efavirenz, nevirapine
- Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
- Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include:
- Antibacterials: ciprofloxacin, clarithromycin, erythromycin
- Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), ritonavir (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE')
- It is recommended that these drugs be used with caution when coadministered with itraconazole capsules. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary.
- Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.
- Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding coadministration with itraconazole:
- Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, and its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adjusted if necessary.
- There are no studies in pregnant women. Itraconazole should be used for the treatment of systemic fungal infectionsin pregnancy only if the benefit outweighs the potential risk.
- Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout itraconazole therapy and for 2 months following the end of treatment.
- During post-marketing experience, cases of congenital abnormalities have been reported.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Itraconazole in women who are pregnant.
- The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5× MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10× MRHD) over 1 year or 160 mg/kg/day (20× MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.
- Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated.
- In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications.
- Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased.
- Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Itraconazole capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.
- For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of itraconazole capsules, discontinue administration.
- Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.
- Itraconazole has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.
- Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and felodipine or nisoldipine is contraindicated.
- Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections.
- Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.
- In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications.
- Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from itraconazole capsules. It is recommended that these drugs be used with caution when coadministered with itraconazole capsules:
- It is recommended that itraconazole capsules be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity.
- It is recommended that acid neutralizing medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of itraconazole capsules.
- Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
- Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Examples include:
- Antibacterials: isoniazid, rifabutin (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), rifampicin
Anticonvulsants: carbamazepine, (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), phenobarbital, phenytoin
- Antivirals: efavirenz, nevirapine
- Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
- Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include:
- Antibacterials: ciprofloxacin, clarithromycin, erythromycin
- Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), ritonavir (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE')
- It is recommended that these drugs be used with caution when coadministered with itraconazole capsules. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary.
- Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, and its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adjusted if necessary.
- Itraconazole exhibits in vitro activity against Blastomycesdermatitidis, Histoplasmacapsulatum, Histoplasmaduboisii, Aspergillusflavus, Aspergillusfumigatus, and Trichophyton species (see INDICATIONS AND USAGE, DESCRIPTION OF CLINICAL STUDIES).
- Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents.
- Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy.
- Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
- Several in vitro studies have reported that some fungal clinical isolates with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed.
- Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillusfumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.
- Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/ml, 1.1 μg/ml and 2.0 μg/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.
- Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%.
- The oral bioavailability of itraconazole is maximal when itraconazole capsules are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases (see PRECAUTIONS, DRUG INTERACTIONS). Absorption of itraconazole under fasted conditions in these subjects is increased when itraconazole capsules are administered with an acidic beverage (such as a non-diet cola). When itraconazole capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that observed when itraconazole capsules were administered alone.
- Itraconazole exposure is lower with the Capsule formulation than with the Oral Solution when the same dose of drug is given (see WARNINGS).
- Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (>700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma.
- Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole.
- Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose.
- As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for at least six months after the end of a 3-month treatment period.
# Special Populations
- Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg oral dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0–8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50 ml/min to 79 ml/min), moderate (defined in this study as CrCl 20 ml/min to 49 ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were similar to that in healthy subjects (range of means 42 to 49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole (see PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
- Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as capsule. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole.
- Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10× the maximum recommended human dose ). Male rats treated with 25 mg/kg/day (3.1× MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25× MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant.
- Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.
- Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5× MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20× MRHD).
100 mg: Aqua blue opaque cap, light blue clear body, imprinted “E 550” in black ink on cap and body, filled with white to off-white pellets and supplied as:
NDC 0185-0550-28 bottles of 28
NDC 0185-0550-30 bottles of 30
NDC 0185-0550-01 bottles of 100
NDC 0185-0550-05 bottles of 500
NDC 0185-0550-83 7-Day Treatment Pack (cartons containing 7 blister packs of 4 capsules each).
Protect from light and moisture.
Keep out of reach of children.
Itraconazole Capsules
100 mg
PHARMACIST: Please dispense with Patient Information provided.
Rx only
30 Capsules
Sandoz
1 Cut
2 Tear
Lot : XX0000
Itraconazole Capsules
Each capsule contains
itraconazole 100 mg
1 Cut
2 Tear
EXP: 00/00
A.M.
Take two 100 mg capsules with a meal in the morning.
N (01) 0 03 0185-0550-90 6
Sandoz
Store at 20°-25°C (68°-77°F) .
Protect from light and moisture. L0622 Rev 09/12
Lot : XX0000
Itraconazole Capsules
Each capsule contains
itraconazole 100 mg
2 Tear
1 Cut
EXP: 00/00
P.M.
Take two 100 mg capsules with a meal in the evening.
N (01) 0 03 0185-0550-90 6
2 Tear
1 Cut
L0615
Rev. 11/10
Fold and tear at notch or
Itraconazole Capsules, 100 mg
This pouch contains four 100 mg capsules, one complete day of treatment
4 x 100 mg Capsules
NDC 0185-0550-83
Itraconazole Capsules
100 mg
Rx only
28 Capsules
7-Day Treatment Pack
- 7 days of treatment
- Information guide
Sandoz
A Novartis company
- The topical effects of mucosal exposure may be different between the itraconazole capsules and oral solution. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Itraconazole capsules should not be used interchangeably with itraconazole oral solution.
- Instruct patients to take itraconazole capsules with a full meal. Itraconazole capsules must be swallowed whole.
- Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during itraconazole administration, they should discontinue itraconazole and contact their healthcare provider immediately.
- Instruct patients to stop itraconazole treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.
- Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.
- Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur.
- Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines.
- This summary contains important information about itraconazole (eye-trah-KON-ah-zole). This information is for patients who have been prescribed itraconazole capsules to treat fungal nail infections. If your doctor prescribed itraconazole for medical problems other than fungal nail infections, ask your doctor if there is any information in this summary that does not apply to you. Read this information carefully each time you start to use itraconazole. This information does not take the place of discussion between you and your doctor. Only your doctor can decide if itraconazole is the right treatment for you. If you do not understand some of this information or have any questions, talk with your doctor or pharmacist.
- Itraconazole is used to treat fungal nail infections. However, itraconazole is not for everyone. Do not take itraconazole for fungal nail infections if you have had heart failure, including congestive heart failure. You should not take itraconazole if you are taking certain medicines that could lead to serious or life-threatening medical problems. (See "WHO SHOULD NOT TAKE ITRACONAZOLE CAPSULES?" below.)
- If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor if it is safe for you to take itraconazole.
- Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread under the nail towards the cuticle. If the fungus spreads, more of the nail may change color, may become thick or brittle, and the tip of the nail may become raised. In some patients, this can cause pain and discomfort.
- Itraconazole is a prescription medicine used to treat fungal infectionsof the toenails and fingernails. It is also used to treat some types of fungal infectionsin other areas of your body. We do not know if itraconazole works in children with fungal nail infections or if it is safe for children to take.
- Itraconazole comes in the form of capsules and liquid (oral solution). The capsule and liquid forms work differently, so you should not use one in place of the other. This Patient Information discusses only the capsule form of itraconazole. You will get these capsules in a medicine bottle or a 7-Day Treatment Pack. The 7-Day Treatment Pack contains 28 capsules for treatment of your fungal nail infection.
- Itraconazole goes into your bloodstream and travels to the source of the infection underneath the nail so that it can fight the infection there. Improved nails may not be obvious for several months after the treatment period is finished because it usually takes about 6 months to grow a new fingernail and 12 months to grow a new toenail.
- Itraconazole is not for everyone. Your doctor will decide if itraconazole is the right treatment for you. Some patients should not take itraconazole because they may have certain health problems or may be taking certain medicines that could lead to serious or life-threatening medical problems.
- Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking, including dietary supplements and herbal remedies. Also tell your doctor about any other medical conditions you have had, especially heart, lung, liver or kidney conditions; or if you have had an allergic reaction to itraconazole or any other antifungal medicines.
- have had heart failure, including congestive heart failure.
- are taking any of the medicines listed below. Dangerous or even life-threatening abnormal heartbeats could result:
- quinidine (such as Cardioquin ®, Quinaglute ®, Quinidex ®)
- dofetilide (such as Tikosyn™)
- cisapride (such as Propulsid ®)
- pimozide (such as Orap ®)
- methadone (such as Dolophine ®)
- disopyramide (such as Norpace ®)
- dronedarone (such as Multaq ®)
- ranolazine (such as Ranexa ®)
- are taking any of the following medicines:
- lovastatin (such as Mevacor ®, Advicor ®, Altocor™)
- simvastatin (such as Zocor ®)
- triazolam (such as Halcion ®)
- midazolam (such as Versed ®)
- lurasidone (such as Latuda ®)
- nisoldipine (such as Sular ®)
- felodipine (such as Plendil ®)
- ergot alkaloids (such as Migranal ®, Ergonovine, Cafergot ®, Methergine ®)
- eplerenone (such as Inspra ®)
- irinotecan (such as Camptosar ®)
- colchicine (such as Colcrys™)
- have ever had an allergic reaction to itraconazole.
- Taking itraconazole with certain other medicines could lead to serious or life-threatening medical problems. For example, taking fentanyl, a strong opioid narcotic pain medicine, with itraconazole could cause serious side effects, including trouble breathing, that may be life-threatening. Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking. Your doctor will decide if itraconazole is the right treatment for you.
- Never take itraconazole if you have a fungal nail infection and are pregnant or planning to become pregnant within 2 months after you have finished your treatment.
- If you are able to become pregnant, you should use effective birth control during itraconazole treatment and for 2 months after finishing treatment. Ask your doctor about effective types of birth control.
- If you are breast-feeding, talk with your doctor about whether you should take itraconazole.
- Always take itraconazole capsules during or right after a full meal.
- Your doctor will decide the right dose for you. Depending on your infection, you will take itraconazole once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing schedule. You will receive either a bottle of capsules or a 7-Day Treatment Pack. Do not skip any doses. Be sure to finish all your itraconazole as prescribed by your doctor.
- If you have ever had liver problems, your doctor should do a blood test to check your condition. If you haven't had liver problems, your doctor may recommend blood tests to check the condition of your liver because patients taking itraconazole can develop liver problems.
- Itraconazole can sometimes cause dizziness or blurred/double vision. If you have these symptoms, do not drive or use machines.
- If you forget to take or miss doses of itraconazole, ask your doctor what you should do with the missed doses.
- If you use the 7-Day Treatment Pack, you will take itraconazole for 1 week and then take no itraconazole for the next 3 weeks before repeating the 1-week treatment. This is called “pulse dosing.” The Itraconazole Capsules 7-Day Treatment Pack contains enough medicine for one "pulse" (1 week of treatment).
- The Itraconazole Capsules 7-Day Treatment Pack comes with special instructions. It contains 7 pouches-one for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at the back of the card, fold it back along the dashed line and peel away the backing so that you can remove 2 capsules.
- Take 2 capsules in the morning and 2 capsules in the evening. This means you will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all of the capsules in the 7-Day Treatment Pack.
- After you finish the 7-Day Treatment Pack, do not take any itraconazole for the next 3 weeks. Even though you are not taking any capsules during this time, itraconazole keeps working inside your nails to help fight the fungal infection.
- You will need more than one “pulse” to treat your fungal nail infection. When your doctor prescribes another pulse treatment, be sure to get your refill before the end of week 4.
- The most common side effects include: headache, and digestive system problems (such as nausea, and abdominal pain).
- Stop Itraconazole and call your doctor or get medical assistance right away if you have a severe allergic reaction. Symptoms of an allergic reaction may include skin rash, itching, hives, shortness of breath or difficulty breathing, and/or swelling of the face. Very rarely, an over sensitivity to sunlight, a tingling sensation in the limbs or a severe skin disorder can occur. If any of these symptoms occur, stop taking itraconazole and contact your doctor.
- Stop Itraconazole and call your doctor right away if you develop shortness of breath; have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually tired; cough up white or pink phlegm; have unusual fast heartbeats; or begin to wake up at night. In rare cases, patients taking itraconazole could develop serious heart problems, and these could be warning signs of heart failure.
- Stop Itraconazole and call your doctor right away if you become unusually tired; lose your appetite; or develop nausea, abdominal pain, or vomiting, a yellow color to your skin or eyes, or dark colored urine or pale stools (bowel movements). In rare cases, patients taking itraconazole could develop serious liver problems and these could be warning signs.
- Stop Itraconazole and call your doctor right away if you experience any hearing loss symptoms. In very rare cases, patients taking itraconazole have reported temporary or permanent hearing loss.
- Call your doctor right away if you develop tingling or numbness in your extremities (hands or feet), if your vision gets blurry or you see double, if you hear a ringing in your ears, if you lose the ability to control your urine or urinate much more than usual.
- Additional possible side effects include upset stomach, vomiting, constipation, fever, inflammation of the pancreas, menstrual disorder, erectile dysfunction, dizziness, muscle pain, painful joints, unpleasant taste, or hair loss. These are not all the side effects of itraconazole. Your doctor or pharmacist can give you a more complete list.
- If you think you took too much itraconazole, call your doctor or local poison control center, or go to the nearest hospital emergency room right away.
- Keep all medicines, including itraconazole, out of the reach of children.
- Store itraconazole capsules and the 7-Day Treatment Pack at room temperature in a dry place away from light.
- Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use itraconazole for a condition for which it was not prescribed. Do not give itraconazole to other people, even if they have the same symptoms you have. It may harm them.
- This leaflet summarizes the most important information about itraconazole. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about itraconazole that is written for health professionals.
- This patient information has been approved by the U.S. Food and Drug Administration.
- For Patient Information, please visit WWW.US.SANDOZ.COM or call 1-800-507-2130.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Sandoz Inc.
Princeton, NJ 08540
OS7722, Rev. 08/14
MF0550REV08/14
MG #35963
and
OS8359, Rev. 08/14
MF0550REV08/14
Onmel
[[Category:Drug | Itraconazole
- Congestive Heart Failure, Cardiac Effects and Drug Interactions
- blastomycosis, pulmonary and extrapulmonary
- histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and
- aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.
- Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly.
- Itraconazole capsules are also indicated for the treatment of the following fungal infectionsin non-immunocompromised patients:
- onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and
- onychomycosis of the fingernail due to dermatophytes (tinea unguium).
Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.
### Description of Clinical Studies
- Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.
- Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.
- Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.
- Analyses were conducted on data from an open-label, "single-patient-use" protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 mg to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.
- Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given itraconazole capsules) in which patients with onychomycosis of the toenails received 200 mg of itraconazole capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).
- Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given itraconazole capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of itraconazole capsules b.i.d., followed by a 3-week period without itraconazole, which was followed by a second 1-week pulse of 200 mg of itraconazole capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed.
### Dosing Information
- Itraconazole capsules should be taken with a full meal to ensure maximal absorption. Itraconazole capsules must be swallowed whole.
- Itraconazole capsules is a different preparation than itraconazole oral solution and should not be used interchangeably.
- The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses.
- A daily dose of 200 mg to 400 mg is recommended.
- In life-threatening situations, a loading dose should be used.
- Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (400 mg/day) be given for the first 3 days of treatment.
- Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.
- Itraconazole capsules and itraconazole oral solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.
- Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.
- Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without itraconazole.
- Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population (see CLINICAL PHARMACOLOGY, SPECIAL POPULATIONS and PRECAUTIONS).
- Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population.
- Allergic bronchopulmonary aspergillosis
- Candidal vulvovaginitis
- Candidal vulvovaginitis - HIV infection
- Chromoblastomycosis
- Chromoblastomycosi
- Coccidioidomycosis
- Coccidioidomycosis; Prophylaxis - HIV infection
- Coccidioidomycosis - HIV infection
- Cryptococcal meningitis - HIV infection
- CryptococcosisView
- Febrile neutropenia, Empiric antifungal therapy
- histoplasmosis, Central Nervous System - HIV infection
- histoplasmosis; Prophylaxis - HIV infection
- Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.
- Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole. Plasma concentrations increase for the following drugs: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effect and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia.
- Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.
- Itraconazole is contraindicated for patients who have shown hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing itraconazole to patients with hypersensitivity to other azoles.
- Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole is contraindicated.
- Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Itraconazole capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.
- For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of itraconazole capsules, discontinue administration.
- Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.
- Itraconazole has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.
- Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and felodipine or nisoldipine is contraindicated.
- Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections.
### Interaction Potential
- Itraconazole has a potential for clinically important drug interactions. Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS, DRUG INTERACTIONS.
### Interchangeability
- Itraconazole capsules and itraconazole oral solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.
### PRECAUTIONS
- Itraconazole capsules should be administered after a full meal.
- Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a non-diet cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown.
- Rare cases of serious hepatotoxicity have been observed with itraconazole treatment, including some cases within the first week. It is recommended that liver function monitoring be considered in all patients receiving itraconazole. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.
- If neuropathy occurs that may be attributable to itraconazole capsules, the treatment should be discontinued.
- Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
- Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of itraconazole use should be reassessed.
- Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients.
- Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain.
- Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks.
- The following adverse events led to temporary or permanent discontinuation of therapy.
- The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%.
- Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug.
- The following adverse events led to temporary or permanent discontinuation of therapy.
- The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%.
- There is limited information on the use of itraconazole during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with itraconazole has not been established.
- Itraconazole is mainly metabolized through CYP3A4. Other drugs that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other drugs that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust dosages.
- Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from itraconazole capsules. It is recommended that these drugs be used with caution when coadministered with itraconazole capsules:
- It is recommended that itraconazole capsules be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity.
- It is recommended that acid neutralizing medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of itraconazole capsules.
- Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
- Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Examples include:
- Antibacterials: isoniazid, rifabutin (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), rifampicin
Anticonvulsants: carbamazepine, (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), phenobarbital, phenytoin
- Antivirals: efavirenz, nevirapine
- Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
- Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include:
- Antibacterials: ciprofloxacin, clarithromycin, erythromycin
- Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), ritonavir (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE')
- It is recommended that these drugs be used with caution when coadministered with itraconazole capsules. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary.
- Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.
- Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding coadministration with itraconazole:
- Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, and its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adjusted if necessary.
- There are no studies in pregnant women. Itraconazole should be used for the treatment of systemic fungal infectionsin pregnancy only if the benefit outweighs the potential risk.
- Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout itraconazole therapy and for 2 months following the end of treatment.
- During post-marketing experience, cases of congenital abnormalities have been reported.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Itraconazole in women who are pregnant.
- The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5× MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10× MRHD) over 1 year or 160 mg/kg/day (20× MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.
- Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated.
- In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications.
- Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased.
- Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Itraconazole capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.
- For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of itraconazole capsules, discontinue administration.
- Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.
- Itraconazole has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.
- Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and felodipine or nisoldipine is contraindicated.
- Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections.
- Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.
- In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications.
- Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from itraconazole capsules. It is recommended that these drugs be used with caution when coadministered with itraconazole capsules:
- It is recommended that itraconazole capsules be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity.
- It is recommended that acid neutralizing medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of itraconazole capsules.
- Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
- Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Examples include:
- Antibacterials: isoniazid, rifabutin (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), rifampicin
Anticonvulsants: carbamazepine, (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), phenobarbital, phenytoin
- Antivirals: efavirenz, nevirapine
- Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
- Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include:
- Antibacterials: ciprofloxacin, clarithromycin, erythromycin
- Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE'), ritonavir (see also under ' DRUGS THAT MAY HAVE THEIR PLASMA CONCENTRATIONS INCREASED BY ITRACONAZOLE')
- It is recommended that these drugs be used with caution when coadministered with itraconazole capsules. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary.
- Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, and its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adjusted if necessary.
- Itraconazole exhibits in vitro activity against Blastomycesdermatitidis, Histoplasmacapsulatum, Histoplasmaduboisii, Aspergillusflavus, Aspergillusfumigatus, and Trichophyton species (see INDICATIONS AND USAGE, DESCRIPTION OF CLINICAL STUDIES).
- Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents.
- Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy.
- Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
- Several in vitro studies have reported that some fungal clinical isolates with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed.
- Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillusfumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.
- Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/ml, 1.1 μg/ml and 2.0 μg/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.
- Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%.
- The oral bioavailability of itraconazole is maximal when itraconazole capsules are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases (see PRECAUTIONS, DRUG INTERACTIONS). Absorption of itraconazole under fasted conditions in these subjects is increased when itraconazole capsules are administered with an acidic beverage (such as a non-diet cola). When itraconazole capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that observed when itraconazole capsules were administered alone.
- Itraconazole exposure is lower with the Capsule formulation than with the Oral Solution when the same dose of drug is given (see WARNINGS).
- Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (>700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma.
- Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole.
- Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose.
- As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for at least six months after the end of a 3-month treatment period.
### Special Populations
- Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg oral dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0–8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50 ml/min to 79 ml/min), moderate (defined in this study as CrCl 20 ml/min to 49 ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were similar to that in healthy subjects (range of means 42 to 49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole (see PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
- Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as capsule. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole.
- Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10× the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1× MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25× MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant.
- Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.
- Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5× MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20× MRHD).
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- The topical effects of mucosal exposure may be different between the itraconazole capsules and oral solution. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Itraconazole capsules should not be used interchangeably with itraconazole oral solution.
- Instruct patients to take itraconazole capsules with a full meal. Itraconazole capsules must be swallowed whole.
- Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during itraconazole administration, they should discontinue itraconazole and contact their healthcare provider immediately.
- Instruct patients to stop itraconazole treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.
- Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.
- Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur.
- Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines.
- This summary contains important information about itraconazole (eye-trah-KON-ah-zole). This information is for patients who have been prescribed itraconazole capsules to treat fungal nail infections. If your doctor prescribed itraconazole for medical problems other than fungal nail infections, ask your doctor if there is any information in this summary that does not apply to you. Read this information carefully each time you start to use itraconazole. This information does not take the place of discussion between you and your doctor. Only your doctor can decide if itraconazole is the right treatment for you. If you do not understand some of this information or have any questions, talk with your doctor or pharmacist.
- Itraconazole is used to treat fungal nail infections. However, itraconazole is not for everyone. Do not take itraconazole for fungal nail infections if you have had heart failure, including congestive heart failure. You should not take itraconazole if you are taking certain medicines that could lead to serious or life-threatening medical problems. (See "WHO SHOULD NOT TAKE ITRACONAZOLE CAPSULES?" below.)
- If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor if it is safe for you to take itraconazole.
- Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread under the nail towards the cuticle. If the fungus spreads, more of the nail may change color, may become thick or brittle, and the tip of the nail may become raised. In some patients, this can cause pain and discomfort.
- Itraconazole is a prescription medicine used to treat fungal infectionsof the toenails and fingernails. It is also used to treat some types of fungal infectionsin other areas of your body. We do not know if itraconazole works in children with fungal nail infections or if it is safe for children to take.
- Itraconazole comes in the form of capsules and liquid (oral solution). The capsule and liquid forms work differently, so you should not use one in place of the other. This Patient Information discusses only the capsule form of itraconazole. You will get these capsules in a medicine bottle or a 7-Day Treatment Pack. The 7-Day Treatment Pack contains 28 capsules for treatment of your fungal nail infection.
- Itraconazole goes into your bloodstream and travels to the source of the infection underneath the nail so that it can fight the infection there. Improved nails may not be obvious for several months after the treatment period is finished because it usually takes about 6 months to grow a new fingernail and 12 months to grow a new toenail.
- Itraconazole is not for everyone. Your doctor will decide if itraconazole is the right treatment for you. Some patients should not take itraconazole because they may have certain health problems or may be taking certain medicines that could lead to serious or life-threatening medical problems.
- Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking, including dietary supplements and herbal remedies. Also tell your doctor about any other medical conditions you have had, especially heart, lung, liver or kidney conditions; or if you have had an allergic reaction to itraconazole or any other antifungal medicines.
- have had heart failure, including congestive heart failure.
- are taking any of the medicines listed below. Dangerous or even life-threatening abnormal heartbeats could result:
- quinidine (such as Cardioquin ®, Quinaglute ®, Quinidex ®)
- dofetilide (such as Tikosyn™)
- cisapride (such as Propulsid ®)
- pimozide (such as Orap ®)
- methadone (such as Dolophine ®)
- disopyramide (such as Norpace ®)
- dronedarone (such as Multaq ®)
- ranolazine (such as Ranexa ®)
- are taking any of the following medicines:
- lovastatin (such as Mevacor ®, Advicor ®, Altocor™)
- simvastatin (such as Zocor ®)
- triazolam (such as Halcion ®)
- midazolam (such as Versed ®)
- lurasidone (such as Latuda ®)
- nisoldipine (such as Sular ®)
- felodipine (such as Plendil ®)
- ergot alkaloids (such as Migranal ®, Ergonovine, Cafergot ®, Methergine ®)
- eplerenone (such as Inspra ®)
- irinotecan (such as Camptosar ®)
- colchicine (such as Colcrys™) [if you also have pre-existing kidney or liver impairment]
- have ever had an allergic reaction to itraconazole.
- Taking itraconazole with certain other medicines could lead to serious or life-threatening medical problems. For example, taking fentanyl, a strong opioid narcotic pain medicine, with itraconazole could cause serious side effects, including trouble breathing, that may be life-threatening. Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking. Your doctor will decide if itraconazole is the right treatment for you.
- Never take itraconazole if you have a fungal nail infection and are pregnant or planning to become pregnant within 2 months after you have finished your treatment.
- If you are able to become pregnant, you should use effective birth control during itraconazole treatment and for 2 months after finishing treatment. Ask your doctor about effective types of birth control.
- If you are breast-feeding, talk with your doctor about whether you should take itraconazole.
- Always take itraconazole capsules during or right after a full meal.
- Your doctor will decide the right dose for you. Depending on your infection, you will take itraconazole once a day for 12 weeks, or twice a day for 1 week in a “pulse” dosing schedule. You will receive either a bottle of capsules or a 7-Day Treatment Pack. Do not skip any doses. Be sure to finish all your itraconazole as prescribed by your doctor.
- If you have ever had liver problems, your doctor should do a blood test to check your condition. If you haven't had liver problems, your doctor may recommend blood tests to check the condition of your liver because patients taking itraconazole can develop liver problems.
- Itraconazole can sometimes cause dizziness or blurred/double vision. If you have these symptoms, do not drive or use machines.
- If you forget to take or miss doses of itraconazole, ask your doctor what you should do with the missed doses.
- If you use the 7-Day Treatment Pack, you will take itraconazole for 1 week and then take no itraconazole for the next 3 weeks before repeating the 1-week treatment. This is called “pulse dosing.” The Itraconazole Capsules 7-Day Treatment Pack contains enough medicine for one "pulse" (1 week of treatment).
- The Itraconazole Capsules 7-Day Treatment Pack comes with special instructions. It contains 7 pouches-one for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at the back of the card, fold it back along the dashed line and peel away the backing so that you can remove 2 capsules.
- Take 2 capsules in the morning and 2 capsules in the evening. This means you will take 4 capsules a day for 7 days. At the end of 7 days, you will have taken all of the capsules in the 7-Day Treatment Pack.
- After you finish the 7-Day Treatment Pack, do not take any itraconazole for the next 3 weeks. Even though you are not taking any capsules during this time, itraconazole keeps working inside your nails to help fight the fungal infection.
- You will need more than one “pulse” to treat your fungal nail infection. When your doctor prescribes another pulse treatment, be sure to get your refill before the end of week 4.
- The most common side effects include: headache, and digestive system problems (such as nausea, and abdominal pain).
- Stop Itraconazole and call your doctor or get medical assistance right away if you have a severe allergic reaction. Symptoms of an allergic reaction may include skin rash, itching, hives, shortness of breath or difficulty breathing, and/or swelling of the face. Very rarely, an over sensitivity to sunlight, a tingling sensation in the limbs or a severe skin disorder can occur. If any of these symptoms occur, stop taking itraconazole and contact your doctor.
- Stop Itraconazole and call your doctor right away if you develop shortness of breath; have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually tired; cough up white or pink phlegm; have unusual fast heartbeats; or begin to wake up at night. In rare cases, patients taking itraconazole could develop serious heart problems, and these could be warning signs of heart failure.
- Stop Itraconazole and call your doctor right away if you become unusually tired; lose your appetite; or develop nausea, abdominal pain, or vomiting, a yellow color to your skin or eyes, or dark colored urine or pale stools (bowel movements). In rare cases, patients taking itraconazole could develop serious liver problems and these could be warning signs.
- Stop Itraconazole and call your doctor right away if you experience any hearing loss symptoms. In very rare cases, patients taking itraconazole have reported temporary or permanent hearing loss.
- Call your doctor right away if you develop tingling or numbness in your extremities (hands or feet), if your vision gets blurry or you see double, if you hear a ringing in your ears, if you lose the ability to control your urine or urinate much more than usual.
- Additional possible side effects include upset stomach, vomiting, constipation, fever, inflammation of the pancreas, menstrual disorder, erectile dysfunction, dizziness, muscle pain, painful joints, unpleasant taste, or hair loss. These are not all the side effects of itraconazole. Your doctor or pharmacist can give you a more complete list.
- If you think you took too much itraconazole, call your doctor or local poison control center, or go to the nearest hospital emergency room right away.
- Keep all medicines, including itraconazole, out of the reach of children.
- Store itraconazole capsules and the 7-Day Treatment Pack at room temperature in a dry place away from light.
- Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use itraconazole for a condition for which it was not prescribed. Do not give itraconazole to other people, even if they have the same symptoms you have. It may harm them.
- This leaflet summarizes the most important information about itraconazole. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about itraconazole that is written for health professionals.
- This patient information has been approved by the U.S. Food and Drug Administration.
- For Patient Information, please visit WWW.US.SANDOZ.COM or call 1-800-507-2130.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
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2b44acdeb77f82f7640ea248d705ec3f54d2f925 | wikidoc | Itō calculus | Itō calculus
Itō calculus, named after Kiyoshi Itō, extends the methods of calculus to stochastic processes such as Brownian motion (Wiener process). It has important applications in mathematical finance and stochastic differential equations.
The central concept is the Itō stochastic integral
where X is a Brownian motion or, more generally, a semimartingale.
The paths of Brownian motion fail to satisfy the requirements to be able to apply the standard techniques of calculus. In particular, it is not differentiable at any point and has infinite variation over every time interval. As a result, the integral cannot be defined in the usual way (see Riemann-Stieltjes integral).
The main insight is that the integral can be defined as long as the integrand H is adapted, which means that its value at time t can only depend on information available up until this time.
The prices of stocks and other traded financial assets can be modeled by stochastic processes such as Brownian motion or, more often, geometric Brownian motion (see Black-Scholes). Then, the Itō stochastic integral represents the payoff of a continuous-time trading strategy consisting of holding an amount Ht of the stock at time t. In this situation, the condition that H is adapted corresponds to the necessary restriction that the trading strategy can only make use of the available information at any time. This prevents the possibility of unlimited gains through high frequency trading: buying the stock just before each uptick in the market and selling before each downtick. Similarly, the condition that H is adapted implies that the stochastic integral will not diverge when calculated as a limit of Riemann sums.
Important results of Itō calculus include the integration by parts formula and Itō's lemma, which is a change of variables formula. These differ from the formulas of standard calculus, due to quadratic variation terms.
# Notation
The integral of a process H with respect to another process X up until a time t is written as
This is itself a stochastic process with time parameter t, which is also written as H · X. Alternatively, the integral is often written in differential form dY = H dX, which is equivalent to Y - Y0 = H · X.
As Itō calculus is concerned with continuous-time stochastic processes, it is assumed that there is an underlying filtered probability space.
The sigma algebra Ft represents the information available up until time t, and a process X is adapted if Xt is Ft-measurable. A Brownian motion B is understood to be an Ft-Brownian motion, which is just a standard Brownian motion with the property that Bt+s - Bt is independent of Ft for all s,t ≥ 0.
# Integration with respect to Brownian motion
The Itō integral can be defined in a manner similar to the Riemann-Stieltjes integral, that is as a limit in probability of Riemann sums; such a limit does not necessarily exist pathwise. Suppose that B is a Wiener process (Brownian motion) and that H is a left-continuous, adapted and locally bounded process.
If πn is a sequence of partitions of with mesh going to zero, then the Itō integral of H with respect to B up to time t is a random variable
It can be shown that this limit converges in probability.
For some applications, such as martingale representation theorems and local times, the integral is needed for processes that are not continuous.
The predictable processes form the smallest class which is closed under taking limits of sequences and contains all adapted left continuous processes.
If H is any predictable process such that ∫0t H2 ds < ∞ for every t ≥ 0 then the integral of H with respect to B can be defined, and H is said to be B-integrable.
Any such process can be approximated by a sequence Hn of left-continuous, adapted and locally bounded processes, in the sense that
in probability. Then, the Itō integral is
where, again, the limit can be shown to converge in probability.
The stochastic integral satisfies the Itō isometry
which holds when H is bounded or, more generally, when the integral on the right hand side is finite.
# Itō processes
An Itō process is defined to be an adapted stochastic process which can be expressed as the sum of an integral with respect to Brownian motion and an integral with respect to time,
Here, B is a Brownian motion and it is required that σ is a predictable B-integrable process, and μ is predictable and (Lebesgue) integrable. That is,
for each t. The stochastic integral can be extended to such Itō processes,
This is defined for all locally bounded and predictable integrands. More generally, it is required that H σ be B-integrable and H μ be Lebesgue integrable, so that ∫0t(H2σ2 + |H μ|)ds is finite. Such predictable processes H are called X-integrable.
An important result for the study of Itō processes is Itō's lemma. In its simplest form, for any twice continuously differentiable function f on the reals and Itō process X as described above, it states that f(X) is itself an Itō process satisfying
This is the stochastic calculus version of the change of variables formula and chain rule. It differs from the standard result due to the additional term involving the second derivative of f, which comes from the property that Brownian motion has non-zero quadratic variation.
# Semimartingales as integrators
The Itō integral is defined with respect to a semimartingale X. These are processes which can be decomposed as X = M + A for a local martingale M and finite variation process A. Important examples of such processes include Brownian motion, which is a martingale, and Lévy processes.
For a left continuous, locally bounded and adapted process H the integral H · X exists, and can be calculated as a limit of Riemann sums. Let πn be a sequence of partitions of with mesh going to zero,
This limit converges in probability.
The stochastic integral of left-continuous processes is general enough for studying much of stochastic calculus. For example, it is sufficient for applications of Itō's Lemma, changes of measure via Girsanov's theorem, and for the study of stochastic differential equations. However, it is inadequate for other important topics such as martingale representation theorems and local times.
The integral extends to all predictable and locally bounded integrands, in a unique way, such that the dominated convergence theorem holds. That is, if Hn → H and |Hn| ≤ J for a locally bounded process J, then ∫0t Hn dX → ∫0t H dX in probability.
The uniqueness of the extension from left-continuous to predictable integrands is a result of the monotone class lemma.
In general, the stochastic integral H · X can be defined even in cases where the predictable process H is not locally bounded.
If K = 1 / ( 1 + |H| ) then K and KH are bounded. Associativity of stochastic integration implies that H is X-integrable, with integral H · X = Y, if and only if Y0 = 0 and K · Y = (KH) · X. The set of X-integrable processes is denoted by L(X).
# Properties
- The stochastic integral is a càdlàg process. Furthermore, it is a semimartingale.
- The discontinuities of the stochastic integral are given by the jumps of the integrator multiplied by the integrand. The jump of a càdlàg process at a time t is Xt - Xt-, and is often denoted by ΔXt. With this notation, Δ(H · X)=H ΔX. A particular consequence of this is that integrals with respect to a continuous process are always themselves continuous.
- Associativity. Let J, K be predictable processes, and K be X-integrable. Then, J is K · X integrable if and only if JK is X integrable, in which case
- Dominated convergence. Suppose that Hn → H and |Hn| ≤ J, where J is an X-integrable process. then Hn · X → H · X. Convergence is in probability at each time t. In fact, it converges uniformly on compacts in probability.
- The stochastic integral commutes with the operation of taking quadratic covariations. If X and Y are semimartingales then any X-integrable process will also be -integrable, and = H · . A consequence of this is that the quadratic variation process of a stochastic integral is equal to an integral of a quadratic variation process,
# Integration by parts
As with ordinary calculus, integration by parts is an important result in stochastic calculus. The integration by parts formula for the Itō integral differs from the standard result due to the inclusion of a quadratic covariation term. This term comes from the fact that Itō calculus deals with processes with non-zero quadratic variation, which only occurs for infinite variation processes (such as Brownian motion). If X and Y are semimartingales then
where is the quadratic covariation process.
The result is similar to the integration by parts theorem for the Riemann-Stieltjes integral but has an additional quadratic variation term.
# Itō's lemma
Itō's lemma is the version of the chain rule or change of variables formula which applies to the Itō integral.
It is one of the most powerful and frequently used theorems in
stochastic calculus.
For a continuous d-dimensional semimartingale X = (X1,…,Xd) and twice continuously differentiable function f from Rd to R, it states that f(X) is a semimartingale and,
This differs from the chain rule used in standard calculus due to the term involving the quadratic covariation . The formula can be generalized to non-continuous semimartingales by adding a pure jump term to ensure that the jumps of the left and right hand sides agree (see Itō's lemma).
# Martingale integrators
## Local martingales
An important property of the Itō integral is that it preserves the local martingale property. If M is a local martingale and H is a locally bounded predictable process then H · M is also a local martingale.
For integrands which are not locally bounded, there are examples where H · M is not a local martingale. However, this can only occur when M is not continuous.
If M is a continuous local martingale then a predictable process H is M-integrable if and only if ∫0tH2 d is finite for each t, and H · M is always a local martingale.
The most general statement for a discontinuous local martingale M is that if (H2 · )1/2 is locally integrable then H · M exists and is a local martingale.
## Square integrable martingales
For bounded integrands, the Itō stochastic integral preserves the space of square integrable martingales, which is the set of càdlàg martingales M such that E(Mt2) is finite for all t.
For any such square integrable martingale M, the quadratic variation process is integrable, and the Itō isometry states that
This equality holds more generally for any martingale M such that H2 · t is integrable. The Itō isometry is often used as an important step in the construction of the stochastic integral, by defining H · M to be the unique extension of this isometry from a certain class of simple integrands to all bounded and predictable processes.
## p-Integrable martingales
For any p > 1, and bounded predictable integrand, the stochastic integral preserves the space of p-integrable martingales. These are càdlàg martingales such that E(|Mt|p) is finite for all t.
However, this is not always true in the case where p = 1. There are examples of integrals of bounded predictable processes with respect to martingales which are not themselves martingales.
The maximum process of a cadlag process M is written as Mt- = sups ≤t |Ms|. For any p ≥ 1 and bounded predictable integrand, the stochastic integral preserves the space of cadlag martingales M such that E((Mt*)p) is finite for all t.
If p > 1 then this is the same as the space of p-integrable martingales, by Doob's inequalities.
The Burkholder-Davis-Gundy inequalities state that, for any given p ≥ 1, there exists positive constants c,C such that
for all cadlag local martingales M.
These are used to show that if (Mt*)p is integrable and H is a bounded predictable process then
and, consequently, H · M is a p-integrable martingale. More generally, this statement is true whenever (H2 · )p/2 is integrable.
# Existence of the integral
Proofs that the Itō integral is well defined typically proceed by first looking at very simple integrands, such as piecewise constant, left continuous and adapted processes where the integral can be written explicitly. Such simple predictable processes are linear combinations of terms of the form Ht = A1{t > T} for stopping times T and FT -measurable random variables A, for which the integral is
This is extended to all simple predictable processes by the linearity of H · X in H.
For a Brownian motion B, the property that it has independent increments with zero mean and variance Var(Bt) = t can be used to prove the Itō isometry for simple predictable integrands,
By a continuous linear extension, the integral extends uniquely to all predictable integrands satisfying E(∫0tH 2ds) < ∞ in such way that the Itō isometry still holds. It can then be extended to all B-integrable processes by localization. This method allows the integral to be defined with respect to any Itō process.
For a general semimartingale X, the decomposition X =M + A for a local martingale M and finite variation process A can be used. Then, the integral can be shown to exist separately with respect to M and A and combined using linearity, H·X = H·M + H·A, to get the integral with respect to X. The standard Lebesgue-Stieltjes integral allows integration to be defined with respect to finite variation processes, so the existence of the Itō integral for semimartingales will follow from any construction for local martingales.
For a cadlag square integrable martingale M, a generalized form of the Itō isometry can be used. First, the Doob-Meyer decomposition theorem is used to show that a decomposition M2 = N+ exists, where N is a martingale and is a right-continuous, increasing and predictable process starting at zero. This uniquely defines , which is refered to as the predictable quadratic variation of M. The Itō isometry for square integrable martingales is then
which can be proved directly for simple predictable integrands. As with the case above for Brownian motion, a continuous linear extension can be used to uniquely extend to all predictable integrands satisfying E(H2·t) < ∞. This method can be extended to all local square integrable martingales by localization.
Finally, the Doob-Meyer decomposition can be used to decompose any local martingale into the sum of a local square integrable martingale and a finite variation process, allowing the Itō integral to be constructed with respect to any semimartingale.
Many other proofs exist which apply similar methods but which avoid the need to use the Doob-Meyer decomposition theorem, such as the use of the quadratic variation in the Itō isometry, the use of the Doléans measure for submartingales, or the use of the Burkholder-Davis-Gundy inequalities instead of the Itō isometry. The latter applies directly to local martingales without having to first deal with the square integrable martingale case.
Alternative proofs exist only making use of the fact that X is cadlag, adapted, and the set {H·Xt: |H |≤1 is simple previsible} is bounded in probability for each time t, which is an alternative definition for X to be a semimartingale. A continuous linear extension can be used to construct the integral for all left-continuous and adapted integrands with right limits everywhere (caglad or L-processes). This is general enough to be able to apply techniques such as Itō's lemma Template:Harv.
Also, a Khintchine inequality can be used to prove the dominated convergence theorem and extend the integral to general predictable integrands Template:Harv.
# Further extensions of Itō calculus: stochastic derivative
Itō calculus, as ground-breaking and remarkable as it is, for over 60 years has only been an integral calculus: there was no explicit pathwise differentiation theory behind it. However, in 2004 (published in 2006) Hassan Allouba defined the derivative of a given semimartingale S with respect to a Brownian motion B using the derivative of the covariation of S and B (also known as the cross-variation of S and B) with respect to the quadratic variation of B. Given a continuous semimartingale S_{t} = S_{0} + V_{t} + M_{t}, where V is a process of bounded variation on compacts and M is a local martingale, the (strong) derivative of S with respect to a Brownian motion B is defined as the stochastic process \mathbb{D}_{B} S given by
where we used the fact that the covariation of Brownian motion B with itself is just its quadratic variation, which is t.
This stochastic derivative turns out to have many of the properties of the usual derivative of elementary calculus. It leads to a fundamental theorem of stochastic calculus
for this stochastic derivative/integral pair:
It also leads to a stochastic mean value theorem, stochastic chain rules, as well as other differentiation rules that are similar to those in elementary calculus. A key difference is that where an indefinite integral (anti-derivative) in the usual elementary calculus sense is determined only up to an additive constant of integration, an indefinite integral in this stochastic calculus is determined only up to a process of bounded variation on compacts. These processes are the "constants" in this stochastic differentiation theory. Also, if M and B are orthogonal (zero covariation) then \mathbb{D}_{B} M=0; in particular, if M and B are independent then \mathbb{D}_{B} M=0. | Itō calculus
Itō calculus, named after Kiyoshi Itō, extends the methods of calculus to stochastic processes such as Brownian motion (Wiener process). It has important applications in mathematical finance and stochastic differential equations.
The central concept is the Itō stochastic integral
where X is a Brownian motion or, more generally, a semimartingale.
The paths of Brownian motion fail to satisfy the requirements to be able to apply the standard techniques of calculus. In particular, it is not differentiable at any point and has infinite variation over every time interval. As a result, the integral cannot be defined in the usual way (see Riemann-Stieltjes integral).
The main insight is that the integral can be defined as long as the integrand H is adapted, which means that its value at time t can only depend on information available up until this time.
The prices of stocks and other traded financial assets can be modeled by stochastic processes such as Brownian motion or, more often, geometric Brownian motion (see Black-Scholes). Then, the Itō stochastic integral represents the payoff of a continuous-time trading strategy consisting of holding an amount Ht of the stock at time t. In this situation, the condition that H is adapted corresponds to the necessary restriction that the trading strategy can only make use of the available information at any time. This prevents the possibility of unlimited gains through high frequency trading: buying the stock just before each uptick in the market and selling before each downtick. Similarly, the condition that H is adapted implies that the stochastic integral will not diverge when calculated as a limit of Riemann sums.
Important results of Itō calculus include the integration by parts formula and Itō's lemma, which is a change of variables formula. These differ from the formulas of standard calculus, due to quadratic variation terms.
# Notation
The integral of a process H with respect to another process X up until a time t is written as
This is itself a stochastic process with time parameter t, which is also written as H · X. Alternatively, the integral is often written in differential form dY = H dX, which is equivalent to Y - Y0 = H · X.
As Itō calculus is concerned with continuous-time stochastic processes, it is assumed that there is an underlying filtered probability space.
The sigma algebra Ft represents the information available up until time t, and a process X is adapted if Xt is Ft-measurable. A Brownian motion B is understood to be an Ft-Brownian motion, which is just a standard Brownian motion with the property that Bt+s - Bt is independent of Ft for all s,t ≥ 0.
# Integration with respect to Brownian motion
The Itō integral can be defined in a manner similar to the Riemann-Stieltjes integral, that is as a limit in probability of Riemann sums; such a limit does not necessarily exist pathwise. Suppose that B is a Wiener process (Brownian motion) and that H is a left-continuous, adapted and locally bounded process.
If πn is a sequence of partitions of [0,t] with mesh going to zero, then the Itō integral of H with respect to B up to time t is a random variable
It can be shown that this limit converges in probability.
For some applications, such as martingale representation theorems and local times, the integral is needed for processes that are not continuous.
The predictable processes form the smallest class which is closed under taking limits of sequences and contains all adapted left continuous processes.
If H is any predictable process such that ∫0t H2 ds < ∞ for every t ≥ 0 then the integral of H with respect to B can be defined, and H is said to be B-integrable.
Any such process can be approximated by a sequence Hn of left-continuous, adapted and locally bounded processes, in the sense that
in probability. Then, the Itō integral is
where, again, the limit can be shown to converge in probability.
The stochastic integral satisfies the Itō isometry
which holds when H is bounded or, more generally, when the integral on the right hand side is finite.
# Itō processes
An Itō process is defined to be an adapted stochastic process which can be expressed as the sum of an integral with respect to Brownian motion and an integral with respect to time,
Here, B is a Brownian motion and it is required that σ is a predictable B-integrable process, and μ is predictable and (Lebesgue) integrable. That is,
for each t. The stochastic integral can be extended to such Itō processes,
This is defined for all locally bounded and predictable integrands. More generally, it is required that H σ be B-integrable and H μ be Lebesgue integrable, so that ∫0t(H2σ2 + |H μ|)ds is finite. Such predictable processes H are called X-integrable.
An important result for the study of Itō processes is Itō's lemma. In its simplest form, for any twice continuously differentiable function f on the reals and Itō process X as described above, it states that f(X) is itself an Itō process satisfying
This is the stochastic calculus version of the change of variables formula and chain rule. It differs from the standard result due to the additional term involving the second derivative of f, which comes from the property that Brownian motion has non-zero quadratic variation.
# Semimartingales as integrators
The Itō integral is defined with respect to a semimartingale X. These are processes which can be decomposed as X = M + A for a local martingale M and finite variation process A. Important examples of such processes include Brownian motion, which is a martingale, and Lévy processes.
For a left continuous, locally bounded and adapted process H the integral H · X exists, and can be calculated as a limit of Riemann sums. Let πn be a sequence of partitions of [0,t] with mesh going to zero,
This limit converges in probability.
The stochastic integral of left-continuous processes is general enough for studying much of stochastic calculus. For example, it is sufficient for applications of Itō's Lemma, changes of measure via Girsanov's theorem, and for the study of stochastic differential equations. However, it is inadequate for other important topics such as martingale representation theorems and local times.
The integral extends to all predictable and locally bounded integrands, in a unique way, such that the dominated convergence theorem holds. That is, if Hn → H and |Hn| ≤ J for a locally bounded process J, then ∫0t Hn dX → ∫0t H dX in probability.
The uniqueness of the extension from left-continuous to predictable integrands is a result of the monotone class lemma.
In general, the stochastic integral H · X can be defined even in cases where the predictable process H is not locally bounded.
If K = 1 / ( 1 + |H| ) then K and KH are bounded. Associativity of stochastic integration implies that H is X-integrable, with integral H · X = Y, if and only if Y0 = 0 and K · Y = (KH) · X. The set of X-integrable processes is denoted by L(X).
# Properties
- The stochastic integral is a càdlàg process. Furthermore, it is a semimartingale.
- The discontinuities of the stochastic integral are given by the jumps of the integrator multiplied by the integrand. The jump of a càdlàg process at a time t is Xt - Xt-, and is often denoted by ΔXt. With this notation, Δ(H · X)=H ΔX. A particular consequence of this is that integrals with respect to a continuous process are always themselves continuous.
- Associativity. Let J, K be predictable processes, and K be X-integrable. Then, J is K · X integrable if and only if JK is X integrable, in which case
- Dominated convergence. Suppose that Hn → H and |Hn| ≤ J, where J is an X-integrable process. then Hn · X → H · X. Convergence is in probability at each time t. In fact, it converges uniformly on compacts in probability.
- The stochastic integral commutes with the operation of taking quadratic covariations. If X and Y are semimartingales then any X-integrable process will also be [X,Y]-integrable, and [H · X,Y] = H · [X,Y]. A consequence of this is that the quadratic variation process of a stochastic integral is equal to an integral of a quadratic variation process,
# Integration by parts
As with ordinary calculus, integration by parts is an important result in stochastic calculus. The integration by parts formula for the Itō integral differs from the standard result due to the inclusion of a quadratic covariation term. This term comes from the fact that Itō calculus deals with processes with non-zero quadratic variation, which only occurs for infinite variation processes (such as Brownian motion). If X and Y are semimartingales then
where [X, Y] is the quadratic covariation process.
The result is similar to the integration by parts theorem for the Riemann-Stieltjes integral but has an additional quadratic variation term.
# Itō's lemma
Itō's lemma is the version of the chain rule or change of variables formula which applies to the Itō integral.
It is one of the most powerful and frequently used theorems in
stochastic calculus.
For a continuous d-dimensional semimartingale X = (X1,…,Xd) and twice continuously differentiable function f from Rd to R, it states that f(X) is a semimartingale and,
This differs from the chain rule used in standard calculus due to the term involving the quadratic covariation [Xi,Xj ]. The formula can be generalized to non-continuous semimartingales by adding a pure jump term to ensure that the jumps of the left and right hand sides agree (see Itō's lemma).
# Martingale integrators
## Local martingales
An important property of the Itō integral is that it preserves the local martingale property. If M is a local martingale and H is a locally bounded predictable process then H · M is also a local martingale.
For integrands which are not locally bounded, there are examples where H · M is not a local martingale. However, this can only occur when M is not continuous.
If M is a continuous local martingale then a predictable process H is M-integrable if and only if ∫0tH2 d[M] is finite for each t, and H · M is always a local martingale.
The most general statement for a discontinuous local martingale M is that if (H2 · [M])1/2 is locally integrable then H · M exists and is a local martingale.
## Square integrable martingales
For bounded integrands, the Itō stochastic integral preserves the space of square integrable martingales, which is the set of càdlàg martingales M such that E(Mt2) is finite for all t.
For any such square integrable martingale M, the quadratic variation process [M] is integrable, and the Itō isometry states that
This equality holds more generally for any martingale M such that H2 · [M]t is integrable. The Itō isometry is often used as an important step in the construction of the stochastic integral, by defining H · M to be the unique extension of this isometry from a certain class of simple integrands to all bounded and predictable processes.
## p-Integrable martingales
For any p > 1, and bounded predictable integrand, the stochastic integral preserves the space of p-integrable martingales. These are càdlàg martingales such that E(|Mt|p) is finite for all t.
However, this is not always true in the case where p = 1. There are examples of integrals of bounded predictable processes with respect to martingales which are not themselves martingales.
The maximum process of a cadlag process M is written as Mt* = sups ≤t |Ms|. For any p ≥ 1 and bounded predictable integrand, the stochastic integral preserves the space of cadlag martingales M such that E((Mt*)p) is finite for all t.
If p > 1 then this is the same as the space of p-integrable martingales, by Doob's inequalities.
The Burkholder-Davis-Gundy inequalities state that, for any given p ≥ 1, there exists positive constants c,C such that
for all cadlag local martingales M.
These are used to show that if (Mt*)p is integrable and H is a bounded predictable process then
and, consequently, H · M is a p-integrable martingale. More generally, this statement is true whenever (H2 · [M])p/2 is integrable.
# Existence of the integral
Proofs that the Itō integral is well defined typically proceed by first looking at very simple integrands, such as piecewise constant, left continuous and adapted processes where the integral can be written explicitly. Such simple predictable processes are linear combinations of terms of the form Ht = A1{t > T} for stopping times T and FT -measurable random variables A, for which the integral is
This is extended to all simple predictable processes by the linearity of H · X in H.
For a Brownian motion B, the property that it has independent increments with zero mean and variance Var(Bt) = t can be used to prove the Itō isometry for simple predictable integrands,
By a continuous linear extension, the integral extends uniquely to all predictable integrands satisfying E(∫0tH 2ds) < ∞ in such way that the Itō isometry still holds. It can then be extended to all B-integrable processes by localization. This method allows the integral to be defined with respect to any Itō process.
For a general semimartingale X, the decomposition X =M + A for a local martingale M and finite variation process A can be used. Then, the integral can be shown to exist separately with respect to M and A and combined using linearity, H·X = H·M + H·A, to get the integral with respect to X. The standard Lebesgue-Stieltjes integral allows integration to be defined with respect to finite variation processes, so the existence of the Itō integral for semimartingales will follow from any construction for local martingales.
For a cadlag square integrable martingale M, a generalized form of the Itō isometry can be used. First, the Doob-Meyer decomposition theorem is used to show that a decomposition M2 = N+ <M> exists, where N is a martingale and <M> is a right-continuous, increasing and predictable process starting at zero. This uniquely defines <M>, which is refered to as the predictable quadratic variation of M. The Itō isometry for square integrable martingales is then
which can be proved directly for simple predictable integrands. As with the case above for Brownian motion, a continuous linear extension can be used to uniquely extend to all predictable integrands satisfying E(H2·<M>t) < ∞. This method can be extended to all local square integrable martingales by localization.
Finally, the Doob-Meyer decomposition can be used to decompose any local martingale into the sum of a local square integrable martingale and a finite variation process, allowing the Itō integral to be constructed with respect to any semimartingale.
Many other proofs exist which apply similar methods but which avoid the need to use the Doob-Meyer decomposition theorem, such as the use of the quadratic variation [M] in the Itō isometry, the use of the Doléans measure for submartingales, or the use of the Burkholder-Davis-Gundy inequalities instead of the Itō isometry. The latter applies directly to local martingales without having to first deal with the square integrable martingale case.
Alternative proofs exist only making use of the fact that X is cadlag, adapted, and the set {H·Xt: |H |≤1 is simple previsible} is bounded in probability for each time t, which is an alternative definition for X to be a semimartingale. A continuous linear extension can be used to construct the integral for all left-continuous and adapted integrands with right limits everywhere (caglad or L-processes). This is general enough to be able to apply techniques such as Itō's lemma Template:Harv.
Also, a Khintchine inequality can be used to prove the dominated convergence theorem and extend the integral to general predictable integrands Template:Harv.
# Further extensions of Itō calculus: stochastic derivative
Itō calculus, as ground-breaking and remarkable as it is, for over 60 years has only been an integral calculus: there was no explicit pathwise differentiation theory behind it. However, in 2004 (published in 2006) Hassan Allouba defined the derivative of a given semimartingale S with respect to a Brownian motion B using the derivative of the covariation of S and B (also known as the cross-variation of S and B) with respect to the quadratic variation of B. Given a continuous semimartingale <math>S_{t} = S_{0} + V_{t} + M_{t},</math> where V is a process of bounded variation on compacts and M is a local martingale, the (strong) derivative of S with respect to a Brownian motion B is defined as the stochastic process <math>\mathbb{D}_{B} S</math> given by
where we used the fact that the covariation of Brownian motion B with itself is just its quadratic variation, which is t.
This stochastic derivative turns out to have many of the properties of the usual derivative of elementary calculus. It leads to a fundamental theorem of stochastic calculus
for this stochastic derivative/integral pair:
It also leads to a stochastic mean value theorem, stochastic chain rules, as well as other differentiation rules that are similar to those in elementary calculus. A key difference is that where an indefinite integral (anti-derivative) in the usual elementary calculus sense is determined only up to an additive constant of integration, an indefinite integral in this stochastic calculus is determined only up to a process of bounded variation on compacts. These processes are the "constants" in this stochastic differentiation theory. Also, if M and B are orthogonal (zero covariation) then <math>\mathbb{D}_{B} M=0</math>; in particular, if M and B are independent then <math>\mathbb{D}_{B} M=0.</math> | https://www.wikidoc.org/index.php/It%C5%8D_calculus | |
355bf5ebb469b549cce1775f6bfecec3a41d343b | wikidoc | Janus kinase | Janus kinase
# Overview
Janus kinase (JAK) is a family of intracellular non-receptor tyrosine kinases, ranging from 120-140 kDa in size, that transduce cytokine-mediated signals via the JAK-STAT pathway. Initially discovered in a PCR-based screen of kinases and named ironically as "just another kinase" 1 & 2 (since they were two of a large number of new kinases discovered in the screen) JAK1 and JAK2 were ultimately published as Janus kinase 1 and Janus kinase 2. The name is taken from Janus, the Thessalian gatekeeper of heaven worshipped by the Romans; he is described as having two faces while the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity while the other stabilises the JAK's conformational structure enabling it express that activity.
# General functions of the JAK family
Since members of the type I and type II cytokine receptor families possess no catalytic kinase activity, they rely on the JAK family of tyrosine kinases to phosphorylate and activate downstream proteins involved in their signal transduction pathways. The receptors exist as paired polypeptides thus exhibiting two intracellular signal-transducing domains. JAKs associate with a proline-rich region in each intracellular domain, which is adjacent to the cell membrane and called a box1/box2 region. After the receptor associates with its respective cytokine/ligand it goes through a conformational change, bringing the two JAKs close enough to phosphorylate each other. The JAK autophosphorylation induces a conformational change within itself enabling it to transduce the intracellular signal by further phosphorylating and activating transcription factors called STATs. The activated STATs dissociate from the receptor and form dimers before translocating to the cell nucleus where they regulate transcription of selected genes.
# The Janus kinase family
There are four JAK family members:
- Janus kinase 1 (JAK1)
- Janus kinase 2 (JAK2)
- Janus kinase 3 (JAK3)
- Tyrosine kinase 2 (TYK2)
Transgenic mice that do not express JAK1 have defective responses to some cytokines such as interferon-gamma. JAK1 and JAK2 are involved in type II interferon (interferon-gamma) signalling, whereas JAK1 and TYK2 are involved type I interferon signalling. Mice that do not express TYK2 have defective natural killer cell function.
# The structure of JAKs
JAKs have seven defined regions of homology; these are called Janus homology domain 1–7 (JH1-7). JH1 is the kinase domain important for the enzymatic activity of the JAK and contains typical features of a tyrosine kinase such as conserved tyrosines necessary for JAK activation (e.g. Y1038/Y1039 in JAK1, Y1007/Y1008 in JAK2, Y980/Y981 in JAK3, and Y1054/Y1055 in Tyk2). Phosphorylation of these dual tyrosines leads to the conformational changes in the JAK protein to facilitate binding of substrate. JH2 is a pseudokinase domain, a domain structurally similar to a tyrosine kinase and is essential for a normal kinase activity yet lacks enzymatic activity. This domain may be involved in regulating the activity of JH1. The JH3-JH4 domain of JAKs shares homology with Src-homology-2 (SH2) domains. The amino terminal (NH2) end (JH4-JH7) of Jaks is called a FERM domain (short for band 4.1 ezrin, radixin and moesin); this domain is also found in the focal adhesion kinase (FAK) family and is involved in association of JAKs with cytokine receptors and/or other kinases . | Janus kinase
# Overview
Janus kinase (JAK) is a family of intracellular non-receptor tyrosine kinases, ranging from 120-140 kDa in size, that transduce cytokine-mediated signals via the JAK-STAT pathway. Initially discovered in a PCR-based screen of kinases [1] and named ironically as "just another kinase" 1 & 2 (since they were two of a large number of new kinases discovered in the screen) JAK1 and JAK2 were ultimately published as Janus kinase 1 and Janus kinase 2. The name is taken from Janus, the Thessalian gatekeeper of heaven worshipped by the Romans; he is described as having two faces while the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity while the other stabilises the JAK's conformational structure enabling it express that activity.
# General functions of the JAK family
Since members of the type I and type II cytokine receptor families possess no catalytic kinase activity, they rely on the JAK family of tyrosine kinases to phosphorylate and activate downstream proteins involved in their signal transduction pathways. The receptors exist as paired polypeptides thus exhibiting two intracellular signal-transducing domains. JAKs associate with a proline-rich region in each intracellular domain, which is adjacent to the cell membrane and called a box1/box2 region. After the receptor associates with its respective cytokine/ligand it goes through a conformational change, bringing the two JAKs close enough to phosphorylate each other. The JAK autophosphorylation induces a conformational change within itself enabling it to transduce the intracellular signal by further phosphorylating and activating transcription factors called STATs.[2] The activated STATs dissociate from the receptor and form dimers before translocating to the cell nucleus where they regulate transcription of selected genes.
# The Janus kinase family
There are four JAK family members:
- Janus kinase 1 (JAK1)
- Janus kinase 2 (JAK2)
- Janus kinase 3 (JAK3)
- Tyrosine kinase 2 (TYK2)
Transgenic mice that do not express JAK1 have defective responses to some cytokines such as interferon-gamma.[3] JAK1 and JAK2 are involved in type II interferon (interferon-gamma) signalling, whereas JAK1 and TYK2 are involved type I interferon signalling. Mice that do not express TYK2 have defective natural killer cell function.[4]
# The structure of JAKs
JAKs have seven defined regions of homology; these are called Janus homology domain 1–7 (JH1-7). JH1 is the kinase domain important for the enzymatic activity of the JAK and contains typical features of a tyrosine kinase such as conserved tyrosines necessary for JAK activation (e.g. Y1038/Y1039 in JAK1, Y1007/Y1008 in JAK2, Y980/Y981 in JAK3, and Y1054/Y1055 in Tyk2). Phosphorylation of these dual tyrosines leads to the conformational changes in the JAK protein to facilitate binding of substrate. JH2 is a pseudokinase domain, a domain structurally similar to a tyrosine kinase and is essential for a normal kinase activity yet lacks enzymatic activity. This domain may be involved in regulating the activity of JH1. The JH3-JH4 domain of JAKs shares homology with Src-homology-2 (SH2) domains. The amino terminal (NH2) end (JH4-JH7) of Jaks is called a FERM domain (short for band 4.1 ezrin, radixin and moesin); this domain is also found in the focal adhesion kinase (FAK) family and is involved in association of JAKs with cytokine receptors and/or other kinases [2]. | https://www.wikidoc.org/index.php/JAK | |
069bbaf5189b2058f96bcde07fb3fbde7df96676 | wikidoc | James Israel | James Israel
# Overview
James Adolf Israel (February 2, 1848 – February 2, 1926) was a German surgeon who was a native of Berlin. In 1870 he received his medical doctorate from Friedrich-Wilhelms-Universität. He studied under von Bernhard Rudolf Konrad von Langenbeck (1810-1887) and Ludwig Traube (1818-1876). After receiving his doctorate in 1870, he continued his education in Vienna, and in 1872 became assistant physician at the hospital for the Jewish Community.
He was a military physician during the Franco-Prussian War, and later furthered his studies in Vienna and the British Isles. In 1875, after undertaking further education in England and Scotland, he became deputy physician-in-chief of the surgical department of the Jewish hospital in Berlin. He was promoted to chief-in-chief there in 1880, and in 1894 he received the title of professor.
Israel was a pioneer in modern urologic and renal surgery, and made important contributions in the field of plastic surgery, particularly oral and maxillofacial surgery. His inaugural thesis concerned Bright’s kidney disease. His first report of an operation of the kidney came in 1882. He was also an early advocate of Joseph Lister's antiseptic practices in the operating room.
Israel is credited for providing the first description of the genus Actinomyces in humans, which is Gram-positive bacteria that is the cause of actinomycosis. Later this organism was given the name Actinomyces israelii. He published over 170 articles during his career, largely on urologic medicine, and was co-founder of the journal Folia Urologica. He also designed the Lazarettzug, which was a mobile hospital railcar.
- Associated eponym:
- Nicoladoni-Israel-Branham sign: A circulatory phenomenon seen in angioma racemosum of the extremities. It was first described in 1875 by Carl Nicoladoni (1847-1902).
# Selected writings
- Fünf Fälle von diffuser Nephritis (Five cases of diffuse nephritis). Diss med. Berlin 1870
- Angiectasie im Stromgebiete der A. tibialis antica. (Angiectasia in Stromgebiete of Arteria Tibialis antica).
- Beobachtung einiger bemerkenswerther Phaenomene nach Unterbindung der A. femoralis . (Observations of Bemerkenswerther Phenomena after removal of the femoral artery). Klin Arch Chir 21 (1877) 109
- Klinische Beiträge zur Kenntnis der Aktinomykose des Menschen. (Clinical contributions to the knowledge of Actinomycoses of man). Berlin 1885
- Ueber Reincultur des Actinomyces und seine Uebertragbarkeit auf Thiere. Archiv Pathologische Anatomie; (1891); 126:11–28, (with Max Wolff (1844-1923)
- Chirurgische Klinik der Nierenkrankheiten. (Surgical Clinic of Renal diseases). Berlin 1901
- Die Chirurgie der Niere und des Harnleiters. (The surgery of the kidney and ureter). 1926 | James Israel
# Overview
James Adolf Israel (February 2, 1848 – February 2, 1926) was a German surgeon who was a native of Berlin. In 1870 he received his medical doctorate from Friedrich-Wilhelms-Universität. He studied under von Bernhard Rudolf Konrad von Langenbeck (1810-1887) and Ludwig Traube (1818-1876). After receiving his doctorate in 1870, he continued his education in Vienna, and in 1872 became assistant physician at the hospital for the Jewish Community.
He was a military physician during the Franco-Prussian War, and later furthered his studies in Vienna and the British Isles. In 1875, after undertaking further education in England and Scotland, he became deputy physician-in-chief of the surgical department of the Jewish hospital in Berlin. He was promoted to chief-in-chief there in 1880, and in 1894 he received the title of professor.
Israel was a pioneer in modern urologic and renal surgery, and made important contributions in the field of plastic surgery, particularly oral and maxillofacial surgery. His inaugural thesis concerned Bright’s kidney disease. His first report of an operation of the kidney came in 1882. He was also an early advocate of Joseph Lister's antiseptic practices in the operating room[1].
Israel is credited for providing the first description of the genus Actinomyces in humans, which is Gram-positive bacteria that is the cause of actinomycosis. Later this organism was given the name Actinomyces israelii. He published over 170 articles during his career, largely on urologic medicine, and was co-founder of the journal Folia Urologica. He also designed the Lazarettzug, which was a mobile hospital railcar.
- Associated eponym:
- Nicoladoni-Israel-Branham sign: A circulatory phenomenon seen in angioma racemosum of the extremities. It was first described in 1875 by Carl Nicoladoni (1847-1902).
# Selected writings
- Fünf Fälle von diffuser Nephritis (Five cases of diffuse nephritis). Diss med. Berlin 1870
- Angiectasie im Stromgebiete der A. tibialis antica. (Angiectasia in Stromgebiete of Arteria Tibialis antica).
- Beobachtung einiger bemerkenswerther Phaenomene nach Unterbindung der A. femoralis . (Observations of Bemerkenswerther Phenomena after removal of the femoral artery). Klin Arch Chir 21 (1877) 109
- Klinische Beiträge zur Kenntnis der Aktinomykose des Menschen. (Clinical contributions to the knowledge of Actinomycoses of man). Berlin 1885
- Ueber Reincultur des Actinomyces und seine Uebertragbarkeit auf Thiere. Archiv Pathologische Anatomie; (1891); 126:11–28, (with Max Wolff (1844-1923)
- Chirurgische Klinik der Nierenkrankheiten. (Surgical Clinic of Renal diseases). Berlin 1901
- Die Chirurgie der Niere und des Harnleiters. (The surgery of the kidney and ureter). 1926 | https://www.wikidoc.org/index.php/James_Israel | |
52cad18a7f6e0a3cc20d8cccd7e7776bfbd75592 | wikidoc | James Linder | James Linder
Dr. James “Jim” Linder, MD, (born 1954) is president of UNeMed Corporation, the technology transfer entity of the University of Nebraska Medical Center, and is an American authority on university research commercialization. A noted author, academic and business leader, Linder also serves as Associate Vice Chancellor for Research at UNMC, and is a professor of pathology and microbiology. He serves on editorial boards of several medical journals, and is a former president of the American Society for Clinical Pathology. Since 1995 he has been affiliated with Cytyc Corporation, a Massachusetts-based medical company dedicated to women's health.
# Early life
A native of Omaha, Linder earned his B.S. degree in biochemistry and microbiology from Iowa State University in 1976, and his M.D. degree, with distinction, from the University of Nebraska Medical Center in 1980. He completed his residency training in pathology at Duke University Medical Center and UNMC.
# Career highlights
In January 2007, UNMC's intellectual property office merged with UNeMed, and Linder was appointed president of the expanded operation.
Since 1995 he has worked with Cytyc Corporation, a women's health company located in Marlborough, Mass., and served as medical director from 2002-06. A main area of interest has been improving Pap testing.
He is a frequent guest lecturer, and has written five textbooks, including co-authoring the 10th edition of Anderson’s Pathology, a comprehensive two-volume reference for pathologists, residents and medical students. He has written more than 130 professional articles.
He also serves on several editorial boards, including the American Journal of Clinical Pathology and Modern Pathology.
From 1998-99, he was president of the American Society of Clinical Pathologists. He is a member and has served in leadership positions with many medical organizations, including the American Society of Cytopathology and the U.S./Canadian division of the International Academy of Pathology.
He holds several patents, and his academic interests have focused on the application of technology in medical diagnostics, including immunochemistry, molecular diagnostics, computer-aided instruction, cellular imaging, and the use of automated techniques in cytopathology.
Linder has served on the UNMC faculty since 1983 when he joined the Pathology and Microbiology Department. In 1986 he was named associate professor and in 1989 was named professor. He has held numerous administrative positions at UNMC, including vice chairman of pathology and microbiology, director of surgical pathology, director of cytopathology, and associate dean for academic affairs. He is currently Associate Vice Chancellor for Research, responsible for developing clinical research programs at UNMC and statewide. He also served as visiting professor at the Peter Kiewit Institute.
# Awards, honors, community service
Linder has been accorded many professional honors and awards. In 2005, he was presented with the American Society of Clinical Pathologists "Israel Davidsohn Award for Distinguished Service"; he was awarded the "Distinguished Teaching Award" by the UNMC College of Medicine and the "Award for Excellence in Medical Publications" from the American Medical Writers Association.
From 1999-2001, he served on the board of directors of the Omaha Children’s Museum, and has been a volunteer instructor at Roncalli High School in Omaha.
# Personal and family
Linder was married in June 2007 to Karen Allen, a cytotechnologist and past president of the American Society for Cytotechnology, and has three children. He enjoys martial arts, scuba diving, reading and art. | James Linder
Dr. James “Jim” Linder, MD, (born 1954) is president of UNeMed Corporation, the technology transfer entity of the University of Nebraska Medical Center, and is an American authority on university research commercialization.[1] A noted author, academic and business leader, Linder also serves as Associate Vice Chancellor for Research at UNMC, and is a professor of pathology and microbiology. He serves on editorial boards of several medical journals, and is a former president of the American Society for Clinical Pathology.[2] Since 1995 he has been affiliated with Cytyc Corporation, a Massachusetts-based medical company dedicated to women's health.
# Early life
A native of Omaha, Linder earned his B.S. degree in biochemistry and microbiology from Iowa State University in 1976, and his M.D. degree, with distinction, from the University of Nebraska Medical Center in 1980. He completed his residency training in pathology at Duke University Medical Center and UNMC.
# Career highlights
In January 2007, UNMC's intellectual property office merged with UNeMed, and Linder was appointed president of the expanded operation.[3]
Since 1995 he has worked with Cytyc Corporation, a women's health company located in Marlborough, Mass., and served as medical director from 2002-06.[4] A main area of interest has been improving Pap testing.
He is a frequent guest lecturer, and has written five textbooks, including co-authoring the 10th edition of Anderson’s Pathology, a comprehensive two-volume reference for pathologists, residents and medical students.[5] He has written more than 130 professional articles.[6]
He also serves on several editorial boards, including the American Journal of Clinical Pathology[7] and Modern Pathology.[8]
From 1998-99, he was president of the American Society of Clinical Pathologists. He is a member and has served in leadership positions with many medical organizations, including the American Society of Cytopathology[9] and the U.S./Canadian division of the International Academy of Pathology.[10]
He holds several patents, and his academic interests have focused on the application of technology in medical diagnostics, including immunochemistry, molecular diagnostics, computer-aided instruction, cellular imaging, and the use of automated techniques in cytopathology.
Linder has served on the UNMC faculty since 1983 when he joined the Pathology and Microbiology Department. In 1986 he was named associate professor and in 1989 was named professor. He has held numerous administrative positions at UNMC, including vice chairman of pathology and microbiology, director of surgical pathology, director of cytopathology, and associate dean for academic affairs. He is currently Associate Vice Chancellor for Research, responsible for developing clinical research programs at UNMC and statewide.[11] He also served as visiting professor at the Peter Kiewit Institute.
# Awards, honors, community service
Linder has been accorded many professional honors and awards. In 2005, he was presented with the American Society of Clinical Pathologists "Israel Davidsohn Award for Distinguished Service";[12] he was awarded the "Distinguished Teaching Award" by the UNMC College of Medicine and the "Award for Excellence in Medical Publications" from the American Medical Writers Association.[13]
From 1999-2001, he served on the board of directors of the Omaha Children’s Museum, and has been a volunteer instructor at Roncalli High School in Omaha.[14]
# Personal and family
Linder was married in June 2007 to Karen Allen, a cytotechnologist and past president of the American Society for Cytotechnology,[15] and has three children. He enjoys martial arts, scuba diving, reading and art. | https://www.wikidoc.org/index.php/James_Linder | |
dc0b5bff0f14c96ab9516828ab3edbd8a2fdaf9f | wikidoc | James Lunney | James Lunney
James D. Lunney (born September 5, 1951) is a Canadian politician. He is the current Conservative Party of Canada Member of Parliament for the riding of Nanaimo—Alberni.
Born in Winnipeg, Manitoba he received a Bachelor of Science degree from the University of Manitoba in 1972 and a Doctor of Chiropractic from the Canadian Memorial Chiropractic College in Toronto in 1976. He was first elected in Canadian federal election, 2000 as a Canadian Alliance candidate. He was re-elected in Canadian federal election, 2004, Canadian federal election, 2006 and Canadian federal election, 2008 under the banner of the Conservative Party of Canada.
In April 2009, Lunney made a statement in Parliament proclaiming his belief in creationism and attacking theory of evolution. | James Lunney
Template:Infobox CanadianMP
James D. Lunney (born September 5, 1951) is a Canadian politician. He is the current Conservative Party of Canada Member of Parliament for the riding of Nanaimo—Alberni.
Born in Winnipeg, Manitoba he received a Bachelor of Science degree from the University of Manitoba in 1972 and a Doctor of Chiropractic from the Canadian Memorial Chiropractic College in Toronto in 1976. He was first elected in Canadian federal election, 2000 as a Canadian Alliance candidate. He was re-elected in Canadian federal election, 2004, Canadian federal election, 2006 and Canadian federal election, 2008 under the banner of the Conservative Party of Canada.
In April 2009, Lunney made a statement in Parliament proclaiming his belief in creationism and attacking theory of evolution.[1][2] | https://www.wikidoc.org/index.php/James_Lunney | |
cc6daecc2e0b48961dee6a5d5efe3903785c2923 | wikidoc | Jeanna Giese | Jeanna Giese
Jeanna Giese (born 1989) is the first person known to have survived symptomatic rabies without receiving the rabies vaccine. She is only the sixth person known to have survived rabies after the onset of symptoms; the other survivors suffered from vaccine failures.
# Infection with Rabies
In September 2004, Giese, then fifteen years old, picked up a bat that she found in St. Patrick's Church in her hometown of Fond du Lac, Wisconsin. She sustained a small bite on her left index finger, and having treated it with hydrogen peroxide, her mother decided to not seek medical attention. Thirty-seven days after the bite Giese developed symptoms of rabies. She was admitted to the hospital with tremors and trouble walking. Her condition continued to deteriorate, and she was referred to the Children's Hospital of Wisconsin in Wauwatosa, Wisconsin. Doctors there began to suspect rabies, and their diagnosis was confirmed by laboratory tests at the Centers for Disease Control.
# Induced Coma Treatment
Rabies had been considered universally fatal in unvaccinated patients after the onset of symptoms (with treatment generally limited to palliative care), but Giese’s parents agreed to an experimental treatment proposed by her doctors at the Children's Hospital of Wisconsin. The doctors used drugs to put Giese into a coma with the aid of ketamine and midazolam. During the following week she was administered phenobarbital (a sedative) and she was given a cocktail of antiviral drugs (ribavirin and amantadine) while waiting for her immune system to produce antibodies to attack the virus. Giese was brought out of the coma after seven days.
After thirty-one days in the hospital, Giese was declared virus-free and removed from isolation. There was some initial concern about the level of brain damage she had suffered, but while she had suffered nerve damage, the disease seemed to have left her cognitive abilities largely intact. She spent several weeks undergoing rehabilitation therapy and was discharged on January 1, 2005. By November 2005 she was able to walk on her own, had returned to school, and had started driving automobiles.
# Theories about Survival
The reasons for her survival remain controversial. Giese's doctors knew most rabies deaths were caused by temporary brain dysfunction, not permanent brain damage. They reasoned that if they protected Giese's brain by intentionally putting her into a coma, she would survive long enough for her body to fight off the virus. While the treatment appears to have worked as planned, other rabies researchers suggest Giese might have been infected with a particularly weak form of the virus, or that she might have an unusually strong immune system. The bat that bit Giese was not recovered for testing, and doctors were unable to isolate the virus from her body.
# Other Attempts
At least six later attempts to cure symptomatic rabies using a similar medical protocol have been unsuccessful. In May 2006, doctors at the Texas Children's Hospital applied a similar treatment as used on Giese to Zachary Jones, a 16 year-old stricken with symptomatic rabies, but they were unable to save him. From early October to early November of 2006, 10-year old Shannon Carroll was also unsuccessfully treated. This protocol is commonly being referred to as the "'Jeanna Treatment", at the Springs. An article written by her primary care physician in the April 2007 Scientific American calls this the Milwaukee protocol; he indicates that those who attempted to follow this protocol actually violated it, failing to use the combination of drugs he first described.
# Life After Rabies
Jeanna Giese returned to school, and with the extra help of teachers, was able to complete her sophomore year with her class. Despite the obvious setback, she kept at the same level as the rest of her classmates. She graduated high school with honors in May 2007. She expressed her intention to become a veterinarian after graduating. She is attending Marian College in Fond du Lac. Mayo Clinic neurologist Dr. Kenneth Mack described her condition as she entered college: she's recovered "remarkably well" and should continue to improve. | Jeanna Giese
Jeanna Giese (born 1989) is the first person known to have survived symptomatic rabies without receiving the rabies vaccine. She is only the sixth person known to have survived rabies after the onset of symptoms; the other survivors suffered from vaccine failures.
# Infection with Rabies
In September 2004, Giese, then fifteen years old, picked up a bat that she found in St. Patrick's Church in her hometown of Fond du Lac, Wisconsin. She sustained a small bite on her left index finger, and having treated it with hydrogen peroxide, her mother decided to not seek medical attention[1]. Thirty-seven days after the bite Giese developed symptoms of rabies. She was admitted to the hospital with tremors and trouble walking. Her condition continued to deteriorate, and she was referred to the Children's Hospital of Wisconsin in Wauwatosa, Wisconsin. Doctors there began to suspect rabies, and their diagnosis was confirmed by laboratory tests at the Centers for Disease Control.
# Induced Coma Treatment
Rabies had been considered universally fatal in unvaccinated patients after the onset of symptoms (with treatment generally limited to palliative care), but Giese’s parents agreed to an experimental treatment proposed by her doctors at the Children's Hospital of Wisconsin. The doctors used drugs to put Giese into a coma with the aid of ketamine and midazolam. During the following week she was administered phenobarbital (a sedative) and she was given a cocktail of antiviral drugs (ribavirin and amantadine) while waiting for her immune system to produce antibodies to attack the virus. Giese was brought out of the coma after seven days.
After thirty-one days in the hospital, Giese was declared virus-free and removed from isolation. There was some initial concern about the level of brain damage she had suffered, but while she had suffered nerve damage, the disease seemed to have left her cognitive abilities largely intact. She spent several weeks undergoing rehabilitation therapy and was discharged on January 1, 2005. By November 2005 she was able to walk on her own, had returned to school, and had started driving automobiles.
# Theories about Survival
The reasons for her survival remain controversial. Giese's doctors knew most rabies deaths were caused by temporary brain dysfunction, not permanent brain damage. They reasoned that if they protected Giese's brain by intentionally putting her into a coma, she would survive long enough for her body to fight off the virus. While the treatment appears to have worked as planned, other rabies researchers suggest Giese might have been infected with a particularly weak form of the virus, or that she might have an unusually strong immune system. The bat that bit Giese was not recovered for testing, and doctors were unable to isolate the virus from her body.
# Other Attempts
At least six later attempts to cure symptomatic rabies using a similar medical protocol have been unsuccessful. In May 2006, doctors at the Texas Children's Hospital applied a similar treatment as used on Giese to Zachary Jones, a 16 year-old stricken with symptomatic rabies, but they were unable to save him. From early October to early November of 2006, 10-year old Shannon Carroll was also unsuccessfully treated. This protocol is commonly being referred to as the "'Jeanna Treatment", at the Springs. An article written by her primary care physician in the April 2007 Scientific American calls this the Milwaukee protocol[1]; he indicates that those who attempted to follow this protocol actually violated it, failing to use the combination of drugs he first described.
# Life After Rabies
Jeanna Giese returned to school, and with the extra help of teachers, was able to complete her sophomore year with her class. Despite the obvious setback, she kept at the same level as the rest of her classmates. She graduated high school with honors in May 2007. She expressed her intention to become a veterinarian after graduating.[1][2] She is attending Marian College in Fond du Lac.[3] Mayo Clinic neurologist Dr. Kenneth Mack described her condition as she entered college: she's recovered "remarkably well" and should continue to improve.[3]
# External links
- "Rabies survivor leaves hospital". jsonline.com. Milwaukee Journal Sentinel. 2005-01-02. Check date values in: |date= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- "Jeanna Giese struggles to be... just your normal rabies survivor". jsonline.com. Milwaukee Journal Sentinel. 2005-11-26. Check date values in: |date= (help)
- "First Person in Recorded History to Survive Advanced Rabies Without Vaccination or Postexposure". Purple Medical Blog. 2005-12-05. Check date values in: |date= (help)
- "First Unvaccinated Rabies Survivor Goes Home". Daily News Central. 2005-01-03. Check date values in: |date= (help)
- Rodney E. Willoughby, Jr., M.D. (2005-06-16). "Survival after Treatment of Rabies with Induction of Coma". New England Journal of Medicine. 352 (24): 2508–2514. PMID 15958806. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)CS1 maint: Multiple names: authors list (link)
- "Jeanna Giese Learns to Drive". WBAY. 2006-04-08. Check date values in: |date= (help)
- "Surviving Rabies : A Medical First Takes Place at Children's Hospital". Healthlink. Medical College of Wisconsin. 2005-05-26. Check date values in: |date= (help) | https://www.wikidoc.org/index.php/Jeanna_Giese | |
29716ff9f2ada0a200ae67d2d2d0399e6693940b | wikidoc | Jerry Vlasak | Jerry Vlasak
Jerry Vlasak is an American physician, animal rights activist, environmentalist, and press officer for the North American Animal Liberation Press Office. He is a member of the Physicians Committee for Responsible Medicine, a director of the Animal Defense League, a former member of the Sea Shepherd Conservation Society's board of directors and an advisor to SPEAK, the Voice for the Animals.
Inspired by his wife, former actress Pamelyn Ferdin, who is currently president of Stop Huntingdon Animal Cruelty in the U.S., Vlasak became active in promoting animal rights in 1993. His principle role in the animal liberation movement, according to LA Weekly, is to "be a liaison with the public, and to publicize the radical animal-rights underground’s activities."
Vlasak acknowledges his medical background provides a "certain amount of cachet" to his support of the animal rights movement. He holds staff privileges as a doctor at Riverside Community Hospital in Riverside, California despite the fact that as of 2007, he has not worked there for 18 months.
# Controversy
Vlasak stirred controversy in 2003 when, speaking of scientists who perform experiments on animals, he stated that "If these vivisectors were being targeted for assassination, and call it political assassination or what have you ... strictly from a fear and intimidation factor, that would be an effective tactic." The following year in an interview with The Observer he made similar comments, including: "I don't think you'd have to kill too many . I think for five lives, 10 lives, 15 human lives, we could save a million, 2 million, 10 million non-human lives." The remarks led to his being barred from entering the United Kingdom on the grounds his presence "would not be conducive to the public good." Vlasak has since said he was misrepresented.
In October 2005, he stated to the U.S. Senate that the murder of scientists "would be a morally justifiable solution." | Jerry Vlasak
Jerry Vlasak is an American physician, animal rights activist, environmentalist, and press officer for the North American Animal Liberation Press Office. He is a member of the Physicians Committee for Responsible Medicine, a director of the Animal Defense League, a former member of the Sea Shepherd Conservation Society's board of directors and an advisor to SPEAK, the Voice for the Animals. [1]
Inspired by his wife, former actress Pamelyn Ferdin, who is currently president of Stop Huntingdon Animal Cruelty in the U.S., Vlasak became active in promoting animal rights in 1993. His principle role in the animal liberation movement, according to LA Weekly, is to "be a liaison with the public, and to publicize the radical animal-rights underground’s activities." [2]
Vlasak acknowledges his medical background provides a "certain amount of cachet" to his support of the animal rights movement. He holds staff privileges as a doctor at Riverside Community Hospital in Riverside, California despite the fact that as of 2007, he has not worked there for 18 months. [2]
# Controversy
Vlasak stirred controversy in 2003 when, speaking of scientists who perform experiments on animals, he stated that "If these vivisectors were being targeted for assassination, and call it political assassination or what have you ... strictly from a fear and intimidation factor, that would be an effective tactic." The following year in an interview with The Observer he made similar comments, including: "I don't think you'd have to kill too many [researchers]. I think for five lives, 10 lives, 15 human lives, we could save a million, 2 million, 10 million non-human lives." The remarks led to his being barred from entering the United Kingdom on the grounds his presence "would not be conducive to the public good." [3][1] Vlasak has since said he was misrepresented. [1]
In October 2005, he stated to the U.S. Senate that the murder of scientists "would be a morally justifiable solution."[4] | https://www.wikidoc.org/index.php/Jerry_Vlasak | |
2d59427448bdef0f5d956bf9c788ede0f38e430d | wikidoc | Jet injector | Jet injector
A jet injector is a type of medical injecting syringe that uses a high-pressure narrow jet of the injection liquid instead of a hypodermic needle to penetrate the epidermis. It is powered by compressed air or gas, either by a pressure hose from a large cylinder, or from a built-in gas cartridge or small cylinder. Some are multi-shot, and some are one-shot. They are made in various shapes, as the links to images below show.
They are used by diabetics to inject insulin as an alternative to needle syringes, though they are still not very common.
In the Star Trek franchise, and sometimes in other fictional scenarios and occasionally in the real world, it is called a hypospray.
# Types of jet injector
## Jet Injectors
The Jet Injector Gun and the Ped-O-Jet are air-powered medical injector devices designed to administer vaccinations in an extremely efficient manner. Invented by Aaron Ismach, these medical devices were bought in mass quantities by the US Government and provided to governments around the world to eradicate smallpox and other diseases. Servicemen in the Armed Forces were routinely injected with these medical devices to immunize them, and civilian usage included vaccinations during flu epidemics and the like. The Jet Injector is powered by electricity, while the Ped-O-Jet version is powered by a foot pump and does not require electricity to administer the vaccines. These devices has various specialized nozzles for different medication densities and also permitted the efficient inoculation of animal populations as well.
The Biojector® 2000 is a make of gas-cartridge-powered jet injector. It is claimed that it can deliver intramuscular injections and subcutaneous injections up to 1 milliliter. The part which touches the patient's skin is single-use and can be replaced easily. It can be powered from a big compressed gas cylinder instead of gas cartridges. It is made by Bioject.
In October 2006 it was in clinical trials for patients using Fuzeon as part of their HAART treatment for HIV. For clinical trial and related information see
# History
- 19th century: Workmen in France had accidental jet injections with high-powered grease guns
- 1920s: Diesel engines begin to be made in large quantities: thus beginning of serious risk of accidental jet-injection by their fuel injectors as workshop accidents.
- 1937: First known recorded accidental jet injection by a diesel engine's fuel injector.
- 1960: Aaron Ismach invented and patented the Jet Injector medical device which was used for quick mass vaccination of smallpox and other diseases. Ismach was assisted by Dr. Abram Benenson in the development of the Jet Injector Gun. The new method met with tremendous success as teams vaccinated large numbers of people at collecting points in the affected countries. The foot operated gun was called the Ped-O-Jet and the electric operated gun was called the Jet Injector Gun.
- 1962: Robert Andrew Hingson claimed to have invented a prototype jet injector and called it the peace gun, for quick mass vaccination. But sometimes the injection process dislodged infected matter from a patient onto the nozzle of the injector, risking cross-infection.
- 1964: Aaron Ismach was presented with a Gold Medal from the US Government for his efforts related to the Jet Injector Gun. The Jet Injector also appeared on postage stamps as a commemorative of his efforts.
- September 1966: The Star Trek series started, exposing the public to the idea of jet injectors under the name "hypospray".
- 1976: The USA Agency for International Development published a book called War on Hunger which detailed the War Against Smallpox which Ismach's Jet Injector gun was used to eradicate the disease in Africa and Asia. The US Government spent $150 million a year to prevent its reoccurance in North America.
- 1997: The USA Department of Defense, the jet injector's biggest user, announced that it would stop using it for mass vaccinations due to concerns about infection. | Jet injector
A jet injector is a type of medical injecting syringe that uses a high-pressure narrow jet of the injection liquid instead of a hypodermic needle to penetrate the epidermis. It is powered by compressed air or gas, either by a pressure hose from a large cylinder, or from a built-in gas cartridge or small cylinder. Some are multi-shot, and some are one-shot. They are made in various shapes, as the links to images below show.
They are used by diabetics to inject insulin as an alternative to needle syringes, though they are still not very common.
In the Star Trek franchise, and sometimes in other fictional scenarios and occasionally in the real world, it is called a hypospray.
# Types of jet injector
## Jet Injectors
The Jet Injector Gun and the Ped-O-Jet are air-powered medical injector devices designed to administer vaccinations in an extremely efficient manner. Invented by Aaron Ismach, these medical devices were bought in mass quantities by the US Government and provided to governments around the world to eradicate smallpox and other diseases. Servicemen in the Armed Forces were routinely injected with these medical devices to immunize them, and civilian usage included vaccinations during flu epidemics and the like. The Jet Injector is powered by electricity, while the Ped-O-Jet version is powered by a foot pump and does not require electricity to administer the vaccines. These devices has various specialized nozzles for different medication densities and also permitted the efficient inoculation of animal populations as well.
The Biojector® 2000 is a make of gas-cartridge-powered jet injector. It is claimed that it can deliver intramuscular injections and subcutaneous injections up to 1 milliliter. The part which touches the patient's skin is single-use and can be replaced easily. It can be powered from a big compressed gas cylinder instead of gas cartridges. It is made by Bioject.
In October 2006 it was in clinical trials for patients using Fuzeon as part of their HAART treatment for HIV. For clinical trial and related information see http://www.hivdent.org/drugs1/drugBIFI0306.htm
# History
- 19th century: Workmen in France had accidental jet injections with high-powered grease guns [1]
- 1920s: Diesel engines begin to be made in large quantities: thus beginning of serious risk of accidental jet-injection by their fuel injectors as workshop accidents.
- 1937: First known recorded accidental jet injection by a diesel engine's fuel injector[1].
- 1960: Aaron Ismach invented and patented the Jet Injector medical device which was used for quick mass vaccination of smallpox and other diseases. Ismach was assisted by Dr. Abram Benenson in the development of the Jet Injector Gun. The new method met with tremendous success as teams vaccinated large numbers of people at collecting points in the affected countries. The foot operated gun was called the Ped-O-Jet and the electric operated gun was called the Jet Injector Gun.
- 1962: Robert Andrew Hingson claimed to have invented a prototype jet injector and called it the peace gun, for quick mass vaccination. But sometimes the injection process dislodged infected matter from a patient onto the nozzle of the injector, risking cross-infection.
- 1964: Aaron Ismach was presented with a Gold Medal from the US Government for his efforts related to the Jet Injector Gun. The Jet Injector also appeared on postage stamps as a commemorative of his efforts.
- September 1966: The Star Trek series started, exposing the public to the idea of jet injectors under the name "hypospray".
- 1976: The USA Agency for International Development published a book called War on Hunger which detailed the War Against Smallpox which Ismach's Jet Injector gun was used to eradicate the disease in Africa and Asia. The US Government spent $150 million a year to prevent its reoccurance in North America.
- 1997: The USA Department of Defense, the jet injector's biggest user, announced that it would stop using it for mass vaccinations due to concerns about infection.
# External links about jet injectors
- Problems in use of jet injectors by diabetics
- Memory Alpha (Star Trek Wiki) page about the hypospray
## Web pages using "hypospray" for a real jet injector
These three references are all to articles in scientific periodicals:-
- Comparison of two steroid preparations used to treat tennis elbow, using the hypospray (1975)
- The use of the hypospray in the treatment of minor orthopaedic conditions (1969)
- Use of the hypospray jet injector for intra-articular injection (1967)
This link uses the name "hypospray" for an automatic tourniquet.
## Links to pages with images
- [2] in *http://www.dantonioconsultants.com/prod_ji_vet.htm
- MIT-V jet injector with separate CO2 propellant cylinder
- JET 2000 jet injector
- LectraJet jet injector
- Akra Dermojet
- Biojector 2000
- Jet injector in use for mass vaccination
# Accidental jet injection
Accidents have happened in vehicle repair garages and elsewhere where one of these has unintentionally acted as a hypodermic jet injector:-
- A fuel injector of a diesel engine.
- A high-pressure grease gun.
- A pinhole leak in a tube supplying a high-powered grease gun from a separate grease pressure-tank.
- A pinhole leak in a tube of high pressure hydraulic oil equipment.
- A high pressure paint spray.
High pressure injections of oil or paint can cause very serious injuries which may require amputation and can induce fatal blood poisoning. Particular care must be taken around high pressure sprays of this kind to avoid such injuries.
## External links about accidental jet injection
- Safety In Lubrication
- http://www.viscosityoil.com/pdf/msds3/LINK-BELT-DIESEL-ENGINE-OIL-15W40.pdf (scroll down to Section 4)
- http://bmj.bmjjournals.com/cgi/content/full/312/7044/1436
- http://www.napavalleypetroleum.com/msds_napa_no2_diesel_fuel.htm (scroll down to section 7) | https://www.wikidoc.org/index.php/Jet_injector | |
6e5b82749caab6ccb8693dbed9385026ed2473cc | wikidoc | Tinea cruris | Tinea cruris
# Overview
Tinea cruris is the scientific name for fungal infection of the groin region. Official alternative names include Jock itch or dhobi itch (after Indian washermen).
# Diagnosis
## Common Causes
Opportunistic infections (infections that are caused by a diminished immune system) are frequent. Fungus from other parts of the body (commonly tinea pedis or 'athlete's foot') can contribute to jock itch. A warm, damp environment allowing the fungus to cultivate greatly contributes; especially with tight, sweaty or rubbing clothing such as jockstrap or tight undershorts.
The type of fungus that most commonly causes tinea cruris is called Trichophyton rubrum. Some other contributing fungi are Candida albicans, Trichophyton mentagrophytes and Epidermophyton floccosum.
## Symptoms and signs
As the common name for this condition implies, it causes itching or a burning sensation in the groin area, thigh skin folds, or anus. It may involve the inner thighs and genital areas, as well as extending back to the perineum and perianal areas.
Affected areas may appear red, tan, or brown, with flaking, peeling, or cracking skin.
The acute infection begins with an area in the groin fold about a half-inch across, usually on both sides. The area may enlarge, and other sores may develop in no particular pattern. The rash appears as raised red plaques (platelike areas) and scaly patches with sharply defined borders that may blister and ooze.
If the rash advances, it usually advances down the inner thigh. The advancing edge is redder and more raised than areas that have been infected longer. The advancing edge is usually scaly, and very easily distinguished or well demarcated.
The skin within the border turns a reddish-brown and loses much of its scale. The border may exhibit tiny pimples or even pustules, with central areas that are reddish and dry with small scales.
If infected with candidal organisms, the rash tends to be redder and wetter. The skin of the penis may be involved, whereas other organisms spare the penis.
## Physical Examination
### Skin
### Genitalia
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
- Tinea cruris. Adapted from Dermatology Atlas.
# Treatment
Tinea cruris is best treated with antifungal drugs applied topically. Traditionally creams containing clotrimazole or miconazole have been used, although newer agents such as butenafine are also used. These anti-fungal agents work by stopping the fungi from producing a substance called ergosterol, which is an essential component of fungal cell membranes. If ergosterol synthesis is completely or partially inhibited, the cell is no longer able to construct an intact cell membrane. This leads to death of the fungus.
If the skin inflammation causes discomfort and itching, glucocorticoid steroids may be combined with the anti-fungal drug to help prevent further irritation due to the patient scratching the area. Apart from the quicker relief of symptoms, this also helps minimise the risk of secondary bacterial infection caused by the scratching. However steroids, if used alone, for fungal infections may exacerbate the condition.
## Antimicrobial Regimen
- Tinea Cruris
- 1. Topical cream/ointment
- Preferred regimen (1): Butenafine cream applied qd for 14 days
- Preferred regimen (2): Terbinafine cream applied bid for 14 days
- 2. Oral antifungal
- Preferred regimen: Fluconazole 200 mg qd for 10 days AND Terbinafine 250 mg qd for 30 days
- Note: Oral antifungal therapy is generally reserved for cases unresponsive to topical agents or can be used along with topical agents in severe cases. | Tinea cruris
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Tinea cruris is the scientific name for fungal infection of the groin region. Official alternative names include Jock itch or dhobi itch (after Indian washermen).
# Diagnosis
## Common Causes
Opportunistic infections (infections that are caused by a diminished immune system) are frequent. Fungus from other parts of the body (commonly tinea pedis or 'athlete's foot') can contribute to jock itch. A warm, damp environment allowing the fungus to cultivate greatly contributes; especially with tight, sweaty or rubbing clothing such as jockstrap or tight undershorts.
The type of fungus that most commonly causes tinea cruris is called Trichophyton rubrum. Some other contributing fungi are Candida albicans, Trichophyton mentagrophytes and Epidermophyton floccosum.
## Symptoms and signs
As the common name for this condition implies, it causes itching or a burning sensation in the groin area, thigh skin folds, or anus. It may involve the inner thighs and genital areas, as well as extending back to the perineum and perianal areas.
Affected areas may appear red, tan, or brown, with flaking, peeling, or cracking skin.[3][4]
The acute infection begins with an area in the groin fold about a half-inch across, usually on both sides. The area may enlarge, and other sores may develop in no particular pattern. The rash appears as raised red plaques (platelike areas) and scaly patches with sharply defined borders that may blister and ooze.[5]
If the rash advances, it usually advances down the inner thigh. The advancing edge is redder and more raised than areas that have been infected longer. The advancing edge is usually scaly, and very easily distinguished or well demarcated.
The skin within the border turns a reddish-brown and loses much of its scale. The border may exhibit tiny pimples or even pustules, with central areas that are reddish and dry with small scales.[6][7]
If infected with candidal organisms, the rash tends to be redder and wetter. The skin of the penis may be involved, whereas other organisms spare the penis.
## Physical Examination
### Skin
### Genitalia
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
- Tinea cruris. Adapted from Dermatology Atlas.[1]
# Treatment
Tinea cruris is best treated with antifungal drugs applied topically. Traditionally creams containing clotrimazole or miconazole have been used, although newer agents such as butenafine are also used. These anti-fungal agents work by stopping the fungi from producing a substance called ergosterol, which is an essential component of fungal cell membranes. If ergosterol synthesis is completely or partially inhibited, the cell is no longer able to construct an intact cell membrane. This leads to death of the fungus.
If the skin inflammation causes discomfort and itching, glucocorticoid steroids may be combined with the anti-fungal drug to help prevent further irritation due to the patient scratching the area. Apart from the quicker relief of symptoms, this also helps minimise the risk of secondary bacterial infection caused by the scratching. However steroids, if used alone, for fungal infections may exacerbate the condition.
## Antimicrobial Regimen
- Tinea Cruris[2]
- 1. Topical cream/ointment
- Preferred regimen (1): Butenafine cream applied qd for 14 days
- Preferred regimen (2): Terbinafine cream applied bid for 14 days
- 2. Oral antifungal
- Preferred regimen: Fluconazole 200 mg qd for 10 days AND Terbinafine 250 mg qd for 30 days
- Note: Oral antifungal therapy is generally reserved for cases unresponsive to topical agents or can be used along with topical agents in severe cases. | https://www.wikidoc.org/index.php/Jock_Itch | |
8e5114a9c5b08605cafca0a32c30ebd11e99d2e2 | wikidoc | John Grinder | John Grinder
John Grinder, Ph.D. (born 1940) is an American author and linguist. Grinder (pronounced grin-der, Template:IPAEng) is credited (with Richard Bandler) with the creation of the field of Neuro-linguistic programming.
# Biography
John Thomas Grinder graduated from the University of San Francisco with a degree in psychology in the early 1960's. Grinder then entered the United States Army where he served as a Captain in the US Special Forces in Europe during the Cold War; following this he apparently went on to work for a US Intelligence Agency. In the late 1960s, Grinder went back to college to study Linguistics and in 1972 received his Ph.D. from the University of California, San Diego for his work On Deletion Phenomena in English.
In the early 1970s Grinder worked in George A. Miller's lab at Rockefeller University and was then selected as an assistant professor of linguistics at the newly founded University of California, Santa Cruz (UCSC) campus. During his academic career, Grinder focused on Noam Chomsky's theories of transformational grammar specialising in syntax. Other academic works include Guide to Transformational Grammar (co-authored with Suzette Elgin, Holt, Rinehart and Winston, Inc., 1973) and more recently, Steps to an Ecology of Emergence (2005) with Tom Malloy and Carmen Bostic St Clair.
# Development of Neuro-linguistic programming
In 1972, while at UCSC, Grinder was approached by an undergraduate psychology student, Richard Bandler, who requested his assistance to model Gestalt therapy. Bandler had spent a lot of time recording and editing recordings of Fritz Perls (founder of Gestalt therapy) and had learned Gestalt therapy implicitly. Starting with Fritz Perls, followed by leading figure in family therapy Virginia Satir, and later the leading figure in hypnosis in psychiatry Milton Erickson, Grinder and Bandler continued to model the various cognitive behavioral patterns of these therapists, which they published in The Structure of Magic Volumes I & II (1975, 1976), Patterns of the Hypnotic Techniques of Milton H. Erickson, Volumes I & II (1975, 1977) and Changing With Families (1976). This work formed the basis of the methodology that became the foundation of Neuro-Linguistic Programming.
Bandler and Grinder began hosting seminars and practise groups. These served as a place for Bandler and Grinder to practice and test their newly discovered patterns while allowing them to transfer the skills to the participants. Several books were published based on transcripts of their seminars including Frogs into Princes (1979). During this period, a creative group of students and psychotherapists formed around Grinder and Bandler, who made valuable contributions to NLP, including Robert Dilts, Leslie Cameron-Bandler, Judith DeLozier, Stephen Gilligan, David Gordon.
In the 1980s Bandler, Grinder and their group of associates split acrimoniously, and stopped working together. Following this, many members of their group went out on their own and took NLP in their own directions. Some of Bandler and Grinder's books went out of print for a while due to legal problems between the co-authors. Structure I & II, and Patterns I & II considered the foundation of the field were later republished. Bandler attempted to claim legal ownership of the term Neuro-Linguistic Programming (NLP), however it was eventually deemed to be a generic term, and could therefore not be trademarked. Grinder and Bandler settled their claims around 2001, clearing a platform for the future development of NLP as a legitimate field of endeavour.
## New code of NLP
Strongly influenced by his mentor and anthropologist Gregory Bateson, between 1982-1987 John collaborated with Judith DeLozier to develop the New Code of NLP. The patterns presented were designed to provide an aesthetic framework that explicates the involvement of ecology and the unconscious mind in change work. Ecology in NLP is about respecting the integrity of the system as a whole when assessing a change to that system; the 'system' in this case is a person's model of the world and the consequences of that model in the person's environment. Practically, this consideration entails asking questions like "What are the intended effects of this change? What other effects might this change have, and are those effects desirable? Is this change still a good idea?"
The seminars were transcribed and published in 1987, Turtles All the Way Down; Prerequisites to Personal Genius.
The New Code of NLP has been further developed by John Grinder and Carmen Bostic St Clair who founded, Quantum Leap Inc.; a cultural change consultancy firm. Currently John and Carmen present some public seminars on NLP internationally. In 2001, Grinder (with Bostic St Clair) published Whispering in the Wind with " set of recommendations as to how specifically NLP can improve its practice and take its rightful place as a scientifically based endeavor with its precise focus on modeling of the extremes of human behavior: excellence and the high performers who actually do it." Grinder has since, strongly encouraged the field to make a recommitment to what he considers the core activity of NLP, modeling.
# Books
- Bandler, Richard & John Grinder (1975a). The Structure of Magic I: A Book About Language and Therapy. Palo Alto, CA: Science & Behavior Books. ISBN 0831400447..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}
- Bandler, Richard & John Grinder (1975b). The Structure of Magic II: A Book About Communication and Change. PaloAlto, CA: Science & Behavior Books. ISBN 0-8314-0049-8.
- Grinder, John, Richard Bandler (1976). Patterns of the Hypnotic Techniques of Milton H. Erickson, M.D. Volume I. Cupertino, CA :Meta Publications. ISBN 1555520529.CS1 maint: Multiple names: authors list (link)
- John Grinder, Richard Bandler, Judith Delozier (1977). Check |url= value (help). Cupertino, CA :Meta Publications. pp. -. ISBN 1555520537.CS1 maint: Multiple names: authors list (link)
- John Grinder, Richard Bandler (1979). Check |url= value (help). Moab, UT: Real People Press. pp. 194pp. ISBN 0-911226-19-2.
- Grinder, John and Richard Bandler (1981). Check |url= value (help). Moab, UT: Real People Press. pp. -. ISBN 0-911226-23-0.
- Grinder, John and Richard Bandler (1983). Check |url= value (help). Moab, UT: Real People Press. pp. -. ISBN 0-911226-25-7.
- Grinder, John & Judith DeLozier (1987). Turtles All the Way Down: Prerequisites to Personal Genius. Scots Valley, CA: Grinder & Associates. ISBN 1-55552-022-7.
- Grinder, John, Michael McMaster (1993). Precision. ScotsValley, CA: Grinder & Associates. ISBN 1-55552-049-9.CS1 maint: Multiple names: authors list (link)
- Charlotte Bretto Milliner (ed.), John Grinder (ed.) and Sylvia Topel (ed.) (1994). Leaves before the Wind: Leading Edge Applications of NLP. Scots Valley, CA: Grinder & Associates. ISBN 1555520510.CS1 maint: Extra text: authors list (link)
- Grinder, John & Carmen Bostic St Clair (2001.). Whispering in the Wind. CA: J & C Enterprises. pp. -. ISBN 0-9717223-0-7. Check date values in: |year= (help)
- Grinder, John, Carmen Bostic St Clair, Tom Malloy (Working title). RedTail Math: the epistemology of everyday life. Check date values in: |year= (help)CS1 maint: Multiple names: authors list (link)
# Academic papers
- John Grinder, Paul Postal (1971). "Missing Antecedents, Linguistic Inquiry". Mouton & Co.,.
- John Grinder, Suzette Elgin (1972). "On Deletion Phenomena in English". Mouton & Co.,.
- John Grinder, Suzette Elgin (1973). "Guide to Transformational Grammar: History, Theory, Practice".
- Malloy, T. E., Bostic St Clair, C. & Grinder, J. (2005). "Steps to an ecology of emergence" (PDF). Cybernetics & Human Knowing. Vol. 11, no. 3: 102-119.CS1 maint: Multiple names: authors list (link) | John Grinder
Template:Infobox Linguist
Template:Neuro-linguistic programming
John Grinder, Ph.D. (born 1940) is an American author and linguist. Grinder (pronounced grin-der, Template:IPAEng) is credited (with Richard Bandler) with the creation of the field of Neuro-linguistic programming.
# Biography
John Thomas Grinder graduated from the University of San Francisco with a degree in psychology in the early 1960's. Grinder then entered the United States Army where he served as a Captain in the US Special Forces in Europe during the Cold War; following this he apparently went on to work for a US Intelligence Agency. In the late 1960s, Grinder went back to college to study Linguistics and in 1972 received his Ph.D. from the University of California, San Diego for his work On Deletion Phenomena in English.[1]
In the early 1970s Grinder worked in George A. Miller's lab at Rockefeller University[2] and was then selected as an assistant professor of linguistics at the newly founded University of California, Santa Cruz (UCSC) campus. During his academic career, Grinder focused on Noam Chomsky's theories of transformational grammar specialising in syntax. Other academic works include Guide to Transformational Grammar (co-authored with Suzette Elgin, Holt, Rinehart and Winston, Inc., 1973) and more recently, Steps to an Ecology of Emergence (2005)[3] with Tom Malloy and Carmen Bostic St Clair.
# Development of Neuro-linguistic programming
In 1972, while at UCSC, Grinder was approached by an undergraduate psychology student, Richard Bandler, who requested his assistance to model Gestalt therapy. Bandler had spent a lot of time recording and editing recordings of Fritz Perls (founder of Gestalt therapy) and had learned Gestalt therapy implicitly. Starting with Fritz Perls, followed by leading figure in family therapy Virginia Satir, and later the leading figure in hypnosis in psychiatry Milton Erickson, Grinder and Bandler continued to model the various cognitive behavioral patterns of these therapists, which they published in The Structure of Magic Volumes I & II (1975, 1976), Patterns of the Hypnotic Techniques of Milton H. Erickson, Volumes I & II (1975, 1977) and Changing With Families (1976). This work formed the basis of the methodology that became the foundation of Neuro-Linguistic Programming.
Bandler and Grinder began hosting seminars and practise groups. These served as a place for Bandler and Grinder to practice and test their newly discovered patterns while allowing them to transfer the skills to the participants. Several books were published based on transcripts of their seminars including Frogs into Princes (1979). During this period, a creative group of students and psychotherapists formed around Grinder and Bandler, who made valuable contributions to NLP, including Robert Dilts, Leslie Cameron-Bandler, Judith DeLozier, Stephen Gilligan, David Gordon.
In the 1980s Bandler, Grinder and their group of associates split acrimoniously, and stopped working together. Following this, many members of their group went out on their own and took NLP in their own directions. Some of Bandler and Grinder's books went out of print for a while due to legal problems between the co-authors. Structure I & II, and Patterns I & II considered the foundation of the field were later republished. Bandler attempted to claim legal ownership of the term Neuro-Linguistic Programming (NLP), however it was eventually deemed to be a generic term, and could therefore not be trademarked. Grinder and Bandler settled their claims around 2001, clearing a platform for the future development of NLP as a legitimate field of endeavour.[4]
## New code of NLP
Strongly influenced by his mentor and anthropologist Gregory Bateson, between 1982-1987 John collaborated with Judith DeLozier to develop the New Code of NLP. The patterns presented were designed to provide an aesthetic framework that explicates the involvement of ecology and the unconscious mind in change work. Ecology in NLP is about respecting the integrity of the system as a whole when assessing a change to that system; the 'system' in this case is a person's model of the world and the consequences of that model in the person's environment. Practically, this consideration entails asking questions like "What are the intended effects of this change? What other effects might this change have, and are those effects desirable? Is this change still a good idea?"
The seminars were transcribed and published in 1987, Turtles All the Way Down; Prerequisites to Personal Genius.
The New Code of NLP has been further developed by John Grinder and Carmen Bostic St Clair who founded, Quantum Leap Inc.; a cultural change consultancy firm. Currently John and Carmen present some public seminars on NLP internationally. In 2001, Grinder (with Bostic St Clair) published Whispering in the Wind with "[a] set of recommendations as to how specifically NLP can improve its practice and take its rightful place as a scientifically based endeavor with its precise focus on modeling of the extremes of human behavior: excellence and the high performers who actually do it."[5] Grinder has since, strongly encouraged the field to make a recommitment to what he considers the core activity of NLP, modeling.[6]
# Books
- Bandler, Richard & John Grinder (1975a). The Structure of Magic I: A Book About Language and Therapy. Palo Alto, CA: Science & Behavior Books. ISBN 0831400447..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}
- Bandler, Richard & John Grinder (1975b). The Structure of Magic II: A Book About Communication and Change. PaloAlto, CA: Science & Behavior Books. ISBN 0-8314-0049-8.
- Grinder, John, Richard Bandler (1976). Patterns of the Hypnotic Techniques of Milton H. Erickson, M.D. Volume I. Cupertino, CA :Meta Publications. ISBN 1555520529.CS1 maint: Multiple names: authors list (link)
- John Grinder, Richard Bandler, Judith Delozier (1977). [- Patterns of the Hypnotic Techniques of Milton H. Erickson, M.D. Volume II] Check |url= value (help). Cupertino, CA :Meta Publications. pp. -. ISBN 1555520537.CS1 maint: Multiple names: authors list (link)
- John Grinder, Richard Bandler (1979). [- Frogs into Princes: Neuro Linguistic Programming] Check |url= value (help). Moab, UT: Real People Press. pp. 194pp. ISBN 0-911226-19-2.
- Grinder, John and Richard Bandler (1981). [- Trance-Formations: Neuro-Linguistic Programming and the Structure of Hypnosis] Check |url= value (help). Moab, UT: Real People Press. pp. -. ISBN 0-911226-23-0.
- Grinder, John and Richard Bandler (1983). [- Reframing: Neurolinguistic programming and the transformation of meaning] Check |url= value (help). Moab, UT: Real People Press. pp. -. ISBN 0-911226-25-7.
- Grinder, John & Judith DeLozier (1987). Turtles All the Way Down: Prerequisites to Personal Genius. Scots Valley, CA: Grinder & Associates. ISBN 1-55552-022-7.
- Grinder, John, Michael McMaster (1993). Precision. ScotsValley, CA: Grinder & Associates. ISBN 1-55552-049-9.CS1 maint: Multiple names: authors list (link)
- Charlotte Bretto Milliner (ed.), John Grinder (ed.) and Sylvia Topel (ed.) (1994). Leaves before the Wind: Leading Edge Applications of NLP. Scots Valley, CA: Grinder & Associates. ISBN 1555520510.CS1 maint: Extra text: authors list (link)
- Grinder, John & Carmen Bostic St Clair (2001.). Whispering in the Wind. CA: J & C Enterprises. pp. -. ISBN 0-9717223-0-7. Check date values in: |year= (help)
- Grinder, John, Carmen Bostic St Clair, Tom Malloy (Working title). RedTail Math: the epistemology of everyday life. Check date values in: |year= (help)CS1 maint: Multiple names: authors list (link)
# Academic papers
- John Grinder, Paul Postal (1971). "Missing Antecedents, Linguistic Inquiry". Mouton & Co.,.
- John Grinder, Suzette Elgin (1972). "On Deletion Phenomena in English". Mouton & Co.,.
- John Grinder, Suzette Elgin (1973). "Guide to Transformational Grammar: History, Theory, Practice".
- Malloy, T. E., Bostic St Clair, C. & Grinder, J. (2005). "Steps to an ecology of emergence" (PDF). Cybernetics & Human Knowing. Vol. 11, no. 3: 102-119.CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/John_Grinder | |
6493eed5c68559dcd8ca58b18925e23e6e78dd51 | wikidoc | Jonathan Ott | Jonathan Ott
Jonathan Ott is an ethnobotanist, writer, natural products Chemist and Botanical researcher in the area of entheogens and their cultural and historical uses. In his book Ayahuasca Analogues, he identifies numerous plants around the globe containing the harmala alkaloids of Banisteriopsis caapi, which are MAOIs, and plants containing dimethyltryptamine, which together are the chemical base of the South American Ayahuasca brew. He has collaborated with workers like Christian Rätsch and Jochen Gartz. He has co-authored several books and papers with the late ethnomycologist R. Gordon Wasson. He has experience of field collecting in Mexico, where he lives and manages a small natural-products laboratory and botanical garden of medicinal herbs.
# Bibliography
## Books
- Ometochtzin: Las Muertes de Dos Conejo (2001)
- Just Say Blow. Coca and Cocaine: A Scientific Blowjob (2001)
- Shamanic Snuffs or Entheogenic Errhines (2001), ISBN 1-888755-02-4
- Pharmacophilia: The Natural Paradise (1997), ISBN 1-888755-00-8
- Age of Entheogens & the Angels' Dictionary (1995), ISBN 0-9614234-6-3
- Ayahuasca Analogues: Pangaean Entheogens (1995), ISBN 0-9614234-4-7
- Pharmacotheon: Entheogenic drugs, their plant sources and history (1993), ISBN 0-9614234-2-0
- Persephone's Quest: Entheogens and the Origins of Religion (1986), ISBN 0-300-05266-9
- The Cacahuatl Eater: Ruminations of an Unabashed Chocolate Addict (1985) (Natural Products Company) ISBN 0-9614234-1-2
- Teonanacatl: Hallucinogenic Mushrooms of North America (Co-edited by J. Bigwood, 1978), ISBN 0-914842-32-3
- Hallucinogenic Plants of North America (1976), ISBN 0-914728-16-4
## Articles
- Pharmanopo-Psychonautics: Human Intranasal, Sublingual, Intrarectal, Pulmonary and Oral Pharmacology of Bufotenine (2001)
- Applied Psychonautics: Ayahuasca to Pharmahuasca to Anahuasca (2001)
- The Delphic Bee: Bees and toxic honeys as pointers to psychoactive and other medicinal plants (1998)
- Pharmahuasca, Anahuasca and Vinho da Jurema: Human Pharmacology of Oral DMT Plus Harmine (1997)
- Pharmahuasca: On Phenethylamines and Potentiation (1996)
- Ethnopharmacognosy and Human Pharmacology of Salvia divinorum and Salvinorin A (1995) | Jonathan Ott
Jonathan Ott is an ethnobotanist, writer, natural products Chemist and Botanical researcher in the area of entheogens and their cultural and historical uses. In his book Ayahuasca Analogues, he identifies numerous plants around the globe containing the harmala alkaloids of Banisteriopsis caapi, which are MAOIs, and plants containing dimethyltryptamine, which together are the chemical base of the South American Ayahuasca brew. He has collaborated with workers like Christian Rätsch and Jochen Gartz. He has co-authored several books and papers with the late ethnomycologist R. Gordon Wasson. He has experience of field collecting in Mexico, where he lives and manages a small natural-products laboratory and botanical garden of medicinal herbs.
# Bibliography
## Books
- Ometochtzin: Las Muertes de Dos Conejo (2001)
- Just Say Blow. Coca and Cocaine: A Scientific Blowjob (2001)
- Shamanic Snuffs or Entheogenic Errhines (2001), ISBN 1-888755-02-4
- Pharmacophilia: The Natural Paradise (1997), ISBN 1-888755-00-8
- Age of Entheogens & the Angels' Dictionary (1995), ISBN 0-9614234-6-3
- Ayahuasca Analogues: Pangaean Entheogens (1995), ISBN 0-9614234-4-7
- Pharmacotheon: Entheogenic drugs, their plant sources and history (1993), ISBN 0-9614234-2-0
- Persephone's Quest: Entheogens and the Origins of Religion (1986), ISBN 0-300-05266-9
- The Cacahuatl Eater: Ruminations of an Unabashed Chocolate Addict (1985) (Natural Products Company) ISBN 0-9614234-1-2
- Teonanacatl: Hallucinogenic Mushrooms of North America (Co-edited by J. Bigwood, 1978), ISBN 0-914842-32-3
- Hallucinogenic Plants of North America (1976), ISBN 0-914728-16-4
## Articles
- Pharmanopo-Psychonautics: Human Intranasal, Sublingual, Intrarectal, Pulmonary and Oral Pharmacology of Bufotenine (2001)
- Applied Psychonautics: Ayahuasca to Pharmahuasca to Anahuasca (2001)
- The Delphic Bee: Bees and toxic honeys as pointers to psychoactive and other medicinal plants (1998)
- Pharmahuasca, Anahuasca and Vinho da Jurema: Human Pharmacology of Oral DMT Plus Harmine (1997)
- Pharmahuasca: On Phenethylamines and Potentiation (1996)
- Ethnopharmacognosy and Human Pharmacology of Salvia divinorum and Salvinorin A (1995) | https://www.wikidoc.org/index.php/Jonathan_Ott | |
f67ba1130c7b0cdec36e9384b643a4f5f45e494c | wikidoc | Jorge Benach | Jorge Benach
Jorge Benach is a medical researcher at the State University of New York (SUNY) at Stonybrook in New York state. Benach is the chair of the Department of Molecular Genetics and Microbiology. Benach's main area of research is the tick borne spirochete Borrelia burgdorferi which is the causative agent of Lyme disease.
Benach also has begun to investigate organisms that could be used as bioterrorism agents, specifically Francisella tularensis, the bacterial agent of tularemia.
Benach graduated with a PhD from Rutgers University in 1972. Benach was named to a National Advisory Allergy and Infectious Diseases Council (NIAID) in 1998 and was named a 1992 Fulbright-Hays Fellow and Exchange Professor.
# Lyme Disease Research
Benach was one of the early researchers in Lyme disease. Benach and Edward Bosler, Ph.D. collaborated in the dogged and dangerous work of gathering and testing ticks for disease-causing pathogens in 1981 at the Mashomack Preserve on Shelter Island, off the coast of New York. Benach and colleagues at Stonybrook were of the first researchers to identify the role of the spirochete in Lyme Disease.
Benach and Bosler went on to co-author the book Lyme Disease and Related Disease Disorders, New York Academy of Sciences (September 1988).
Benach and pathology colleague Marc Golightly developed the critical laboratory test to detect the presence of antibodies to Borrelia burgdorferi, an ELISA test that became the original “gold standard” for Lyme diagnosis.
Benach continues to work with borrelia organisms at the Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, Stony Brook University. Benach chairs the scientific and advisory board of the Tick-Borne Disease Institute of the New York State department of health and is an ad-hoc committee member of the National Research Fund for Tick-Borne Diseases. | Jorge Benach
Jorge Benach is a medical researcher at the State University of New York (SUNY) at Stonybrook in New York state. Benach is the chair of the Department of Molecular Genetics and Microbiology. Benach's main area of research is the tick borne spirochete Borrelia burgdorferi which is the causative agent of Lyme disease.
Benach also has begun to investigate organisms that could be used as bioterrorism agents, specifically Francisella tularensis, the bacterial agent of tularemia.
Benach graduated with a PhD from Rutgers University in 1972. Benach was named to a National Advisory Allergy and Infectious Diseases Council (NIAID) in 1998 and was named a 1992 Fulbright-Hays Fellow and Exchange Professor.
# Lyme Disease Research
Benach was one of the early researchers in Lyme disease. Benach and Edward Bosler, Ph.D. collaborated in the dogged and dangerous work of gathering and testing ticks for disease-causing pathogens in 1981 at the Mashomack Preserve on Shelter Island, off the coast of New York. Benach and colleagues at Stonybrook were of the first researchers to identify the role of the spirochete in Lyme Disease.[1]
Benach and Bosler went on to co-author the book Lyme Disease and Related Disease Disorders, New York Academy of Sciences (September 1988).
Benach and pathology colleague Marc Golightly developed the critical laboratory test to detect the presence of antibodies to Borrelia burgdorferi, an ELISA test that became the original “gold standard” for Lyme diagnosis.
Benach continues to work with borrelia organisms at the Center for Infectious Diseases, Department of Molecular Genetics and Microbiology, Stony Brook University. Benach chairs the scientific and advisory board of the Tick-Borne Disease Institute of the New York State department of health and is an ad-hoc committee member of the National Research Fund for Tick-Borne Diseases. | https://www.wikidoc.org/index.php/Jorge_Benach | |
646e428d2c47aec766f06beeea49a29d4f0e3b4e | wikidoc | Josef Dvorak | Josef Dvorak
Josef Dvorak is an Austrian psychoanalyst, Catholic theologian (scholar of Karl Rahner), author, and co-founder of the Viennese Actionism.
# Work
For several years, Dvorak worked as a journalist for the Viennese newspapers Kurier and Arbeiter-Zeitung. At least from the beginning of the 1960s, Dvorak worked in Vienna as a therapist. In this time he also got to know Otto Muehl, who conducted a conversation analysis on Dvorak. At the end of the 1960s, Dvorak was an important intellectual source of inspiration for the left-winged Viennese student scene.
End of the 1970s, Dvorak claimed to have had an encounter with Satan while under the influence of LSD. After that, Dvorak retreated into a farmhouse in the Lower Austrian Waldviertel and began celebrating “Satanic masses with plenty of naked flesh and blood” („Satanische Messen mit viel nacktem Fleisch und Blut“ )
In the 1980s, Dvorak celebrated a modification of English occultist Aleister Crowley’s Missa Phoenix in Burgenland and in Bremen. These happenings have been broadcasted on Austrian television and gained Dvorak the reputation of being close to Satanism himself.
Today, Dvorak calls himself a “Satanologist” and, as a free researcher and publicist, is particularly engaged in the history of psychoanalysis and the occult. His 1989 book “Satanismus. Schwarze Rituale, Teufelswahn und Exorzismus, Geschichte und Gegenwart.” (“Satanism. Black rituals, devil obsession and exorcism, history and presence”) is regarded as a standard work of Satanism research.
# Literature
- Josef Dvorak: Satanismus. Schwarze Rituale, Teufelswahn und Exorzismus, Geschichte und Gegenwart. Heyne, Munich, 1989. ISBN 3-453-17258-2 | Josef Dvorak
Josef Dvorak is an Austrian psychoanalyst, Catholic theologian (scholar of Karl Rahner), author, and co-founder of the Viennese Actionism.
# Work
For several years, Dvorak worked as a journalist for the Viennese newspapers Kurier and Arbeiter-Zeitung. At least from the beginning of the 1960s, Dvorak worked in Vienna as a therapist. In this time he also got to know Otto Muehl, who conducted a conversation analysis on Dvorak. At the end of the 1960s, Dvorak was an important intellectual source of inspiration for the left-winged Viennese student scene.
End of the 1970s, Dvorak claimed to have had an encounter with Satan while under the influence of LSD. After that, Dvorak retreated into a farmhouse in the Lower Austrian Waldviertel and began celebrating “Satanic masses with plenty of naked flesh and blood” („Satanische Messen mit viel nacktem Fleisch und Blut“ [1])
In the 1980s, Dvorak celebrated a modification of English occultist Aleister Crowley’s Missa Phoenix in Burgenland and in Bremen. These happenings have been broadcasted on Austrian television and gained Dvorak the reputation of being close to Satanism himself.
Today, Dvorak calls himself a “Satanologist” and, as a free researcher and publicist, is particularly engaged in the history of psychoanalysis and the occult. His 1989 book “Satanismus. Schwarze Rituale, Teufelswahn und Exorzismus, Geschichte und Gegenwart.” (“Satanism. Black rituals, devil obsession and exorcism, history and presence”) is regarded as a standard work of Satanism research.
# Literature
- Josef Dvorak: Satanismus. Schwarze Rituale, Teufelswahn und Exorzismus, Geschichte und Gegenwart. Heyne, Munich, 1989. ISBN 3-453-17258-2 | https://www.wikidoc.org/index.php/Josef_Dvorak | |
8ad1bce7058173ac58b0f34f3f0d8415d885d2e0 | wikidoc | Joseph Barth | Joseph Barth
Joseph Barth October 28, 1746, Valletta, Malta - April 7, 1818, Vienna, Austria, was a notable 18th century ophthalmologist.
# Education
Anatomical & Surgical School at Sacra Infermeria, Valletta (Malta), Santo Spirito Hospital in Rome (Italy), University of Vienna (Austria). Qualified 1772.
# Career
Appointed Public Teacher in Ophthalmology and Anatomy (1773), Professor of Ophthalmology and Anatomy (1774) and Oculist and Professor of Physiology (1786) at University of Vienna; nominated Royal Counsellor (1774) and appointed oculist to Emperor Joseph II (1776); retired 1791 but maintained post of personal imperial physician and ophthalmologist until his death.
# Achievements
Joseph Barth was to gain renown in ophthalmologic practice and to occupy the first Chair of Ophthalmology in Europe. His appointment to the post by the Empress Maria Theresa of Austria was made in consideration of his "special skill in eye diseases as well as his aptitude in finer anatomy". The professorship occupied by Barth remained the leader in ophthalmology with the subsequent professorship being instituted in Berlin only in 1866.
In Malta the professorship in ophthalmology was only established in 1880 being incumbent by Professor Lawrence Manche. Barth also opened a private nursing home and the first public eye clinic in the Vienna General Hospital in 1784, wherein he operated on cases of cataract. He apparently designed the original version of the "Beer's knife" that was subsequently modified and popularised by his student. His clinical renown led to his appointment as Imperial Oculist after he successfully treated Kaiser Joseph II of a stubborn "ophthalmitis".
Barth was very much a clinical teacher and was responsible for the training of several renowned physicians, notably Joseph Ehrenritter, Johann Adam Schmidt, Georg Joseph Beer, Georg Prochaska, Jacob Santerelli, G.B. Quadri, and Pietro Magistretti. He also established an Anatomical Museum that housed an assembly of 1576 specimens, some prepared by Barth himself. He also founded a medical library that contained 1500 volumes. Barth did not publish extensively preferring clinical teaching.
His publications included an anatomical work on myology Anfangsgrunde der Muskellehre (Vienna, 1786, 2nd ed. 1819) and an operative text on cataract removal Etwas uber die Ausziehung des graven Staars fur den genubten Operateur (Vienna, 1797, Salzburg, 1797). In 1827, Dr Stefano Zerafa described Joseph Barth as "a man of great merits, Maltese citizen, Chief Physician and Counsellor to Her Sacred Majesty, Professor of Sublime Anatomy and Physiology in the Academy of Vienna, undoubtedly the first among ophthalmologists." | Joseph Barth
Template:Infobox Scientist
Joseph Barth October 28, 1746, Valletta, Malta - April 7, 1818, Vienna, Austria, was a notable 18th century ophthalmologist.
# Education
Anatomical & Surgical School at Sacra Infermeria, Valletta (Malta), Santo Spirito Hospital in Rome (Italy), University of Vienna (Austria). Qualified 1772.
# Career
Appointed Public Teacher in Ophthalmology and Anatomy (1773), Professor of Ophthalmology and Anatomy (1774) and Oculist and Professor of Physiology (1786) at University of Vienna; nominated Royal Counsellor (1774) and appointed oculist to Emperor Joseph II (1776); retired 1791 but maintained post of personal imperial physician and ophthalmologist until his death.
# Achievements
Joseph Barth was to gain renown in ophthalmologic practice and to occupy the first Chair of Ophthalmology in Europe. His appointment to the post by the Empress Maria Theresa of Austria was made in consideration of his "special skill in eye diseases as well as his aptitude in finer anatomy". The professorship occupied by Barth remained the leader in ophthalmology with the subsequent professorship being instituted in Berlin only in 1866.
In Malta the professorship in ophthalmology was only established in 1880 being incumbent by Professor Lawrence Manche. Barth also opened a private nursing home and the first public eye clinic in the Vienna General Hospital in 1784, wherein he operated on cases of cataract. He apparently designed the original version of the "Beer's knife" that was subsequently modified and popularised by his student. His clinical renown led to his appointment as Imperial Oculist after he successfully treated Kaiser Joseph II of a stubborn "ophthalmitis".
Barth was very much a clinical teacher and was responsible for the training of several renowned physicians, notably Joseph Ehrenritter, Johann Adam Schmidt, Georg Joseph Beer, Georg Prochaska, Jacob Santerelli, G.B. Quadri, and Pietro Magistretti. He also established an Anatomical Museum that housed an assembly of 1576 specimens, some prepared by Barth himself. He also founded a medical library that contained 1500 volumes. Barth did not publish extensively preferring clinical teaching.
His publications included an anatomical work on myology Anfangsgrunde der Muskellehre (Vienna, 1786, 2nd ed. 1819) and an operative text on cataract removal Etwas uber die Ausziehung des graven Staars fur den genubten Operateur (Vienna, 1797, Salzburg, 1797). In 1827, Dr Stefano Zerafa described Joseph Barth as "a man of great merits, Maltese citizen, Chief Physician and Counsellor to Her Sacred Majesty, Professor of Sublime Anatomy and Physiology in the Academy of Vienna, undoubtedly the first among ophthalmologists."
# External links
- Barth's neurotree profile
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Joseph_Barth | |
f88b903beb799022fdc78af55bfece5e1cc53fc3 | wikidoc | Joseph Janse | Joseph Janse
Joseph Janse was born in Middelberg, Netherlands,
in 1909. He was the third child of Jan Pieter and Gertrude (De Voogd) Janse. Arriving in the US at age 6, he attended the Weber County, UT public schools, and he received two years of Pre-medical education at Weber State College by 1930. After three years in Europe as a missionary, he transferred to University of Utah to complete his pre-medical studies. He entered National College of Chiropractic in the spring of 1935 and received both the DC and ND degrees on June 17, 1938. On June 24, 1938 he married Gloria Julie Schade in Utah and they had three children.
# Biography
Upon graduation from National College, he immediately joined their faculty, and taught in the departments of Anatomy and Chiropractic, continuing through his tenure as President .
He was named one of four Deans, and then in December, 1944, he was elected to the College's Board of Trustees. And in their Minutes of that meeting , he was elected President of National College.
Dr. Janse was licensed to practice in eleven States, and qualified by the Canadian board as well. He was known as a "fire and brimstone" orator, and was much in demand throughout the profession.
- 1947 - He spearheaded the formation of the Council on Chiropractic Education – USA, and served as its Secretary from 1947-1959, and President from 1951-1961 and foreign liaison until 1982, the Board took the unprecedented step of naming him "President Emeritus".
- 1967 - He was honored to have been selected to deliver a paper called "The Scientific Basis of Chiropractic" before the U.S. Congressional Ad Hoc Committee on Chiropractic.
- 1971 - His contributions to the science of Chiropractic were so great , that the International College of Chiropractors elected him to the rank of "Dean" of the "Faculty" of the (Honorary) College; a post he held until his passing in 1985. | Joseph Janse
Template:Infobox Person
Joseph Janse was born in Middelberg, Netherlands,[1]
in 1909. He was the third child of Jan Pieter and Gertrude (De Voogd) Janse. [1] Arriving in the US at age 6, he attended the Weber County, UT public schools, and he received two years of Pre-medical education at Weber State College by 1930. After three years in Europe as a missionary, he transferred to University of Utah[1] to complete his pre-medical studies. He entered National College of Chiropractic in the spring of 1935 and received both the DC and ND degrees on June 17, 1938. On June 24, 1938 he married Gloria Julie Schade [1] in Utah and they had three children.
# Biography
Upon graduation from National College, he immediately joined their faculty, [1] and taught in the departments of Anatomy and Chiropractic, continuing through his tenure as President [1].
He was named one of four Deans, and then in December, 1944, [1] he was elected to the College's Board of Trustees. And in their Minutes of that meeting , he was elected President of National College. [2] [1]
Dr. Janse was licensed to practice in eleven States,[1] and qualified by the Canadian board as well. He was known as a "fire and brimstone" orator, and was much in demand throughout the profession. [1]
- 1947 - He spearheaded the formation of the Council on Chiropractic Education – USA, [3]and served as its Secretary from 1947-1959,[1] and President from 1951-1961 and foreign liaison until 1982, [1]the Board took the unprecedented step of naming him "President Emeritus".[1]
- 1967 - He was honored to have been selected to deliver a paper called "The Scientific Basis of Chiropractic" before the U.S. Congressional Ad Hoc Committee on Chiropractic.[1]
- 1971 - His contributions to the science of Chiropractic were so great [4], that the International College of Chiropractors elected him to the rank of "Dean" of the "Faculty" of the (Honorary) College; a post he held until his passing in 1985.[1] | https://www.wikidoc.org/index.php/Joseph_Janse | |
82a8efcdddbc228af4884b4221c3738f2e2f5f70 | wikidoc | Juan Mezzich | Juan Mezzich
# Background
Juan E. Mezzich, M.D., Ph. D. (b. 1945) is the president of the World Psychiatric Association (WPA).
He currently works as the Professor of Psychiatry and Director at the Division of Psychiatric Epidemiology and International Center for Mental Health at the Mount Sinai School of Medicine, New York University.
During his life he was awarded the Simon Bolivar Award of the American Psychiatric Association, Doctor Honoris Causal at Athens University (Greece), Cordoba University (Argentina), and University of Cluj-Napoca (Romania).
He also received a Honorary Professorship at Cayetano Heredia Peruvian and Belgrade (Serbia) Universities.
Mezzich is author/coauthor of over 200 scientific journal articles and book chapters and wrote more then 20 books and monographs and is the Editor/coeditor of Psychopathology , Basel , and Psiquiatría y Salud Integral, New York. He is also an editorial board member of 12 other psychiatric journals in the Americas and Europe.
# Biography
Mezzich was born in 1945, in Lima, Peru, of Yugoslavian and Peruvian ancestries.
He graduated at the Cayetano Heredia Peruvian University and was the president of the University Student Association.
He received psychiatric residency training at Ohio State University and was the diplomate of the American Board of Psychiatry and Neurology, and has a Ph. D. in Mathematical and Statistical Psychology at the Ohio State University.
From 1996 to 1999 he was the Secretary General of the WPA. Currently he is the president of the WPA.
# Currently researching
Currently Mezzich is researching on:
- New International Classification and Diagnostic Systems (ICD-11 and Comprehensive Diagnostic Model)
- Mental and General Health Comorbidity
- Culture-Informed Assessment of Mental Health (Multi-ethnic Bicultural Scale, Personal Health Scale, and Quality of Life Index)
- DSM-IV Cultural Formulation (educational developments and research evaluation of its impact on clinical care).
# Books written by Juan Mezzich
- Psychiatry and Sexual Health: An Integrative Approach (2006)
- Philosophical & Methodological Bases of Psychiatric Diagnosis
- Comprehensive Health & Integration of Services: New York & International Perspectives
- Guía Latinoamericana de Diagnóstico Psiquiátrico (GLADP) (APAL, 2004)
- Personality Disorders (2004)
- WPA International Guidelines for Diagnostic Assessment (IGDA) (2003)
- International Classification and Diagnosis: Critical Experience and Future Directions (2002)
- Cultural Psychiatry: International Perspectives (2001)
- The City and Mental Health (2000), Culture and Psychiatric Diagnosis: A DSM-IV Perspective (1996)
- Psychiatric Diagnosis: A World Perspective (1995)
- Psychiatric Epidemiology (1994)
- The 1986-1987 initial evaluation summary report (1988) | Juan Mezzich
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Juan E. Mezzich, M.D., Ph. D. (b. 1945) is the president of the World Psychiatric Association (WPA).
He currently works as the Professor of Psychiatry and Director at the Division of Psychiatric Epidemiology and International Center for Mental Health at the Mount Sinai School of Medicine, New York University.
During his life he was awarded the Simon Bolivar Award of the American Psychiatric Association, Doctor Honoris Causal at Athens University (Greece), Cordoba University (Argentina), and University of Cluj-Napoca (Romania).
He also received a Honorary Professorship at Cayetano Heredia Peruvian and Belgrade (Serbia) Universities.
Mezzich is author/coauthor of over 200 scientific journal articles and book chapters and wrote more then 20 books and monographs and is the Editor/coeditor of Psychopathology , Basel , and Psiquiatría y Salud Integral, New York. He is also an editorial board member of 12 other psychiatric journals in the Americas and Europe.
# Biography
Mezzich was born in 1945, in Lima, Peru, of Yugoslavian and Peruvian ancestries.
He graduated at the Cayetano Heredia Peruvian University and was the president of the University Student Association.
He received psychiatric residency training at Ohio State University and was the diplomate of the American Board of Psychiatry and Neurology, and has a Ph. D. in Mathematical and Statistical Psychology at the Ohio State University.
From 1996 to 1999 he was the Secretary General of the WPA. Currently he is the president of the WPA.
# Currently researching
Currently Mezzich is researching on:
- New International Classification and Diagnostic Systems (ICD-11 and Comprehensive Diagnostic Model)
- Mental and General Health Comorbidity
- Culture-Informed Assessment of Mental Health (Multi-ethnic Bicultural Scale, Personal Health Scale, and Quality of Life Index)
- DSM-IV Cultural Formulation (educational developments and research evaluation of its impact on clinical care).
# Books written by Juan Mezzich
- Psychiatry and Sexual Health: An Integrative Approach (2006)
- Philosophical & Methodological Bases of Psychiatric Diagnosis
- Comprehensive Health & Integration of Services: New York & International Perspectives
- Guía Latinoamericana de Diagnóstico Psiquiátrico (GLADP) (APAL, 2004)
- Personality Disorders (2004)
- WPA International Guidelines for Diagnostic Assessment (IGDA) (2003)
- International Classification and Diagnosis: Critical Experience and Future Directions (2002)
- Cultural Psychiatry: International Perspectives (2001)
- The City and Mental Health (2000), Culture and Psychiatric Diagnosis: A DSM-IV Perspective (1996)
- Psychiatric Diagnosis: A World Perspective (1995)
- Psychiatric Epidemiology (1994)
- The 1986-1987 initial evaluation summary report (1988)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Juan_Mezzich | |
a4ad6425a6cf306d4195a2fa0cec4585f37955df | wikidoc | Jugular vein | Jugular vein
The jugular veins are veins that bring deoxygenated blood from the head back to the heart via the superior vena cava.
# Internal and external
There are two sets of jugular veins: external and internal.
- The internal jugular vein is formed by the anastomosis of blood from the sigmoid sinus of the dura mater and the common facial vein. The internal jugular runs with the common carotid artery and vagus nerve inside the carotid sheath. It provides venous drainage for the contents of the skull.
- The external jugular runs superficially to sternocleidomastoid.
Both connect to the brachocephalic veins, the external jugular joining more laterally than the internal. The brachicephalic veins then join the subclavian veins from both sides then join to form the superior vena cava.
There is also another, minor, jugular vein, the anterior jugular vein, draining the the submaxillary region.
# Cultural references
- The jugular vein is the major point of damage when performing Jigai, a traditional way for Japanese women to commit suicide. This method was most commonly used because of its quick, painless, and certain outcome.
- In popular culture, the jugular is stereotypically what dogs and other animals are thought to go after with the intent of killing another animal, generally because of the awareness that it will incapacitate the opponent with little effort. In reality the injury that does this is to the carotid artery, as the flow from venial bleeding is easily stopped.
- It is also the Islamic method of slaughtering animals. Muslims traditionally pronounce "God is Great" before pulling a sharpened blade from a concealed place, and then slicing through both veins in the neck, as this numbs creatures and brings about instant death. The resulting Halal meat is made from the animal to consume after all the blood is drained from the openings.
# Additional images
- Human embryo of about fourteen days, with yolk-sac.
- Human embryo with heart and anterior body-wall removed to show the sinus venosus and its tributaries. | Jugular vein
Template:Infobox Vein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The jugular veins are veins that bring deoxygenated blood from the head back to the heart via the superior vena cava.
# Internal and external
There are two sets of jugular veins: external and internal.
- The internal jugular vein is formed by the anastomosis of blood from the sigmoid sinus of the dura mater and the common facial vein. The internal jugular runs with the common carotid artery and vagus nerve inside the carotid sheath. It provides venous drainage for the contents of the skull.
- The external jugular runs superficially to sternocleidomastoid.
Both connect to the brachocephalic veins, the external jugular joining more laterally than the internal. The brachicephalic veins then join the subclavian veins from both sides then join to form the superior vena cava.[1]
There is also another, minor, jugular vein, the anterior jugular vein, draining the the submaxillary region.
# Cultural references
- The jugular vein is the major point of damage when performing Jigai, a traditional way for Japanese women to commit suicide. This method was most commonly used because of its quick, painless, and certain outcome.
- In popular culture, the jugular is stereotypically what dogs and other animals are thought to go after with the intent of killing another animal, generally because of the awareness that it will incapacitate the opponent with little effort. In reality the injury that does this is to the carotid artery, as the flow from venial bleeding is easily stopped.
- It is also the Islamic method of slaughtering animals. Muslims traditionally pronounce "God is Great" before pulling a sharpened blade from a concealed place, and then slicing through both veins in the neck, as this numbs creatures and brings about instant death. The resulting Halal meat is made from the animal to consume after all the blood is drained from the openings.
# Additional images
- Human embryo of about fourteen days, with yolk-sac.
- Human embryo with heart and anterior body-wall removed to show the sinus venosus and its tributaries. | https://www.wikidoc.org/index.php/Jugular | |
466e072ab4e90ed51ede23a236160dadb16eba54 | wikidoc | Karl Jaspers | Karl Jaspers
# Overview
Karl Theodor Jaspers (February 23, 1883 – February 26, 1969) was a German psychiatrist and philosopher who had a strong influence on modern theology, psychiatry and philosophy.
# Biography
Jaspers was born in Oldenburg in 1883 to a mother from a local farming community, and a jurist father. He showed an early interest in philosophy, but his father's experience with the legal system undoubtedly influenced his decision to study law at university. It soon became clear that Jaspers did not particularly enjoy law, and he switched to studying medicine in 1902.
Jaspers graduated from medical school in 1909 and began work at a psychiatric hospital in Heidelberg where Emil Kraepelin had worked some years earlier. Jaspers became dissatisfied with the way the medical community of the time approached the study of mental illness and set himself the task of improving the psychiatric approach. In 1913 Jaspers gained a temporary post as a psychology teacher at Heidelberg University. The post later became permanent, and Jaspers never returned to clinical practice.
At the age of 40 Jaspers turned from psychology to philosophy, expanding on themes he had developed in his psychiatric works. He became a renowned philosopher, well respected in Germany and Europe. In 1948 Jaspers moved to the University of Basel in Switzerland. He remained prominent in the philosophical community until his death in Basel in 1969.
# Contributions to Psychiatry
Jaspers' dissatisfaction with the popular understanding of mental illness led him to question both the diagnostic criteria and the methods of clinical psychiatry. He published a revolutionary paper in 1910 in which he addressed the problem of whether paranoia was an aspect of personality or the result of biological changes. Whilst not broaching new ideas, this article introduced a new method of study. Jaspers studied several patients in detail, giving biographical information on the people concerned as well as providing notes on how the patients themselves felt about their symptoms. This has become known as the biographical method and now forms the mainstay of modern psychiatric practice.
Jaspers set about writing his views on mental illness in a book which he published as General Psychopathology. The two volumes which make up this work have become a classic in the psychiatric literature and many modern diagnostic criteria stem from ideas contained within them. Of particular importance, Jaspers believed that psychiatrists should diagnose symptoms (particularly of psychosis) by their form rather than by their content. For example, in diagnosing an hallucination, the fact that a person experiences visual phenomena when no sensory stimuli account for it (form) assumes more importance than what the patient sees (content).
Jaspers felt that psychiatry could also diagnose delusions in the same way. He argued that clinicians should not consider a belief delusional based on the content of the belief, but only based on the way in which a patient holds such a belief (see delusion for further discussion). Jaspers also distinguished between primary and secondary delusions. He defined primary delusions as
autochthonous meaning arising without apparent cause, appearing incomprehensible in terms of normal mental processes. (This is a distinctly different use of the term autochthonous than its usual medical or sociological meaning of indigenous.) Secondary delusions, on the other hand, he classified as influenced by the person's background, current situation or mental state.
Jaspers considered primary delusions as ultimately 'un-understandable,' as he believed no coherent reasoning process existed behind their formation. This view has caused some controversy, and the likes of R. D. Laing and Richard Bentall have criticised it, stressing that taking this stance can lead therapists into the complacency of assuming that because they do not understand a patient, the patient is deluded and further investigation on the part of the therapist will have no effect.
# Contributions to Philosophy and Theology
Most commentators associate Jaspers with the philosophy of existentialism, in part because he draws largely upon the existentialist roots of Nietzsche and Kierkegaard, and in part because the theme of individual freedom permeates his work.
In Philosophy (3 vols, 1932), Jaspers gave his view of the history of philosophy and introduced his major themes. Beginning with modern science and empiricism, Jaspers points out that as we question reality, we confront borders that an empirical (or scientific) method can simply not transcend. At this point, the individual faces a choice: sink into despair and resignation, or take a leap of faith toward what Jaspers calls Transcendence. In making this leap, individuals confront their own limitless freedom, which Jaspers calls Existenz, and can finally experience authentic existence.
Transcendence (paired with the term The Encompassing in later works) is, for Jaspers, that which exists beyond the world of time and space. Jaspers' formulation of Transcendence as ultimate non-objectivity (or no-thing-ness) has led many philosophers to argue that ultimately, Jaspers became a monist, though Jaspers himself continually stressed the necessity of recognizing the validity of the concepts both of subjectivity and of objectivity.
Although he rejected explicit religious doctrines, including the notion of a personal God, Jaspers influenced contemporary theology through his philosophy of transcendence and the limits of human experience. Mystic Christian traditions influenced Jaspers himself tremendously, particularly those of Meister Eckhart and of Nicholas of Cusa. He also took an active interest in Eastern philosophies, particularly Buddhism, and developed the theory of an Axial Age, a period of substantial philosophical and religious development. Jaspers also entered public debates with Rudolf Bultmann, wherein Jaspers roundly criticized Bultmann's "demythologizing" of Christianity.
Jaspers also wrote extensively on the threat to human freedom posed by modern science and modern economic and political institutions. During World War II, he had to abandon his teaching post because his wife was Jewish. After the war he resumed his teaching position, and in his work The Question of German Guilt he unabashedly examined the culpability of Germany as a whole in the atrocities of Hitler's Third Reich.
Jaspers' major works, lengthy and detailed, can seem daunting in their complexity. His last great attempt at a systematic philosophy of Existenz — Von Der Wahrheit (On Truth) — has not yet appeared in English. However, he also wrote accessible and entertaining shorter works, most notably Philosophy is for Everyman.
Commentators often compare Jaspers' philosophy to that of his contemporary, Martin Heidegger. Indeed, both sought to explore the meaning of being (Sein) and existence (Dasein). While the two did maintain a brief friendship, their relationship deteriorated - due in part to Heidegger's affiliation with the Nazi party, but also due to the (probably over-emphasized) philosophical differences between the two.
The two major proponents of phenomenological hermeneutics, Paul Ricoeur (a student of Jaspers) and Hans-Georg Gadamer (Jaspers' successor at Heidelberg) both display Jaspers' influence in their works.
Other important work appeared in Philosophy and Existence (1938). For Jaspers, the term "existence" (Existenz) designates the indefinable experience of freedom and possibility; an experience which constitutes the authentic being of individuals who become aware of "the encompassing" by confronting suffering, conflict, guilt, chance, and death.
# Jaspers in relation to Kierkegaard and Nietzsche
Jaspers held Kierkegaard and Nietzsche to be two of the most important figures in post-Kantian philosophy. In his compilation, The Great Philosophers, he wrote:
I approach the presentation of Kierkegaard with some trepidation. Next to Nietzsche, or rather, prior to Nietzsche, I consider him to be the most important thinker of our post-Kantian age. With Goethe and Hegel, an epoch had reached its conclusion, and our prevalent way of thinking - that is, the positivistic, natural-scientific one - cannot really be considered as philosophy.
Jaspers also questions whether the two philosophers could be taught. For Kierkegaard, at least, Jaspers felt that Kierkegaard's whole method of indirect communication precludes any attempts to properly expound his thought into any sort of systematic teaching.
# Books
- Philosophy of Existence - ISBN 0-8122-1010-7
- Reason and Existenz - ISBN 0-87462-611-0
- Way to Wisdom - ISBN 0-300-00134-7
### Translations
- Jaspers, Karl (1953). The Origin and Goal of History. translated by Michael Bullock. New Haven, CT: Yale University Press..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}
- Jaspers, Karl (1955). Reason and Existenz. translated by William Earle. New York: Noonday Press.
ar:كارل ياسبرز
bs:Karl Jaspers
bg:Карл Ясперс
ca:Karl Jaspers
cs:Karl Jaspers
da:Karl Jaspers
de:Karl Jaspers
et:Karl Jaspers
eo:Karl Jaspers
fa:کارل یاسپرس
ko:카를 야스퍼스
hr:Karl Jaspers
io:Karl Jaspers
is:Karl Jaspers
it:Karl Jaspers
he:קרל יאספרס
la:Carolus Theodorus Jaspers
lt:Karl Jaspers
hu:Karl Jaspers
nl:Karl Jaspers
no:Karl Jaspers
-c:Karl Jaspers
sk:Karl Jaspers
sr:Karl Jaspers
fi:Karl Jaspers
sv:Karl Jaspers
uk:Ясперс Карл | Karl Jaspers
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Karl Theodor Jaspers (February 23, 1883 – February 26, 1969) was a German psychiatrist and philosopher who had a strong influence on modern theology, psychiatry and philosophy.
# Biography
Jaspers was born in Oldenburg in 1883 to a mother from a local farming community, and a jurist father. He showed an early interest in philosophy, but his father's experience with the legal system undoubtedly influenced his decision to study law at university. It soon became clear that Jaspers did not particularly enjoy law, and he switched to studying medicine in 1902.
Jaspers graduated from medical school in 1909 and began work at a psychiatric hospital in Heidelberg where Emil Kraepelin had worked some years earlier. Jaspers became dissatisfied with the way the medical community of the time approached the study of mental illness and set himself the task of improving the psychiatric approach. In 1913 Jaspers gained a temporary post as a psychology teacher at Heidelberg University. The post later became permanent, and Jaspers never returned to clinical practice.
At the age of 40 Jaspers turned from psychology to philosophy, expanding on themes he had developed in his psychiatric works. He became a renowned philosopher, well respected in Germany and Europe. In 1948 Jaspers moved to the University of Basel in Switzerland. He remained prominent in the philosophical community until his death in Basel in 1969.
# Contributions to Psychiatry
Jaspers' dissatisfaction with the popular understanding of mental illness led him to question both the diagnostic criteria and the methods of clinical psychiatry. He published a revolutionary paper in 1910 in which he addressed the problem of whether paranoia was an aspect of personality or the result of biological changes. Whilst not broaching new ideas, this article introduced a new method of study. Jaspers studied several patients in detail, giving biographical information on the people concerned as well as providing notes on how the patients themselves felt about their symptoms. This has become known as the biographical method and now forms the mainstay of modern psychiatric practice.
Jaspers set about writing his views on mental illness in a book which he published as General Psychopathology. The two volumes which make up this work have become a classic in the psychiatric literature and many modern diagnostic criteria stem from ideas contained within them. Of particular importance, Jaspers believed that psychiatrists should diagnose symptoms (particularly of psychosis) by their form rather than by their content. For example, in diagnosing an hallucination, the fact that a person experiences visual phenomena when no sensory stimuli account for it (form) assumes more importance than what the patient sees (content).
Jaspers felt that psychiatry could also diagnose delusions in the same way. He argued that clinicians should not consider a belief delusional based on the content of the belief, but only based on the way in which a patient holds such a belief (see delusion for further discussion). Jaspers also distinguished between primary and secondary delusions. He defined primary delusions as
autochthonous meaning arising without apparent cause, appearing incomprehensible in terms of normal mental processes. (This is a distinctly different use of the term autochthonous than its usual medical or sociological meaning of indigenous.) Secondary delusions, on the other hand, he classified as influenced by the person's background, current situation or mental state.
Jaspers considered primary delusions as ultimately 'un-understandable,' as he believed no coherent reasoning process existed behind their formation. This view has caused some controversy, and the likes of R. D. Laing and Richard Bentall have criticised it, stressing that taking this stance can lead therapists into the complacency of assuming that because they do not understand a patient, the patient is deluded and further investigation on the part of the therapist will have no effect.
# Contributions to Philosophy and Theology
Most commentators associate Jaspers with the philosophy of existentialism, in part because he draws largely upon the existentialist roots of Nietzsche and Kierkegaard, and in part because the theme of individual freedom permeates his work.[citation needed]
In Philosophy (3 vols, 1932), Jaspers gave his view of the history of philosophy and introduced his major themes. Beginning with modern science and empiricism, Jaspers points out that as we question reality, we confront borders that an empirical (or scientific) method can simply not transcend. At this point, the individual faces a choice: sink into despair and resignation, or take a leap of faith toward what Jaspers calls Transcendence. In making this leap, individuals confront their own limitless freedom, which Jaspers calls Existenz, and can finally experience authentic existence.
Transcendence (paired with the term The Encompassing in later works) is, for Jaspers, that which exists beyond the world of time and space. Jaspers' formulation of Transcendence as ultimate non-objectivity (or no-thing-ness) has led many philosophers to argue that ultimately, Jaspers became a monist, though Jaspers himself continually stressed the necessity of recognizing the validity of the concepts both of subjectivity and of objectivity.
Although he rejected explicit religious doctrines, including the notion of a personal God, Jaspers influenced contemporary theology through his philosophy of transcendence and the limits of human experience. Mystic Christian traditions influenced Jaspers himself tremendously, particularly those of Meister Eckhart and of Nicholas of Cusa. He also took an active interest in Eastern philosophies, particularly Buddhism, and developed the theory of an Axial Age, a period of substantial philosophical and religious development. Jaspers also entered public debates with Rudolf Bultmann, wherein Jaspers roundly criticized Bultmann's "demythologizing" of Christianity.
Jaspers also wrote extensively on the threat to human freedom posed by modern science and modern economic and political institutions. During World War II, he had to abandon his teaching post because his wife was Jewish. After the war he resumed his teaching position, and in his work The Question of German Guilt he unabashedly examined the culpability of Germany as a whole in the atrocities of Hitler's Third Reich.
Jaspers' major works, lengthy and detailed, can seem daunting in their complexity. His last great attempt at a systematic philosophy of Existenz — Von Der Wahrheit (On Truth) — has not yet appeared in English. However, he also wrote accessible and entertaining shorter works, most notably Philosophy is for Everyman.
Commentators often compare Jaspers' philosophy to that of his contemporary, Martin Heidegger. Indeed, both sought to explore the meaning of being (Sein) and existence (Dasein). While the two did maintain a brief friendship, their relationship deteriorated - due in part to Heidegger's affiliation with the Nazi party, but also due to the (probably over-emphasized) philosophical differences between the two.
The two major proponents of phenomenological hermeneutics, Paul Ricoeur (a student of Jaspers) and Hans-Georg Gadamer (Jaspers' successor at Heidelberg) both display Jaspers' influence in their works.
Other important work appeared in Philosophy and Existence (1938). For Jaspers, the term "existence" (Existenz) designates the indefinable experience of freedom and possibility; an experience which constitutes the authentic being of individuals who become aware of "the encompassing" by confronting suffering, conflict, guilt, chance, and death.
# Jaspers in relation to Kierkegaard and Nietzsche
Jaspers held Kierkegaard and Nietzsche to be two of the most important figures in post-Kantian philosophy. In his compilation, The Great Philosophers, he wrote:
I approach the presentation of Kierkegaard with some trepidation. Next to Nietzsche, or rather, prior to Nietzsche, I consider him to be the most important thinker of our post-Kantian age. With Goethe and Hegel, an epoch had reached its conclusion, and our prevalent way of thinking - that is, the positivistic, natural-scientific one - cannot really be considered as philosophy.
Jaspers also questions whether the two philosophers could be taught. For Kierkegaard, at least, Jaspers felt that Kierkegaard's whole method of indirect communication precludes any attempts to properly expound his thought into any sort of systematic teaching.
# Books
- Philosophy of Existence - ISBN 0-8122-1010-7
- Reason and Existenz - ISBN 0-87462-611-0
- Way to Wisdom - ISBN 0-300-00134-7
### Translations
- Jaspers, Karl (1953). The Origin and Goal of History. translated by Michael Bullock. New Haven, CT: Yale University Press..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}
- Jaspers, Karl (1955). Reason and Existenz. translated by William Earle. New York: Noonday Press.
Template:Link FA
ar:كارل ياسبرز
bs:Karl Jaspers
bg:Карл Ясперс
ca:Karl Jaspers
cs:Karl Jaspers
da:Karl Jaspers
de:Karl Jaspers
et:Karl Jaspers
eo:Karl Jaspers
fa:کارل یاسپرس
ko:카를 야스퍼스
hr:Karl Jaspers
io:Karl Jaspers
is:Karl Jaspers
it:Karl Jaspers
he:קרל יאספרס
la:Carolus Theodorus Jaspers
lt:Karl Jaspers
hu:Karl Jaspers
nl:Karl Jaspers
no:Karl Jaspers
oc:Karl Jaspers
sk:Karl Jaspers
sr:Karl Jaspers
fi:Karl Jaspers
sv:Karl Jaspers
uk:Ясперс Карл
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Karl_Jaspers | |
9f615dcf8c71939a218c822994cda20486dd42d9 | wikidoc | Kdd Ontology | Kdd Ontology
As data mining applications became more popular, organizations providing KDD (Knowledge Discovery in Database) services have accumulated a growing number of stored documents and processes of their past projects. Moreover, developing KDD projects usually demands several tools, programming languages and methodologies, as well several descriptions of data generated during the development of such projects. In fact, one the major practical problems regarding KDD is how to provide interoperability among different platforms.
Another important practical problem with KDD is the lack of platforms capable of supporting the reuse of knowledge acquired from past projects.
This work proposes an ontology to the KDD projects and at using these metadata for knowledge reuse and evaluating new data mining projects (meta-data mining).
# Example
In Construction... | Kdd Ontology
As data mining applications became more popular, organizations providing KDD (Knowledge Discovery in Database) services have accumulated a growing number of stored documents and processes of their past projects. Moreover, developing KDD projects usually demands several tools, programming languages and methodologies, as well several descriptions of data generated during the development of such projects. In fact, one the major practical problems regarding KDD is how to provide interoperability among different platforms.
Another important practical problem with KDD is the lack of platforms capable of supporting the reuse of knowledge acquired from past projects.
This work proposes an ontology to the KDD projects and at using these metadata for knowledge reuse and evaluating new data mining projects (meta-data mining).
# Example
In Construction... | https://www.wikidoc.org/index.php/Kdd_Ontology | |
93b49167e54d01e39d366da308a4d9ba08f9852e | wikidoc | Kendra's Law | Kendra's Law
Kendra's Law is a New York State law concerning involuntary outpatient commitment. This piece of legislation grants judges the authority to issue orders that require people receiving mental health services to take psychiatric drugs, regularly undergo psychiatric treatment, or both. Failure to comply could result in commitment for up to 72 hours.
# Background
Two similar subway assaults occurred in the New York City subway in 1999. In each, a man diagnosed with schizophrenia pushed a person into the path of an oncoming train. An assault by Julio Perez, age 43, caused the amputation of Edgar Rivera's legs. The assault by Andrew Goldstein, age 29, killed Kendra Webdale. Both men had been dismissed by psychiatric facilities with little or no medication. One of the men was homeless and the other had repeatedly sought a supervised living arrangement.
Kendra's law, introduced by Governor George E. Pataki, was created as a response to these incidents. In 2005, the law was extended for 5 years.
# Support
E. Fuller Torrey, founder of the Treatment Advocacy Center, lobbied heavily in support of of Kendra's Law.
# Opposition
Kendra's law is opposed for different reasons by many groups, most notably the Anti-Psychiatry movement and the New York Civil Liberties Union. Opponents say that the law has harmed the mental health system, because it can scare patients away from seeking treatment. The implementation of the law is also criticized as being racially and socioeconomically biased. | Kendra's Law
Kendra's Law is a New York State law concerning involuntary outpatient commitment. This piece of legislation grants judges the authority to issue orders that require people receiving mental health services to take psychiatric drugs, regularly undergo psychiatric treatment, or both. Failure to comply could result in commitment for up to 72 hours.
# Background
Two similar subway assaults occurred in the New York City subway in 1999. In each, a man diagnosed with schizophrenia pushed a person into the path of an oncoming train. An assault by Julio Perez, age 43, caused the amputation of Edgar Rivera's legs. The assault by Andrew Goldstein, age 29, killed Kendra Webdale. Both men had been dismissed by psychiatric facilities with little or no medication. One of the men was homeless and the other had repeatedly sought a supervised living arrangement.
Kendra's law, introduced by Governor George E. Pataki, was created as a response to these incidents.[1] In 2005, the law was extended for 5 years. [2]
# Support
E. Fuller Torrey, founder of the Treatment Advocacy Center, lobbied heavily in support of of Kendra's Law.
# Opposition
Kendra's law is opposed for different reasons by many groups, most notably the Anti-Psychiatry movement and the New York Civil Liberties Union. Opponents say that the law has harmed the mental health system, because it can scare patients away from seeking treatment.[3] The implementation of the law is also criticized as being racially and socioeconomically biased.[4][5] | https://www.wikidoc.org/index.php/Kendra%27s_Law | |
1789374e428c5b37dda557a247b4f394af9adf5a | wikidoc | Kennel cough | Kennel cough
Kennel cough or tracheobronchitis is a highly contagious canine illness characterized by inflammation of the upper respiratory system. It can be caused by viral infections such as canine distemper, canine adenovirus, canine parainfluenza virus, or canine respiratory coronavirus, or bacterial infections such as Bordetella bronchiseptica. It is so named because the infection can spread quickly among dogs, such as in the close quarters of a kennel.
# Infection
Both viral and bacterial causes of kennel cough are spread through the air by infected dogs sneezing and coughing. It can also spread through contact with contaminated surfaces and through direct contact. It is highly contagious, even days or weeks after symptoms disappear. Exposure occurs in environments where there are other dogs in proximity, such as pet stores, kennels, dog shows, and groomers. Symptoms begin usually 3 to 5 days after exposure. The disease can progress to pneumonia.
# Symptoms
Symptoms can include a harsh, dry hacking/coughing, retching, sneezing, snorting or gagging;in response to light pressing of the trachea or after excitement or exercise. The presence of a fever varies from case to case. The disease can last from 10-20 days. Diagnosis is made by seeing these symptoms and having a history of exposure.
# Treatment and prevention
Antibiotics are given to treat any bacterial infection present. Cough suppressants are used if the cough is not productive (nothing is being coughed up). The prognosis is good. Prevention is by vaccinating for canine adenovirus, distemper, parainfluenza, and Bordetella. In kennels, the best prevention is to keep all the cages disinfected. Most kennels will not board dogs without proof of vaccination. | Kennel cough
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Kennel cough or tracheobronchitis is a highly contagious canine illness characterized by inflammation of the upper respiratory system. It can be caused by viral infections such as canine distemper, canine adenovirus, canine parainfluenza virus, or canine respiratory coronavirus, or bacterial infections such as Bordetella bronchiseptica.[1] It is so named because the infection can spread quickly among dogs, such as in the close quarters of a kennel.
# Infection
Both viral and bacterial causes of kennel cough are spread through the air by infected dogs sneezing and coughing. It can also spread through contact with contaminated surfaces and through direct contact. It is highly contagious, even days or weeks after symptoms disappear. Exposure occurs in environments where there are other dogs in proximity, such as pet stores, kennels, dog shows, and groomers. Symptoms begin usually 3 to 5 days after exposure.[1] The disease can progress to pneumonia.
# Symptoms
Symptoms can include a harsh, dry hacking/coughing, retching, sneezing, snorting or gagging;in response to light pressing of the trachea or after excitement or exercise. The presence of a fever varies from case to case. The disease can last from 10-20 days. Diagnosis is made by seeing these symptoms and having a history of exposure.
# Treatment and prevention
Antibiotics are given to treat any bacterial infection present. Cough suppressants are used if the cough is not productive (nothing is being coughed up). The prognosis is good. Prevention is by vaccinating for canine adenovirus, distemper, parainfluenza, and Bordetella. In kennels, the best prevention is to keep all the cages disinfected. Most kennels will not board dogs without proof of vaccination. | https://www.wikidoc.org/index.php/Kennel_cough | |
055527ec6215f280947850ff4dd0ffadb48d2972 | wikidoc | Keratinocyte | Keratinocyte
The keratinocyte is the major cell type of the epidermis, making up about 90% of epidermal cells. The epidermis is divided into four or five layers (depending on the type of skin) based on keratinocyte morphology:
- stratum basale (at the junction with the dermis)
- stratum spinosum
- stratum granulosum
- stratum lucidum (only present in thick skin - i.e. palms of hand and soles of feet)
- stratum corneum
Keratinocytes originate in the basal layer from the division of keratinocyte stem cells. They are pushed up through the layers of the epidermis, undergoing gradual differentiation until they reach the stratum corneum where they form a layer of enucleated, flattened, highly keratinized cells called squamous cells. This layer forms an effective barrier to the entry of foreign matter and infectious agents into the body and minimises moisture loss.
Keratinocytes are shed and replaced continuously from the stratum corneum. The time of transit from basal layer to shedding is approximately one month. Although that approximate time frame can be accelerated in conditions of keratinocyte hyperproliferation, such as psoriasis.
# See Also
- Amphiregulin
de:Keratinozyt
lt:Keratinocitas | Keratinocyte
The keratinocyte is the major cell type of the epidermis, making up about 90% of epidermal cells. The epidermis is divided into four or five layers (depending on the type of skin) based on keratinocyte morphology:
- stratum basale (at the junction with the dermis)
- stratum spinosum
- stratum granulosum
- stratum lucidum (only present in thick skin - i.e. palms of hand and soles of feet)
- stratum corneum
Keratinocytes originate in the basal layer from the division of keratinocyte stem cells. They are pushed up through the layers of the epidermis, undergoing gradual differentiation until they reach the stratum corneum where they form a layer of enucleated, flattened, highly keratinized cells called squamous cells. This layer forms an effective barrier to the entry of foreign matter and infectious agents into the body and minimises moisture loss.
Keratinocytes are shed and replaced continuously from the stratum corneum. The time of transit from basal layer to shedding is approximately one month. Although that approximate time frame can be accelerated in conditions of keratinocyte hyperproliferation, such as psoriasis.
# See Also
- Amphiregulin
de:Keratinozyt
lt:Keratinocitas
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Keratinocyte | |
a6b3f1924abb65a7a57eada00b5b61cc3965c333 | wikidoc | Keratoglobus | Keratoglobus
Keratoglobus (from Greek: kerato- horn, cornea; and globus round), is a degenerative non-inflammatory disorder of the eye in which structural changes within the cornea cause it to become extremely thin and change to a more globular shape than its normal gradual curve. It causes corneal thinning, primarily at the margins, resulting in a spherical, slightly enlarged eye.
# Epidemiology
It is a much rarer condition than keratoconus, which is the most common dystrophy of the cornea. Similar to keratoconus it is typically diagnosed in the patient's adolescent years and attains its most severe state in the twenties and thirties.
# Pathophysiology
Keratoglobus is a little-understood disease with an uncertain cause, and its progression following diagnosis is unpredictable. If afflicting both eyes, the deterioration in vision can affect the patient's ability to drive a car or read normal print. It does not however lead to blindness per se.
# Prognosis
Keratoglobus continues to be a somewhat mysterious disease, but it can be successfully managed with a variety of clinical and surgical techniques. The patient is at risk for globe perforation because the thinned out cornea is extremely weak.
# Surgical treatment
Further progression of the disease usually leads to a need for surgery because of extreme thinning of the cornea. Primarily, large size penetrating keratoplasty has been advocated. Recent additions of techniques specifically for keratoglobus include the "tuck procedure", whereby a 12 mm corneo-scleral donor graft is taken and trimmed at its outer edges. A host pocket is formed at the limbal margin and the donor tissue is "tucked" into the host pocket. | Keratoglobus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Keratoglobus (from Greek: kerato- horn, cornea; and globus round), is a degenerative non-inflammatory disorder of the eye in which structural changes within the cornea cause it to become extremely thin and change to a more globular shape than its normal gradual curve. It causes corneal thinning, primarily at the margins, resulting in a spherical, slightly enlarged eye.
# Epidemiology
It is a much rarer condition than keratoconus, which is the most common dystrophy of the cornea.[2] Similar to keratoconus it is typically diagnosed in the patient's adolescent years and attains its most severe state in the twenties and thirties.
# Pathophysiology
Keratoglobus is a little-understood disease with an uncertain cause, and its progression following diagnosis is unpredictable. If afflicting both eyes, the deterioration in vision can affect the patient's ability to drive a car or read normal print. It does not however lead to blindness per se.
# Prognosis
Keratoglobus continues to be a somewhat mysterious disease, but it can be successfully managed with a variety of clinical and surgical techniques. The patient is at risk for globe perforation because the thinned out cornea is extremely weak.
# Surgical treatment
Further progression of the disease usually leads to a need for surgery because of extreme thinning of the cornea. Primarily, large size penetrating keratoplasty has been advocated. Recent additions of techniques specifically for keratoglobus include the "tuck procedure", whereby a 12 mm corneo-scleral donor graft is taken and trimmed at its outer edges. A host pocket is formed at the limbal margin and the donor tissue is "tucked" into the host pocket. | https://www.wikidoc.org/index.php/Keratoglobus | |
e97a775cebc4b4d5af2742fcea261cad0388a9c9 | wikidoc | Kerley lines | Kerley lines
# Overview
Kerley lines are a sign seen on chest x-rays with interstitial pulmonary edema. They are thin linear pulmonary opacities caused by fluid or cellular infiltration into the interstitium of the lungs. They are suggestive for the diagnosis of congestive heart failure, but are also seen in various non-cardiac conditions such as pulmonary fibrosis, interstitial deposition of heavy metal particles or carcinomatosis of the lung. Chronic Kerley B lines may be caused by fibrosis or hemosiderin deposition caused by recurrent pulmonary oedema.
# Kerley A lines
Kerley A lines are longer (at least 2 cm) unbranching lines coursing diagonally from the periphery toward the hila in the inner half of the lungs. They are caused by distension of anastomotic channels between peripheral and central lymphatics of the lungs. Kerley A lines are less commonly seen than Kerley B lines. Kerley A lines are never seen without Kerley B or C lines also present.
# Kerley B lines
Kerley B lines are short parallel lines at the lung periphery. These lines represent distended interlobular septa, which are usually less than 1 cm in length and parallel to one another at right angles to the pleura. They are located peripherally in contact with the pleura, but are generally absent along fissural surfaces. They may be seen in any zone but are most frequently observed at the lung bases at the costophrenic angles on the PA radiograph, and in the substernal region on lateral radiographs.
# Kerley C lines
Kerley C lines are the least commonly seen of the Kerley lines. They are short, fine "spider web" polygonal opacities distributed primarily in a peripheral and subpleural location. They may represent thickening of anastomotic lymphatics or superimposition of many Kerley B lines. Keyley C lines may be associated with conditions such as pulmonary fibrosis and hypersensitivity pneumonitis.
# Diagnostic Findings
- Plain film: Mitral stenosis, Kerley B lines
- Plain film: Mitral stenosis, Kerley B lines
- Plain film: Mitral stenosis, Kerley B lines
- Acute heart failure due to atrial fibrillation with Kerley B lines. (Image courtesy of Radiopaedia.org)
- Pulmonary edema with Kerley B lines. (Image courtesy of Radiopaedia.org)
- Heart failure with Kerley B lines. (Image courtesy of Radiopaedia.org)
- Pulmonary congestion in heart failure with Kerley B lines. (Image courtesy of Radiopaedia.org) | Kerley lines
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Kerley lines are a sign seen on chest x-rays with interstitial pulmonary edema. They are thin linear pulmonary opacities caused by fluid or cellular infiltration into the interstitium of the lungs. They are suggestive for the diagnosis of congestive heart failure, but are also seen in various non-cardiac conditions such as pulmonary fibrosis, interstitial deposition of heavy metal particles or carcinomatosis of the lung. Chronic Kerley B lines may be caused by fibrosis or hemosiderin deposition caused by recurrent pulmonary oedema.
# Kerley A lines
Kerley A lines are longer (at least 2 cm) unbranching lines coursing diagonally from the periphery toward the hila in the inner half of the lungs. They are caused by distension of anastomotic channels between peripheral and central lymphatics of the lungs. Kerley A lines are less commonly seen than Kerley B lines. Kerley A lines are never seen without Kerley B or C lines also present.
# Kerley B lines
Kerley B lines are short parallel lines at the lung periphery. These lines represent distended interlobular septa, which are usually less than 1 cm in length and parallel to one another at right angles to the pleura. They are located peripherally in contact with the pleura, but are generally absent along fissural surfaces. They may be seen in any zone but are most frequently observed at the lung bases at the costophrenic angles on the PA radiograph, and in the substernal region on lateral radiographs.
# Kerley C lines
Kerley C lines are the least commonly seen of the Kerley lines. They are short, fine "spider web" polygonal opacities distributed primarily in a peripheral and subpleural location. They may represent thickening of anastomotic lymphatics or superimposition of many Kerley B lines. Keyley C lines may be associated with conditions such as pulmonary fibrosis and hypersensitivity pneumonitis.
# Diagnostic Findings
- Plain film: Mitral stenosis, Kerley B lines
- Plain film: Mitral stenosis, Kerley B lines
- Plain film: Mitral stenosis, Kerley B lines
- Acute heart failure due to atrial fibrillation with Kerley B lines. (Image courtesy of Radiopaedia.org)
- Pulmonary edema with Kerley B lines. (Image courtesy of Radiopaedia.org)
- Heart failure with Kerley B lines. (Image courtesy of Radiopaedia.org)
- Pulmonary congestion in heart failure with Kerley B lines. (Image courtesy of Radiopaedia.org) | https://www.wikidoc.org/index.php/Kerley_B_lines | |
2752ea08c360dac3ce13e010c2e59ba606a4f71c | wikidoc | Kernel trick | Kernel trick
In machine learning, the kernel trick is a method for using a linear classifier algorithm to solve a non-linear problem by mapping the original non-linear observations into a higher-dimensional space, where the linear classifier is subsequently used; this makes a linear classification in the new space equivalent to non-linear classification in the original space.
This is done using Mercer's theorem, which states that any continuous, symmetric, positive semi-definite kernel function K(x, y) can be expressed as a dot product in a high-dimensional space.
More specifically, if the arguments to the kernel are in a measurable space X, and if the kernel is positive semi-definite — i.e.
for any finite subset {x1, ..., xn} of X and subset {c1, ..., cn} of objects (typically real numbers) — then there exists a function φ(x) whose range is in an inner product space of possibly high dimension, such that
The kernel trick transforms any algorithm that solely depends on the dot product between two vectors. Wherever a dot product is used, it is replaced with the kernel function. Thus, a linear algorithm can easily be transformed into a non-linear algorithm. This non-linear algorithm is equivalent to the linear algorithm operating in the range space of φ. However, because kernels are used, the φ function is never explicitly computed. This is desirable, because the high-dimensional space may be infinite-dimensional (as is the case when the kernel is a Gaussian).
The kernel trick was first published by Aizerman et al.
It has been applied to several kinds of algorithm in machine learning and statistics, including:
- Perceptrons
- Support vector machines
- Principal components analysis
- Canonical correlation analysis
- Fisher's linear discriminant analysis
- Clustering
The origin of the term kernel trick is not known. | Kernel trick
In machine learning, the kernel trick is a method for using a linear classifier algorithm to solve a non-linear problem by mapping the original non-linear observations into a higher-dimensional space, where the linear classifier is subsequently used; this makes a linear classification in the new space equivalent to non-linear classification in the original space.
This is done using Mercer's theorem, which states that any continuous, symmetric, positive semi-definite kernel function K(x, y) can be expressed as a dot product in a high-dimensional space.
More specifically, if the arguments to the kernel are in a measurable space X, and if the kernel is positive semi-definite — i.e.
for any finite subset {x1, ..., xn} of X and subset {c1, ..., cn} of objects (typically real numbers) — then there exists a function φ(x) whose range is in an inner product space of possibly high dimension, such that
The kernel trick transforms any algorithm that solely depends on the dot product between two vectors. Wherever a dot product is used, it is replaced with the kernel function. Thus, a linear algorithm can easily be transformed into a non-linear algorithm. This non-linear algorithm is equivalent to the linear algorithm operating in the range space of φ. However, because kernels are used, the φ function is never explicitly computed. This is desirable, because the high-dimensional space may be infinite-dimensional (as is the case when the kernel is a Gaussian).
The kernel trick was first published by Aizerman et al.[1]
It has been applied to several kinds of algorithm in machine learning and statistics, including:
- Perceptrons
- Support vector machines
- Principal components analysis
- Canonical correlation analysis
- Fisher's linear discriminant analysis
- Clustering
The origin of the term kernel trick is not known. | https://www.wikidoc.org/index.php/Kernel_trick | |
c6248539fc7bc33409b995c9daca23e56d857db7 | wikidoc | Ketobemidone | Ketobemidone
# Overview
Ketobemidone is a powerful opioid analgesic. Its potency is equal to morphine, and it also has some NMDA-antagonist properties. This makes it useful for some types of pain that don't respond well to other opioids.
It is used for all types of severe pain, such as postoperative, cancer, kidney stones and fractures.
# History
It was first synthesized in 1942 by Eisleb. The first study of it in man was published in 1946, and it was introduced in clinical medicine shortly after.
# Chemistry
Ketobemidone is 1-methyl-4-(3-hydroxyphenyl)-4-propionylpiperidine. It is usually available as the hydrochloride, which is a white powder. It is synthesized by alkylating (3-methoxyphenyl)acetonitrile with bis(2-chloroethyl)methylamine, followed by reaction with ethylmagnesiumbromide, and finally O-demethylation with hydrobromic acid.
# Pharmacology
Experiments on former addicts indicated it was more addictive than other opioids, so in 1954 the Economic and Social Council took a resolution urging governments to stop manufacture and use of ketobemidone
. As a result ketobemidone is mostly used in the Scandinavian countries, with Denmark topping the statistics
. This result was not in agreement with clinical observations, and another study in 1958 didn't find it more addictive than morphine. That study noticed that while for morphine the dose for euphoria is the same as that for analgesia, for ketobemidone the analgesic dose was well below the euphoric dose.
Analgesia after 5-10 mg orally or 5-7.5 mg intravenously lasts 3-5 hours. Ketobemidone is also available in preparations with a spasmolytic, which can improve the analgesia.
Ketobemidone is mainly metabolised by conjugation of the phenolic hydroxyl group, and by N-desmethylation. Only about 16% is excreted unchanged.
Pfizer manufactures ketobemidone under the tradenames Ketogan and Ketorax. It is available as tablets, suppositories and injection fluid. A sustained release formulation exists sold as Ketodur in some countries containing 10 or 25 mg ketobemidone. | Ketobemidone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ketobemidone is a powerful opioid analgesic. Its potency is equal to morphine, and it also has some NMDA-antagonist properties. This makes it useful for some types of pain that don't respond well to other opioids.
It is used for all types of severe pain, such as postoperative, cancer, kidney stones and fractures.
# History
It was first synthesized in 1942 by Eisleb. The first study of it in man was published in 1946, and it was introduced in clinical medicine shortly after.
# Chemistry
Ketobemidone is 1-methyl-4-(3-hydroxyphenyl)-4-propionylpiperidine. It is usually available as the hydrochloride, which is a white powder. It is synthesized by alkylating (3-methoxyphenyl)acetonitrile with bis(2-chloroethyl)methylamine, followed by reaction with ethylmagnesiumbromide, and finally O-demethylation with hydrobromic acid.
# Pharmacology
Experiments on former addicts indicated it was more addictive than other opioids, so in 1954 the Economic and Social Council took a resolution urging governments to stop manufacture and use of ketobemidone[1]
. As a result ketobemidone is mostly used in the Scandinavian countries, with Denmark topping the statistics[2]
. This result was not in agreement with clinical observations, and another study in 1958 didn't find it more addictive than morphine[3]. That study noticed that while for morphine the dose for euphoria is the same as that for analgesia, for ketobemidone the analgesic dose was well below the euphoric dose.
Analgesia after 5-10 mg orally or 5-7.5 mg intravenously lasts 3-5 hours. Ketobemidone is also available in preparations with a spasmolytic, which can improve the analgesia.
Ketobemidone is mainly metabolised by conjugation of the phenolic hydroxyl group, and by N-desmethylation. Only about 16% is excreted unchanged.
Pfizer manufactures ketobemidone under the tradenames Ketogan and Ketorax. It is available as tablets, suppositories and injection fluid. A sustained release formulation exists sold as Ketodur in some countries containing 10 or 25 mg ketobemidone. | https://www.wikidoc.org/index.php/Ketobemidone | |
e031c0a086d1a5695839b208eece604737242b33 | wikidoc | Killip class | Killip class
# Overview
The Killip classification is a system used in individuals with an acute myocardial infarction (heart attack), in order to risk stratify them. Individuals with a low Killip class are less likely to die within the first 30 days after their myocardial infarction than individuals with a high Killip class.
# The study
The study was a case series with unblinded, unobjective outcomes, not adjusted for confounding factors, nor validated in an independent set of patients. The setting was the coronary care unit of a university hospital in the USA.
250 patients were included in the study (aged 28 to 94; mean 64, 72% male) with a myocardial infarction. Patients with a cardiac arrest prior to admission were excluded.
Patients were ranked by Killip class in the following way:
- Killip class I includes individuals with no clinical signs of heart failure.
- Killip class II includes individuals with rales or crackles in the lungs, an S3 gallop, and elevated jugular venous pressure.
- Killip class III describes individuals with frank acute pulmonary edema.
- Killip class IV describes individuals in cardiogenic shock or hypotension (measured as systolic blood pressure lower than 90 mmHg), and evidence of peripheral vasoconstriction (oliguria, cyanosis or sweating).
# Conclusions
Within a 95% confidence interval the patient outcome was as follows:
- Killip class I: 81/250 patients; 32% (27 to 38%). Mortality rate was found to be at 6%.
- Killip class II: 96/250 patients; 38% (32 to 44%). Mortality rate was found to be at 17%.
- Killip class III: 26/250 patients; 10% (6.6 to 14%). Mortality rate was found to be at 38%.
- Killip class IV: 47/250 patients; 19% (14 to 24%). Mortality rate was found to be at 81%.
The Killip-Kimball classification has played a fundamental role in classic cardiology, having been used as a stratifying criteria for many other studies. Worsening Killip class has been found to be independently associated with increasing mortality in several studies.
Killip class 1 and no evidence of hypotension or bradycardia, in patients presenting with acute coronary syndrome, should be considered for immediate IV beta blocker therapy. | Killip class
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Killip classification is a system used in individuals with an acute myocardial infarction (heart attack), in order to risk stratify them. Individuals with a low Killip class are less likely to die within the first 30 days after their myocardial infarction than individuals with a high Killip class.[1]
# The study
The study was a case series with unblinded, unobjective outcomes, not adjusted for confounding factors, nor validated in an independent set of patients. The setting was the coronary care unit of a university hospital in the USA.
250 patients were included in the study (aged 28 to 94; mean 64, 72% male) with a myocardial infarction. Patients with a cardiac arrest prior to admission were excluded.
Patients were ranked by Killip class in the following way:
- Killip class I includes individuals with no clinical signs of heart failure.
- Killip class II includes individuals with rales or crackles in the lungs, an S3 gallop, and elevated jugular venous pressure.
- Killip class III describes individuals with frank acute pulmonary edema.
- Killip class IV describes individuals in cardiogenic shock or hypotension (measured as systolic blood pressure lower than 90 mmHg), and evidence of peripheral vasoconstriction (oliguria, cyanosis or sweating).
# Conclusions
Within a 95% confidence interval the patient outcome was as follows:
- Killip class I: 81/250 patients; 32% (27 to 38%). Mortality rate was found to be at 6%.
- Killip class II: 96/250 patients; 38% (32 to 44%). Mortality rate was found to be at 17%.
- Killip class III: 26/250 patients; 10% (6.6 to 14%). Mortality rate was found to be at 38%.
- Killip class IV: 47/250 patients; 19% (14 to 24%). Mortality rate was found to be at 81%.
The Killip-Kimball classification has played a fundamental role in classic cardiology, having been used as a stratifying criteria for many other studies. Worsening Killip class has been found to be independently associated with increasing mortality in several studies.
Killip class 1 and no evidence of hypotension or bradycardia, in patients presenting with acute coronary syndrome, should be considered for immediate IV beta blocker therapy. | https://www.wikidoc.org/index.php/Killip_class | |
7befeea45c511a50c50aad0c45cb06a0af87159d | wikidoc | Koilocytosis | Koilocytosis
# Overview
Koilocytosis (a.k.a koilocytotic atypia) is cell changes caused by HPV. By microscopic observation, the cells have halo nuclei. These changes are neither precancerous nor dangerous in and of themselves. Koilocytosis often co-exists with dysplasia, and it's the dysplasia that could lead to cancer, and thus, needs treatment.
# Diagnosis
A distinctive abnormality in the appearance of the cells of the skin of the cervix, in which some of the nuclei are surrounded by tiny "halos."
Most commonly, these changes occur in the presence of HPV (Human Papilloma Virus) but occasionally are associated with more serious problems such a cervical dysplasia or even early malignancy.
Patients demonstrating koilocytosis who previously had normal Pap smears are ideally evaluated with colposcopy and cervical biopsies to determine the source of the koilocytes, although such evaluation can usually safely wait for weeks to a few months if necessary because of operational requirements. | Koilocytosis
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Koilocytosis (a.k.a koilocytotic atypia) is cell changes caused by HPV. By microscopic observation, the cells have halo nuclei. These changes are neither precancerous nor dangerous in and of themselves. Koilocytosis often co-exists with dysplasia, and it's the dysplasia that could lead to cancer, and thus, needs treatment.
# Diagnosis
A distinctive abnormality in the appearance of the cells of the skin of the cervix, in which some of the nuclei are surrounded by tiny "halos."
Most commonly, these changes occur in the presence of HPV (Human Papilloma Virus) but occasionally are associated with more serious problems such a cervical dysplasia or even early malignancy.
Patients demonstrating koilocytosis who previously had normal Pap smears are ideally evaluated with colposcopy and cervical biopsies to determine the source of the koilocytes, although such evaluation can usually safely wait for weeks to a few months if necessary because of operational requirements.
Template:Skin and subcutaneous tissue symptoms and signs
Template:Nervous and musculoskeletal system symptoms and signs
Template:Urinary system symptoms and signs
Template:Cognition, perception, emotional state and behaviour symptoms and signs
Template:Speech and voice symptoms and signs
Template:General symptoms and signs
Template:WikiDoc Sources
- ↑ http://picasaweb.google.com/mcmumbi/USMLEIIImages | https://www.wikidoc.org/index.php/Koilocytosis | |
dc89d1c0362bdf0b7bad164e8d3977a1e0e62a4b | wikidoc | Mifepristone | Mifepristone
# 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
Mifepristone is an antagonist of progesterone and cortisol receptors that is FDA approved for the treatment of Cushing's syndrome. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, peripheral edema, hypokalemia, abdominal pain, decreased apetite, diarrhea, nauseas, vomiting, dizziness, headache, abnormal vaginal bleeding, uterine cramps, hypertrophic endometrial disorder and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: 300 mg PO / day taken with meals.
Maximun dose: 1200 mg/day or 20 mg/kg PO.
Increases in dose should not occur more frequently than once every 2-4 weeks.
- Maximun dose: 1200 mg/day or 20 mg/kg PO.
- Increases in dose should not occur more frequently than once every 2-4 weeks.
Changes in glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms may provide an early assessment of response (within 6 weeks) and may help guide early dose titration. Improvements in cushingoid appearance, acne, hirsutism, striae, and body weight occur over a longer period of time and, along with measures of glucose control, may be used to determine dose changes beyond the first 2 months of therapy. Careful and gradual titration of Mifepristone accompanied by monitoring for recognized adverse reactions may reduce the risk of severe adverse reactions. Dose reduction or even dose discontinuation may be needed in some clinical situations. If Mifepristone treatment is interrupted, it should be reinitiated at the lowest dose (300 mg). If treatment was interrupted because of adverse reactions, the titration should aim for a dose lower than the one that resulted in treatment interruption.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mifepristone in adult patients.
### Non–Guideline-Supported Use
- Dosage: 600 mg PO.
Administered 48 hours before procedures which need cervical canal dilation.
- Administered 48 hours before procedures which need cervical canal dilation.
- Dosage:
10 mg PO: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
25 mg PO: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
Both doses prove to have the same efficacy.
600 mg: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse. In two clinical trials, 600 mg Mifepristone demonstrated to be 100% effective in emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
- 10 mg PO: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
- 25 mg PO: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
Both doses prove to have the same efficacy.
- Both doses prove to have the same efficacy.
- 600 mg: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse. In two clinical trials, 600 mg Mifepristone demonstrated to be 100% effective in emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
- Dosage: 50 mg PO once every 4 weeks.
- Dosage
200 mg Mifepristone PO combined with 800 mcg Misoprostol vaginally 24 hours after (both in single dose).
600 mg/day PO for 2 days.
400 mg/day for 3 days.
- 200 mg Mifepristone PO combined with 800 mcg Misoprostol vaginally 24 hours after (both in single dose).
- 600 mg/day PO for 2 days.
- 400 mg/day for 3 days.
- Dosage: 200 mg/day PO.
- Dosage: 5 mg PO daily.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosage: 300 mg PO / day taken with meals.
Maximun dose: 1200 mg/day or 20 mg/kg PO.
Increases in dose should not occur more frequently than once every 2-4 weeks.
- Maximun dose: 1200 mg/day or 20 mg/kg PO.
- Increases in dose should not occur more frequently than once every 2-4 weeks.
Changes in glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms may provide an early assessment of response (within 6 weeks) and may help guide early dose titration. Improvements in cushingoid appearance, acne, hirsutism, striae, and body weight occur over a longer period of time and, along with measures of glucose control, may be used to determine dose changes beyond the first 2 months of therapy. Careful and gradual titration of Mifepristone accompanied by monitoring for recognized adverse reactions may reduce the risk of severe adverse reactions. Dose reduction or even dose discontinuation may be needed in some clinical situations. If Mifepristone treatment is interrupted, it should be reinitiated at the lowest dose (300 mg). If treatment was interrupted because of adverse reactions, the titration should aim for a dose lower than the one that resulted in treatment interruption.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mifepristone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mifepristone in pediatric patients.
# Contraindications
- Mifepristone is contraindicated in women who are pregnant. Pregnancy must be excluded before the initiation of treatment with Mifepristone or if treatment is interrupted for more than 14 days in females of reproductive potential. Nonhormonal contraceptives should be used during and one month after stopping treatment in all women of reproductive potential.
Mifepristone is contraindicated in patients taking simvastatin, lovastatin, and CYP3A substrates with narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, due to an increased risk of adverse events.
Mifepristone is contraindicated in patients who require concomitant treatment with systemic corticosteroids for serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation) because Mifepristone antagonizes the effect of glucocorticoids.
Mifepristone is contraindicated in the following:
- Women with a history of unexplained vaginal bleeding
- Women with endometrial hyperplasia with atypia or endometrial carcinoma
- Mifepristone is contraindicated in patients with prior hypersensitivity reactions to mifepristone or to any of the product components.
# Warnings
- Patients receiving mifepristone may experience adrenal insufficiency. Because serum cortisol levels remain elevated and may even increase during treatment with Mifepristone, serum cortisol levels do not provide an accurate assessment of hypoadrenalism in patients receiving Mifepristone. Patients should be closely monitored for signs and symptoms of adrenal insufficiency, including weakness, nausea, increased fatigue, hypotension, and hypoglycemia. If adrenal insufficiency is suspected, discontinue treatment with Mifepristone immediately and administer glucocorticoids without delay. High doses of supplemental glucocorticoids may be needed to overcome the glucocorticoid receptor blockade produced by mifepristone. Factors considered in deciding on the duration of glucocorticoid treatment should include the long half-life of mifepristone (85 hours).
- Treatment with Mifepristone at a lower dose can be resumed after resolution of adrenal insufficiency. Patients should also be evaluated for precipitating causes of hypoadrenalism (infection, trauma, etc.).
- In a study of patients with Cushing's syndrome, hypokalemia was observed in 44% of subjects during treatment with Mifepristone. Hypokalemia should be corrected prior to initiating Mifepristone. During Mifepristone administration, serum potassium should be measured 1 to 2 weeks after starting or increasing the dose of Mifepristone and periodically thereafter. Hypokalemia can occur at any time during Mifepristone treatment. Mifepristone-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists in spite of potassium supplementation, consider adding mineralocorticoid antagonists.
- Being an antagonist of the progesterone receptor, mifepristone promotes unopposed endometrial proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and vaginal bleeding. Mifepristone should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy. Women who experience vaginal bleeding during Mifepristone treatment should be referred to a gynecologist for further evaluation.
- Mifepristone and its metabolites block IKr. Mifepristone prolongs the QTc interval in a dose-related manner. There is little or no experience with high exposure, concomitant dosing with other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval. To minimize risk, the lowest effective dose should always be used.
- Use of Mifepristone in patients who receive corticosteroids for other conditions (e.g., autoimmune disorders) may lead to exacerbation or deterioration of such conditions, as Mifepristone antagonizes the desired effects of glucocorticoid in these clinical settings. For medical conditions in which chronic corticosteroid therapy is lifesaving (e.g., immunosuppression in organ transplantation), Mifepristone is contraindicated.
- Mifepristone should be used with extreme caution in patients taking ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole, as these could substantially increase the concentration of mifepristone in the blood. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. Mifepristone should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 300 mg per day.
- Patients with endogenous Cushing's syndrome are at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia during Mifepristone treatment. Patients may present with respiratory distress shortly after initiation of Mifepristone. Appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered.
- Mifepristone does not reduce serum cortisol levels. Elevated cortisol levels may activate mineralocorticoid receptors which are also expressed in cardiac tissues. Caution should be used in patients with underlying heart conditions including heart failure and coronary vascular disease.
# Adverse Reactions
## Clinical Trials Experience
- Nausea
- Vomiting
- Dry-mouth
- Diarrhea
- Constipation
- Fatigue
- Peripheral edema
- Pain
- Headache
- Dizziness
- Somnolence
- Arthralgia
- Back pain
- Myalgia
- Pain in Extremity
- Hypokalemia
- Abnormal thyroid function test (High TSH levels)
- Reduction of HDL-C serum levels
- Sinusitis
- Nasopharyngitis
- Decreased appetite
- Anorexia
- Hypertension
- Endometrial Hyperthrophy
- Vaginal Bleeding
- Dyspnea
- Anxiety
## Postmarketing Experience
There is limited information regarding Mifepristone Postmarketing Experience in the drug label.
# Drug Interactions
Based on the long terminal half-life of mifepristone after reaching steady state, at least 2 weeks should elapse after cessation of Mifepristone before initiating or increasing the dose of any interacting concomitant medication.
- Because Mifepristone is an inhibitor of CYP3A, concurrent use of Mifepristone with a drug whose metabolism is largely or solely mediated by CYP3A is likely to result in increased plasma concentrations of the drug. Discontinuation or dose reduction of such medications may be necessary with Mifepristone co-administration.
- Mifepristone increased the exposure to simvastatin and simvastatin acid significantly in healthy subjects. Concomitant use of simvastatin or lovastatin is contraindicated because of the increased risk of myopathy rhabdomyolysis.
- The exposure of other substrates of CYP3A with narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, may be increased by concomitant administration with Mifepristone. Therefore, the concomitant use of such CYP3A substrates with Mifepristone is contraindicated.
- Other drugs with similar high first pass metabolism in which CYP3A is the primary route of metabolism should be used with extreme caution if co-administered with Mifepristone. The lowest possible dose and/or a decreased frequency of dosing must be used with therapeutic drug monitoring when possible. Use of alternative drugs without these metabolic characteristics is advised when possible with concomitant Mifepristone.
If drugs that undergo low first pass metabolism by CYP3A or drugs in which CYP3A is not the major metabolic route are co-administered with Mifepristone, use the lowest dose of concomitant medication necessary, with appropriate monitoring and follow-up.
- Medications that inhibit CYP3A could increase plasma mifepristone concentrations and dose reduction of Mifepristone may be required.
- Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, mibefradil, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole may increase exposure to mifepristone significantly. The clinical impact of this interaction has not been studied. Therefore, extreme caution should be used when these drugs are prescribed in combination with Mifepristone. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. The dose of Mifepristone should be limited to 300 mg and used only when necessary.
- Moderate inhibitors of CYP3A, such as amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, or verapamil, should be used with caution when administered in combination with Mifepristone.
- No medications that induce CYP3A have been studied when co-administered with Mifepristone. Avoid co-administration of Mifepristone and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort.
- Because Mifepristone is an inhibitor of CYP2C8/CYP2C9, concurrent use of Mifepristone with a drug whose metabolism is largely or solely mediated by CYP2C8/CYP2C9 is likely to result in increased plasma concentrations of the drug. Mifepristone significantly increased exposure of fluvastatin, a typical CYP2C8/CYP2C9 substrate, in healthy subjects. When given concomitantly with Mifepristone, drugs that are substrates of CYP2C8/CYP2C9 (including non-steroidal anti-inflammatory drugs, warfarin, and repaglinide) should be used at the smallest recommended doses, and patients should be closely monitored for adverse effects.
- Mifepristone is an inhibitor of CYP2B6 and may cause significant increases in exposure of drugs that are metabolized by CYP2B6 such as bupropion and efavirenz. Since no study has been conducted to evaluate the effect of mifepristone on substrates of CYP2B6, the concomitant use of bupropion and efavirenz should be undertaken with caution.
- Mifepristone is a progesterone-receptor antagonist and will interfere with the effectiveness of hormonal contraceptives. Therefore, non-hormonal contraceptive methods should be used.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Contraindicated in pregnancy. Mifepristone can cause fetal harm when administered to a pregnant woman because the use of Mifepristone results in pregnancy loss. The inhibition of both endogenous and exogenous progesterone by mifepristone at the progesterone receptor results in pregnancy loss. If Mifepristone is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mifepristone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mifepristone during labor and delivery.
### Nursing Mothers
- Mifepristone is present in human milk of women taking the drug. Because of the potential for serious adverse reactions in nursing infants from Mifepristone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of Mifepristone in pediatric patients have not been established.
### Geriatic Use
- Clinical studies with Mifepristone did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger people.
### Gender
There is no FDA guidance on the use of Mifepristone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mifepristone with respect to specific racial populations.
### Renal Impairment
- The pharmacokinetics of mifepristone in subjects with severe renal impairment (creatinine clearance CrCL < 30 mL/min, but not on dialysis) was evaluated following multiple doses of 1200 mg Mifepristone for 7 days. Mean exposure to mifepristone increased 31%, with similar or smaller increases in metabolite exposure as compared to subjects with normal renal function (CrCL ≥ 90 mL/min). There was large variability in the exposure of mifepristone and its metabolites in subjects with severe renal impairment as compared to subjects with normal renal function (geometric least square mean ratio for AUC of mifepristone: 1.21 ; metabolite 1: 1.43 ; metabolite 2: 1.18 and metabolite 3: 1.19 ). No change in the initial dose of Mifepristone is needed for renal impairment; the maximum dose should not exceed 600 mg per day.
### Hepatic Impairment
- The pharmacokinetics of mifepristone in subjects with moderate hepatic impairment (Child-Pugh Class B) was evaluated in a single- and multiple-dose study (600 mg for 7 days). The pharmacokinetics in subjects with moderate hepatic impairment was similar to those with normal hepatic function. There was large variability in the exposure of mifepristone and its metabolites in subjects with moderate hepatic impairment as compared to subjects with normal hepatic function (geometric least square mean ratio for AUC of mifepristone: 1.02 ; metabolite 1: 0.95 ; metabolite 2: 1.37 and metabolite 3: 0.62 ). Due to limited information on safety in patients with mild-to-moderate hepatic impairment, the maximum dose should not exceed 600 mg per day. The pharmacokinetics of mifepristone in patients with severe hepatic disease has not been studied. Mifepristone is not recommended in patients with severe hepatic disease.
### Females of Reproductive Potential and Males
- Due to its anti-progestational activity, Mifepristone causes pregnancy loss. Exclude pregnancy before the initiation of treatment with Mifepristone or if treatment is interrupted for more than 14 days in females of reproductive potential. Recommend contraception for the duration of treatment and for one month after stopping treatment using a non-hormonal medically acceptable method of contraception. If the patient has had surgical sterilization, no additional contraception is needed.
### Immunocompromised Patients
There is no FDA guidance one the use of Mifepristone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
- Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency.
- Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment.
# IV Compatibility
There is limited information regarding the compatibility of Mifepristone and IV administrations.
# Overdosage
There is no experience with overdosage
# Pharmacology
## Mechanism of Action
- Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses. Mifepristone has high affinity for the GR-II receptor but little affinity for the GR-I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors.
## Structure
- The chemical name of mifepristone is 11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4, 9-dien-3-one. The chemical formula is C29H35NO2; the molecular weight is 429.60, and the structural formula is:
## Pharmacodynamics
- Because mifepristone acts at the receptor level to block the effects of cortisol, its antagonistic actions affect the hypothalamic-pituitary-adrenal (HPA) axis in such a way as to further increase circulating cortisol levels while, at the same time, blocking their effects.
- Mifepristone and the three active metabolites have greater affinity for the glucocorticoid receptor (100%, 61%, 48%, and 45%, respectively) than either dexamethasone (23%) or cortisol (9%).
## Pharmacokinetics
- Following oral administration, time to peak plasma concentrations of mifepristone occurred between 1 and 2 hours following single dose, and between 1 and 4 hours following multiple doses of 600 mg of Mifepristone in healthy volunteers. Mean plasma concentrations of three active metabolites of mifepristone peak between 2 and 8 hours after multiple doses of 600 mg/day, and the combined concentrations of the metabolites exceed that of the parent mifepristone. Exposure to mifepristone is substantially less than dose proportional. Time to steady state is within 2 weeks, and the mean (SD) half-life of the parent mifepristone was 85 (61) hours following multiple doses of 600 mg/day of Mifepristone. Studies evaluating the effects of food on the pharmacokinetics of Mifepristone demonstrate a significant increase in plasma levels of mifepristone when dosed with food. To achieve consistent plasma drug concentrations, patients should be instructed to always take their medication with meals.
- Mifepristone is highly bound to alpha-1-acid glycoprotein (AAG) and approaches saturation at doses of 100 mg (2.5 μM) or more. Mifepristone and its metabolites also bind to albumin and are distributed to other tissues, including the central nervous system (CNS). As determined in vitro by equilibrium dialysis, binding of mifepristone and its three active metabolites to human plasma proteins was concentration-dependent. Binding was approximately 99.2% for mifepristone, and ranged from 96.1 to 98.9% for the three active metabolites at clinically relevant concentrations.
- Cytochrome P450 3A4 (CYP3A4) has been shown to be involved in mifepristone metabolism in human liver microsomes. Two of the known active metabolites are the product of demethylation (one monodemethylated and one di-demethylated), while a third active metabolite results from hydroxylation (monohydroxylated).
- Excretion is primarily (approximately 90%) via the fecal route.
## Nonclinical Toxicology
- Mifepristone was evaluated for carcinogenicity potential in rats and mice. Rats were dosed for up to two years at doses of 5, 25, and 125 mg/kg of mifepristone. The high dose was the maximum tolerated dose, but exposure at all doses was below exposure at the maximum clinical dose based on AUC comparison. Female rats had a statistically significant increase in follicular cell adenomas/carcinomas and liver adenomas. It is plausible that these tumors are due to drug-induced enzyme metabolism, a mechanism not considered clinically relevant, but studies confirming this mechanism were not conducted with mifepristone. Mice were also tested for up to 2 years at mifepristone doses up to the maximum tolerated dose of 125 mg/kg, which provided exposure below the maximum clinical dose based on AUC. No drug-related tumors were seen in mice. Mifepristone was not genotoxic in a battery of bacterial, yeast, and mammalian in vitro assays, and an in vivo micronucleus study in mice.
- The pharmacological activity of mifepristone disrupts the estrus cycle of adult rats at a dose of 0.3 mg/kg (less than human exposure at the maximum clinical dose, based on body surface area). However, following withdrawal of treatment and subsequent resumption of the estrus cycle, there was no effect on reproductive function when mated. A single subcutaneous dose of mifepristone (up to 100 mg/kg) to rats on the first day after birth did not adversely affect future reproductive function in males or females, although the onset of puberty was slightly premature in dosed females. Repeated doses of mifepristone (1 mg every other day) to neonatal rats resulted in potentially adverse fertility effects, including oviduct and ovary malformations in females, delayed male puberty, deficient male sexual behavior, reduced testicular size, and lowered ejaculation frequency.
Mifepristone was not genotoxic in a battery of bacterial, yeast, and mammalian in vitro assays, and an in vivo micronucleus study in mice.
- The pharmacological activity of mifepristone disrupts the estrus cycle of adult rats at a dose of 0.3 mg/kg (less than human exposure at the maximum clinical dose, based on body surface area). However, following withdrawal of treatment and subsequent resumption of the estrus cycle, there was no effect on reproductive function when mated.
- A single subcutaneous dose of mifepristone (up to 100 mg/kg) to rats on the first day after birth did not adversely affect future reproductive function in males or females, although the onset of puberty was slightly premature in dosed females. Repeated doses of mifepristone (1 mg every other day) to neonatal rats resulted in potentially adverse fertility effects, including oviduct and ovary malformations in females, delayed male puberty, deficient male sexual behavior, reduced testicular size, and lowered ejaculation frequency.
# Clinical Studies
- Patients in the diabetes cohort underwent standard oral glucose tolerance tests at baseline and periodically during the clinical study. Anti-diabetic medications were allowed but had to be kept stable during the trial and patients had to be on stable anti-diabetic regimens prior to enrollment. The primary efficacy analysis for the diabetes cohort was an analysis of responders. A responder was defined as a patient who had a ≥ 25% reduction from baseline in glucose AUC. The primary efficacy analysis was conducted in the modified intent-to-treat population (n=25) defined as all patients who received a minimum of 30 days on Mifepristone. Fifteen of 25 patients (60%) were treatment responders (95% CI: 39%,78%).
- Mean HbA1c was 7.4% in the 24 patients with HbA1c values at baseline and Week 24. For these 24 patients mean reduction in HbA1c was 1.1% (95% CI -1.6, -0.7) from baseline to the end of the trial. Fourteen of 24 patients had above normal HbA1c levels at baseline, ranging between 6.7% and 10.4%; all of these patients had reductions in HbA1c by the end of the study (range -0.4 to -4.4%) and eight of 14 patients (57%) normalized HbA1c levels at trial end. Antidiabetic medications were reduced in 7 of the 15 DM subjects taking antidiabetic medication and remained constant in the others.
- There were no changes in mean systolic blood pressure and diastolic blood pressures at the end of the trial relative to baseline in the modified intent-to-treat population (n=21).
- Individual patients showed varying degrees of improvement in Cushing's syndrome manifestations such as cushingoid appearance, acne, hirsutism, striae, psychiatric symptoms, and excess total body weight. Because of the variability in clinical presentation and variability of response in this open label trial, it is uncertain whether these changes could be ascribed to the effects of Mifepristone.
# How Supplied
Mifepristone is supplied as a light yellow to yellow, film-coated, oval-shaped tablet debossed with “Corcept” on one side and “300” on the other. Each tablet contains 300 mg of mifepristone. Mifepristone tablets are available in bottles of 28 tablets (NDC 76346-073-01) and bottles of 280 tablets (NDC 76346-073-02).
## Storage
Store at controlled room temperature, 25 °C (77 °F); excursions permitted to 15 to 30 ° C (59 – 86 °F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
As a part of patient counseling, doctors must review the Mifepristone Medication Guide with every patient.
- Advise patients that Mifepristone will cause termination of pregnancy. Mifepristone is contraindicated in pregnant patients.
- Counsel females of reproductive potential regarding pregnancy prevention and planning with a non-hormonal contraceptive prior to use of Mifepristone and up to one month after the end of treatment.
- Instruct patients to contact their physician immediately if they suspect or confirm they are pregnant.
# Precautions with Alcohol
Alcohol-Mifepristone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Myfeprex
- Korlym
# Look-Alike Drug Names
There is limited information regarding Mifepristone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Mifepristone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Black Box Warning
# Overview
Mifepristone is an antagonist of progesterone and cortisol receptors that is FDA approved for the treatment of Cushing's syndrome. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, peripheral edema, hypokalemia, abdominal pain, decreased apetite, diarrhea, nauseas, vomiting, dizziness, headache, abnormal vaginal bleeding, uterine cramps, hypertrophic endometrial disorder and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: 300 mg PO / day taken with meals.
Maximun dose: 1200 mg/day or 20 mg/kg PO.
Increases in dose should not occur more frequently than once every 2-4 weeks.
- Maximun dose: 1200 mg/day or 20 mg/kg PO.
- Increases in dose should not occur more frequently than once every 2-4 weeks.
Changes in glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms may provide an early assessment of response (within 6 weeks) and may help guide early dose titration. Improvements in cushingoid appearance, acne, hirsutism, striae, and body weight occur over a longer period of time and, along with measures of glucose control, may be used to determine dose changes beyond the first 2 months of therapy. Careful and gradual titration of Mifepristone accompanied by monitoring for recognized adverse reactions may reduce the risk of severe adverse reactions. Dose reduction or even dose discontinuation may be needed in some clinical situations. If Mifepristone treatment is interrupted, it should be reinitiated at the lowest dose (300 mg). If treatment was interrupted because of adverse reactions, the titration should aim for a dose lower than the one that resulted in treatment interruption.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mifepristone in adult patients.
### Non–Guideline-Supported Use
- Dosage: 600 mg PO[1].
Administered 48 hours before procedures which need cervical canal dilation.
- Administered 48 hours before procedures which need cervical canal dilation.
- Dosage:
10 mg PO: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
25 mg PO: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
Both doses prove to have the same efficacy[2].
600 mg: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse[3]. In two clinical trials, 600 mg Mifepristone demonstrated to be 100% effective in emergency contraception during the first 120 hours of a single unprotected sexual intercourse[4].
- 10 mg PO: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
- 25 mg PO: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse.
Both doses prove to have the same efficacy[2].
- Both doses prove to have the same efficacy[2].
- 600 mg: Emergency contraception during the first 120 hours of a single unprotected sexual intercourse[3]. In two clinical trials, 600 mg Mifepristone demonstrated to be 100% effective in emergency contraception during the first 120 hours of a single unprotected sexual intercourse[4].
- Dosage: 50 mg PO once every 4 weeks[5].
- Dosage
200 mg Mifepristone PO combined with 800 mcg Misoprostol vaginally 24 hours after (both in single dose)[6].
600 mg/day PO for 2 days[7].
400 mg/day for 3 days[8].
- 200 mg Mifepristone PO combined with 800 mcg Misoprostol vaginally 24 hours after (both in single dose)[6].
- 600 mg/day PO for 2 days[7].
- 400 mg/day for 3 days[8].
- Dosage: 200 mg/day PO[9].
- Dosage: 5 mg PO daily[10].
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosage: 300 mg PO / day taken with meals.
Maximun dose: 1200 mg/day or 20 mg/kg PO.
Increases in dose should not occur more frequently than once every 2-4 weeks.
- Maximun dose: 1200 mg/day or 20 mg/kg PO.
- Increases in dose should not occur more frequently than once every 2-4 weeks.
Changes in glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms may provide an early assessment of response (within 6 weeks) and may help guide early dose titration. Improvements in cushingoid appearance, acne, hirsutism, striae, and body weight occur over a longer period of time and, along with measures of glucose control, may be used to determine dose changes beyond the first 2 months of therapy. Careful and gradual titration of Mifepristone accompanied by monitoring for recognized adverse reactions may reduce the risk of severe adverse reactions. Dose reduction or even dose discontinuation may be needed in some clinical situations. If Mifepristone treatment is interrupted, it should be reinitiated at the lowest dose (300 mg). If treatment was interrupted because of adverse reactions, the titration should aim for a dose lower than the one that resulted in treatment interruption.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mifepristone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Mifepristone in pediatric patients.
# Contraindications
- Mifepristone is contraindicated in women who are pregnant. Pregnancy must be excluded before the initiation of treatment with Mifepristone or if treatment is interrupted for more than 14 days in females of reproductive potential. Nonhormonal contraceptives should be used during and one month after stopping treatment in all women of reproductive potential.
Mifepristone is contraindicated in patients taking simvastatin, lovastatin, and CYP3A substrates with narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, due to an increased risk of adverse events.
Mifepristone is contraindicated in patients who require concomitant treatment with systemic corticosteroids for serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation) because Mifepristone antagonizes the effect of glucocorticoids.
Mifepristone is contraindicated in the following:
- Women with a history of unexplained vaginal bleeding
- Women with endometrial hyperplasia with atypia or endometrial carcinoma
- Mifepristone is contraindicated in patients with prior hypersensitivity reactions to mifepristone or to any of the product components.
# Warnings
- Patients receiving mifepristone may experience adrenal insufficiency. Because serum cortisol levels remain elevated and may even increase during treatment with Mifepristone, serum cortisol levels do not provide an accurate assessment of hypoadrenalism in patients receiving Mifepristone. Patients should be closely monitored for signs and symptoms of adrenal insufficiency, including weakness, nausea, increased fatigue, hypotension, and hypoglycemia. If adrenal insufficiency is suspected, discontinue treatment with Mifepristone immediately and administer glucocorticoids without delay. High doses of supplemental glucocorticoids may be needed to overcome the glucocorticoid receptor blockade produced by mifepristone. Factors considered in deciding on the duration of glucocorticoid treatment should include the long half-life of mifepristone (85 hours).
- Treatment with Mifepristone at a lower dose can be resumed after resolution of adrenal insufficiency. Patients should also be evaluated for precipitating causes of hypoadrenalism (infection, trauma, etc.).
- In a study of patients with Cushing's syndrome, hypokalemia was observed in 44% of subjects during treatment with Mifepristone. Hypokalemia should be corrected prior to initiating Mifepristone. During Mifepristone administration, serum potassium should be measured 1 to 2 weeks after starting or increasing the dose of Mifepristone and periodically thereafter. Hypokalemia can occur at any time during Mifepristone treatment. Mifepristone-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists in spite of potassium supplementation, consider adding mineralocorticoid antagonists.
- Being an antagonist of the progesterone receptor, mifepristone promotes unopposed endometrial proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and vaginal bleeding. Mifepristone should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy. Women who experience vaginal bleeding during Mifepristone treatment should be referred to a gynecologist for further evaluation.
- Mifepristone and its metabolites block IKr. Mifepristone prolongs the QTc interval in a dose-related manner. There is little or no experience with high exposure, concomitant dosing with other QT-prolonging drugs, or potassium channel variants resulting in a long QT interval. To minimize risk, the lowest effective dose should always be used.
- Use of Mifepristone in patients who receive corticosteroids for other conditions (e.g., autoimmune disorders) may lead to exacerbation or deterioration of such conditions, as Mifepristone antagonizes the desired effects of glucocorticoid in these clinical settings. For medical conditions in which chronic corticosteroid therapy is lifesaving (e.g., immunosuppression in organ transplantation), Mifepristone is contraindicated.
- Mifepristone should be used with extreme caution in patients taking ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole, as these could substantially increase the concentration of mifepristone in the blood. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. Mifepristone should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 300 mg per day.
- Patients with endogenous Cushing's syndrome are at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia during Mifepristone treatment. Patients may present with respiratory distress shortly after initiation of Mifepristone. Appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered.
- Mifepristone does not reduce serum cortisol levels. Elevated cortisol levels may activate mineralocorticoid receptors which are also expressed in cardiac tissues. Caution should be used in patients with underlying heart conditions including heart failure and coronary vascular disease.
# Adverse Reactions
## Clinical Trials Experience
- Nausea
- Vomiting
- Dry-mouth
- Diarrhea
- Constipation
- Fatigue
- Peripheral edema
- Pain
- Headache
- Dizziness
- Somnolence
- Arthralgia
- Back pain
- Myalgia
- Pain in Extremity
- Hypokalemia
- Abnormal thyroid function test (High TSH levels)
- Reduction of HDL-C serum levels
- Sinusitis
- Nasopharyngitis
- Decreased appetite
- Anorexia
- Hypertension
- Endometrial Hyperthrophy
- Vaginal Bleeding
- Dyspnea
- Anxiety
## Postmarketing Experience
There is limited information regarding Mifepristone Postmarketing Experience in the drug label.
# Drug Interactions
Based on the long terminal half-life of mifepristone after reaching steady state, at least 2 weeks should elapse after cessation of Mifepristone before initiating or increasing the dose of any interacting concomitant medication.
- Because Mifepristone is an inhibitor of CYP3A, concurrent use of Mifepristone with a drug whose metabolism is largely or solely mediated by CYP3A is likely to result in increased plasma concentrations of the drug. Discontinuation or dose reduction of such medications may be necessary with Mifepristone co-administration.
- Mifepristone increased the exposure to simvastatin and simvastatin acid significantly in healthy subjects. Concomitant use of simvastatin or lovastatin is contraindicated because of the increased risk of myopathy rhabdomyolysis.
- The exposure of other substrates of CYP3A with narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, may be increased by concomitant administration with Mifepristone. Therefore, the concomitant use of such CYP3A substrates with Mifepristone is contraindicated.
- Other drugs with similar high first pass metabolism in which CYP3A is the primary route of metabolism should be used with extreme caution if co-administered with Mifepristone. The lowest possible dose and/or a decreased frequency of dosing must be used with therapeutic drug monitoring when possible. Use of alternative drugs without these metabolic characteristics is advised when possible with concomitant Mifepristone.
If drugs that undergo low first pass metabolism by CYP3A or drugs in which CYP3A is not the major metabolic route are co-administered with Mifepristone, use the lowest dose of concomitant medication necessary, with appropriate monitoring and follow-up.
- Medications that inhibit CYP3A could increase plasma mifepristone concentrations and dose reduction of Mifepristone may be required.
- Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, boceprevir, clarithromycin, conivaptan, lopinavir, mibefradil, posaconazole, saquinavir, telaprevir, telithromycin, or voriconazole may increase exposure to mifepristone significantly. The clinical impact of this interaction has not been studied. Therefore, extreme caution should be used when these drugs are prescribed in combination with Mifepristone. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. The dose of Mifepristone should be limited to 300 mg and used only when necessary.
- Moderate inhibitors of CYP3A, such as amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, or verapamil, should be used with caution when administered in combination with Mifepristone.
- No medications that induce CYP3A have been studied when co-administered with Mifepristone. Avoid co-administration of Mifepristone and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort.
- Because Mifepristone is an inhibitor of CYP2C8/CYP2C9, concurrent use of Mifepristone with a drug whose metabolism is largely or solely mediated by CYP2C8/CYP2C9 is likely to result in increased plasma concentrations of the drug. Mifepristone significantly increased exposure of fluvastatin, a typical CYP2C8/CYP2C9 substrate, in healthy subjects. When given concomitantly with Mifepristone, drugs that are substrates of CYP2C8/CYP2C9 (including non-steroidal anti-inflammatory drugs, warfarin, and repaglinide) should be used at the smallest recommended doses, and patients should be closely monitored for adverse effects.
- Mifepristone is an inhibitor of CYP2B6 and may cause significant increases in exposure of drugs that are metabolized by CYP2B6 such as bupropion and efavirenz. Since no study has been conducted to evaluate the effect of mifepristone on substrates of CYP2B6, the concomitant use of bupropion and efavirenz should be undertaken with caution.
- Mifepristone is a progesterone-receptor antagonist and will interfere with the effectiveness of hormonal contraceptives. Therefore, non-hormonal contraceptive methods should be used.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Contraindicated in pregnancy. Mifepristone can cause fetal harm when administered to a pregnant woman because the use of Mifepristone results in pregnancy loss. The inhibition of both endogenous and exogenous progesterone by mifepristone at the progesterone receptor results in pregnancy loss. If Mifepristone is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mifepristone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Mifepristone during labor and delivery.
### Nursing Mothers
- Mifepristone is present in human milk of women taking the drug. Because of the potential for serious adverse reactions in nursing infants from Mifepristone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of Mifepristone in pediatric patients have not been established.
### Geriatic Use
- Clinical studies with Mifepristone did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger people.
### Gender
There is no FDA guidance on the use of Mifepristone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Mifepristone with respect to specific racial populations.
### Renal Impairment
- The pharmacokinetics of mifepristone in subjects with severe renal impairment (creatinine clearance CrCL < 30 mL/min, but not on dialysis) was evaluated following multiple doses of 1200 mg Mifepristone for 7 days. Mean exposure to mifepristone increased 31%, with similar or smaller increases in metabolite exposure as compared to subjects with normal renal function (CrCL ≥ 90 mL/min). There was large variability in the exposure of mifepristone and its metabolites in subjects with severe renal impairment as compared to subjects with normal renal function (geometric least square mean ratio [CI] for AUC of mifepristone: 1.21 [0.71-2.06]; metabolite 1: 1.43 [0.84-2.44]; metabolite 2: 1.18 [0.64-2.17] and metabolite 3: 1.19 [0.71-1.99]). No change in the initial dose of Mifepristone is needed for renal impairment; the maximum dose should not exceed 600 mg per day.
### Hepatic Impairment
- The pharmacokinetics of mifepristone in subjects with moderate hepatic impairment (Child-Pugh Class B) was evaluated in a single- and multiple-dose study (600 mg for 7 days). The pharmacokinetics in subjects with moderate hepatic impairment was similar to those with normal hepatic function. There was large variability in the exposure of mifepristone and its metabolites in subjects with moderate hepatic impairment as compared to subjects with normal hepatic function (geometric least square mean ratio [CI] for AUC of mifepristone: 1.02 [0.59-1.76]; metabolite 1: 0.95 [0.52-1.71]; metabolite 2: 1.37 [0.71-2.62] and metabolite 3: 0.62 [0.33-1.16]). Due to limited information on safety in patients with mild-to-moderate hepatic impairment, the maximum dose should not exceed 600 mg per day. The pharmacokinetics of mifepristone in patients with severe hepatic disease has not been studied. Mifepristone is not recommended in patients with severe hepatic disease.
### Females of Reproductive Potential and Males
- Due to its anti-progestational activity, Mifepristone causes pregnancy loss. Exclude pregnancy before the initiation of treatment with Mifepristone or if treatment is interrupted for more than 14 days in females of reproductive potential. Recommend contraception for the duration of treatment and for one month after stopping treatment using a non-hormonal medically acceptable method of contraception. If the patient has had surgical sterilization, no additional contraception is needed.
### Immunocompromised Patients
There is no FDA guidance one the use of Mifepristone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
- Adrenal insufficiency: Patients should be closely monitored for signs and symptoms of adrenal insufficiency.
- Hypokalemia: Hypokalemia should be corrected prior to treatment and monitored for during treatment.
# IV Compatibility
There is limited information regarding the compatibility of Mifepristone and IV administrations.
# Overdosage
There is no experience with overdosage
# Pharmacology
## Mechanism of Action
- Mifepristone is a selective antagonist of the progesterone receptor at low doses and blocks the glucocorticoid receptor (GR-II) at higher doses. Mifepristone has high affinity for the GR-II receptor but little affinity for the GR-I (MR, mineralocorticoid) receptor. In addition, mifepristone appears to have little or no affinity for estrogen, muscarinic, histaminic, or monoamine receptors.
## Structure
- The chemical name of mifepristone is 11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4, 9-dien-3-one. The chemical formula is C29H35NO2; the molecular weight is 429.60, and the structural formula is:
## Pharmacodynamics
- Because mifepristone acts at the receptor level to block the effects of cortisol, its antagonistic actions affect the hypothalamic-pituitary-adrenal (HPA) axis in such a way as to further increase circulating cortisol levels while, at the same time, blocking their effects.
- Mifepristone and the three active metabolites have greater affinity for the glucocorticoid receptor (100%, 61%, 48%, and 45%, respectively) than either dexamethasone (23%) or cortisol (9%).
## Pharmacokinetics
- Following oral administration, time to peak plasma concentrations of mifepristone occurred between 1 and 2 hours following single dose, and between 1 and 4 hours following multiple doses of 600 mg of Mifepristone in healthy volunteers. Mean plasma concentrations of three active metabolites of mifepristone peak between 2 and 8 hours after multiple doses of 600 mg/day, and the combined concentrations of the metabolites exceed that of the parent mifepristone. Exposure to mifepristone is substantially less than dose proportional. Time to steady state is within 2 weeks, and the mean (SD) half-life of the parent mifepristone was 85 (61) hours following multiple doses of 600 mg/day of Mifepristone. Studies evaluating the effects of food on the pharmacokinetics of Mifepristone demonstrate a significant increase in plasma levels of mifepristone when dosed with food. To achieve consistent plasma drug concentrations, patients should be instructed to always take their medication with meals.
- Mifepristone is highly bound to alpha-1-acid glycoprotein (AAG) and approaches saturation at doses of 100 mg (2.5 μM) or more. Mifepristone and its metabolites also bind to albumin and are distributed to other tissues, including the central nervous system (CNS). As determined in vitro by equilibrium dialysis, binding of mifepristone and its three active metabolites to human plasma proteins was concentration-dependent. Binding was approximately 99.2% for mifepristone, and ranged from 96.1 to 98.9% for the three active metabolites at clinically relevant concentrations.
- Cytochrome P450 3A4 (CYP3A4) has been shown to be involved in mifepristone metabolism in human liver microsomes. Two of the known active metabolites are the product of demethylation (one monodemethylated and one di-demethylated), while a third active metabolite results from hydroxylation (monohydroxylated).
- Excretion is primarily (approximately 90%) via the fecal route.
## Nonclinical Toxicology
- Mifepristone was evaluated for carcinogenicity potential in rats and mice. Rats were dosed for up to two years at doses of 5, 25, and 125 mg/kg of mifepristone. The high dose was the maximum tolerated dose, but exposure at all doses was below exposure at the maximum clinical dose based on AUC comparison. Female rats had a statistically significant increase in follicular cell adenomas/carcinomas and liver adenomas. It is plausible that these tumors are due to drug-induced enzyme metabolism, a mechanism not considered clinically relevant, but studies confirming this mechanism were not conducted with mifepristone. Mice were also tested for up to 2 years at mifepristone doses up to the maximum tolerated dose of 125 mg/kg, which provided exposure below the maximum clinical dose based on AUC. No drug-related tumors were seen in mice. Mifepristone was not genotoxic in a battery of bacterial, yeast, and mammalian in vitro assays, and an in vivo micronucleus study in mice.
- The pharmacological activity of mifepristone disrupts the estrus cycle of adult rats at a dose of 0.3 mg/kg (less than human exposure at the maximum clinical dose, based on body surface area). However, following withdrawal of treatment and subsequent resumption of the estrus cycle, there was no effect on reproductive function when mated. A single subcutaneous dose of mifepristone (up to 100 mg/kg) to rats on the first day after birth did not adversely affect future reproductive function in males or females, although the onset of puberty was slightly premature in dosed females. Repeated doses of mifepristone (1 mg every other day) to neonatal rats resulted in potentially adverse fertility effects, including oviduct and ovary malformations in females, delayed male puberty, deficient male sexual behavior, reduced testicular size, and lowered ejaculation frequency.
Mifepristone was not genotoxic in a battery of bacterial, yeast, and mammalian in vitro assays, and an in vivo micronucleus study in mice.
- The pharmacological activity of mifepristone disrupts the estrus cycle of adult rats at a dose of 0.3 mg/kg (less than human exposure at the maximum clinical dose, based on body surface area). However, following withdrawal of treatment and subsequent resumption of the estrus cycle, there was no effect on reproductive function when mated.
- A single subcutaneous dose of mifepristone (up to 100 mg/kg) to rats on the first day after birth did not adversely affect future reproductive function in males or females, although the onset of puberty was slightly premature in dosed females. Repeated doses of mifepristone (1 mg every other day) to neonatal rats resulted in potentially adverse fertility effects, including oviduct and ovary malformations in females, delayed male puberty, deficient male sexual behavior, reduced testicular size, and lowered ejaculation frequency.
# Clinical Studies
- Patients in the diabetes cohort underwent standard oral glucose tolerance tests at baseline and periodically during the clinical study. Anti-diabetic medications were allowed but had to be kept stable during the trial and patients had to be on stable anti-diabetic regimens prior to enrollment. The primary efficacy analysis for the diabetes cohort was an analysis of responders. A responder was defined as a patient who had a ≥ 25% reduction from baseline in glucose AUC. The primary efficacy analysis was conducted in the modified intent-to-treat population (n=25) defined as all patients who received a minimum of 30 days on Mifepristone. Fifteen of 25 patients (60%) were treatment responders (95% CI: 39%,78%).
- Mean HbA1c was 7.4% in the 24 patients with HbA1c values at baseline and Week 24. For these 24 patients mean reduction in HbA1c was 1.1% (95% CI -1.6, -0.7) from baseline to the end of the trial. Fourteen of 24 patients had above normal HbA1c levels at baseline, ranging between 6.7% and 10.4%; all of these patients had reductions in HbA1c by the end of the study (range -0.4 to -4.4%) and eight of 14 patients (57%) normalized HbA1c levels at trial end. Antidiabetic medications were reduced in 7 of the 15 DM subjects taking antidiabetic medication and remained constant in the others.
- There were no changes in mean systolic blood pressure and diastolic blood pressures at the end of the trial relative to baseline in the modified intent-to-treat population (n=21).
- Individual patients showed varying degrees of improvement in Cushing's syndrome manifestations such as cushingoid appearance, acne, hirsutism, striae, psychiatric symptoms, and excess total body weight. Because of the variability in clinical presentation and variability of response in this open label trial, it is uncertain whether these changes could be ascribed to the effects of Mifepristone.
# How Supplied
Mifepristone is supplied as a light yellow to yellow, film-coated, oval-shaped tablet debossed with “Corcept” on one side and “300” on the other. Each tablet contains 300 mg of mifepristone. Mifepristone tablets are available in bottles of 28 tablets (NDC 76346-073-01) and bottles of 280 tablets (NDC 76346-073-02).
## Storage
Store at controlled room temperature, 25 °C (77 °F); excursions permitted to 15 to 30 ° C (59 – 86 °F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
As a part of patient counseling, doctors must review the Mifepristone Medication Guide with every patient.
- Advise patients that Mifepristone will cause termination of pregnancy. Mifepristone is contraindicated in pregnant patients.
- Counsel females of reproductive potential regarding pregnancy prevention and planning with a non-hormonal contraceptive prior to use of Mifepristone and up to one month after the end of treatment.
- Instruct patients to contact their physician immediately if they suspect or confirm they are pregnant.
# Precautions with Alcohol
Alcohol-Mifepristone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Myfeprex
- Korlym
# Look-Alike Drug Names
There is limited information regarding Mifepristone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Korlym | |
070fce4204b9b7ef9d33692770394664dce1c950 | wikidoc | Ku (protein) | Ku (protein)
Ku is a dimeric protein complex that binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. Ku is evolutionarily conserved from bacteria to humans. The ancestral bacterial Ku is a homodimer (two copies of the same protein bound to each other). Eukaryotic Ku is a heterodimer of two polypeptides, Ku70 (XRCC6) and Ku80 (XRCC5), so named because the molecular weight of the human Ku proteins is around 70 kDa and 80 kDa. The two Ku subunits form a basket-shaped structure that threads onto the DNA end. Once bound, Ku can slide down the DNA strand, allowing more Ku molecules to thread onto the end. In higher eukaryotes, Ku forms a complex with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the full DNA-dependent protein kinase, DNA-PK. Ku is thought to function as a molecular scaffold to which other proteins involved in NHEJ can bind, orienting the double-strand break for ligation.
The Ku70 and Ku80 proteins consist of three structural domains. The N-terminal domain is an alpha/beta domain. This domain only makes a small contribution to the dimer interface. The domain comprises a six stranded beta sheet of the Rossman fold. The central domain of Ku70 and Ku80 is a DNA-binding beta-barrel domain. Ku makes only a few contacts with the sugar-phosphate backbone, and none with the DNA bases, but it fits sterically to major and minor groove contours forming a ring that encircles duplex DNA, cradling two full turns of the DNA molecule. By forming a bridge between the broken DNA ends, Ku acts to structurally support and align the DNA ends, to protect them from degradation, and to prevent promiscuous binding to unbroken DNA. Ku effectively aligns the DNA, while still allowing access of polymerases, nucleases and ligases to the broken DNA ends to promote end joining. The C-terminal arm is an alpha helical region which embraces the central beta-barrel domain of the opposite subunit. In some cases a fourth domain is present at the C-terminus, which binds to DNA-dependent protein kinase catalytic subunit.
Both subunits of Ku have been experimentally knocked out in mice. These mice exhibit chromosomal instability, indicating that NHEJ is important for genome maintenance.
In many organisms, Ku has additional functions at telomeres in addition to its role in DNA repair.
Abundance of Ku80 seems to be related to species longevity.
# Aging
Mutant mice defective in Ku70, or Ku80, or double mutant mice deficient in both Ku70 and Ku80 exhibit early aging. The mean lifespans of the three mutant mouse strains were similar to each other, at about 37 weeks, compared to 108 weeks for the wild-type control. Six specific signs of aging were examined, and the three mutant mice were found to display the same aging signs as the control mice, but at a much earlier age. Cancer incidence was not increased in the mutant mice. These results suggest that Ku function is important for longevity assurance and that the NHEJ pathway of DNA repair (mediated by Ku) has a key role in repairing DNA double-strand breaks that would otherwise cause early aging. (Also see DNA damage theory of aging.)
# Plants
Ku70 and Ku80 have also been experimentally characterized in plants, where they appear to play a similar role to that in other eukaryotes. In rice, suppression of either protein has been shown to promote homologous recombination (HR) This effect was exploited to improve gene targeting (GT) efficiency in Arabidopsis thaliana. In the study, the frequency of HR-based GT using a zinc-finger nuclease (ZFN) was increased up to sixteen times in ku70 mutants This result has promising implications for genome editing across eukaryotes as DSB repair mechanisms are highly conserved. A substantial difference is that in plants, Ku is also involved in maintaining an alternate telomere morphology characterized by blunt-ends or short (≤ 3-nt) 3’ overhangs. This function is independent of the role of Ku in DSB repair, as removing the ability of the Ku complex to translocate along DNA has been shown to preserve blunt-ended telomeres while impeding DNA repair.
# Name
The name 'Ku' is derived from the surname of the Japanese patient in which it was discovered. | Ku (protein)
Ku is a dimeric protein complex that binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. Ku is evolutionarily conserved from bacteria to humans. The ancestral bacterial Ku is a homodimer (two copies of the same protein bound to each other).[2] Eukaryotic Ku is a heterodimer of two polypeptides, Ku70 (XRCC6) and Ku80 (XRCC5), so named because the molecular weight of the human Ku proteins is around 70 kDa and 80 kDa. The two Ku subunits form a basket-shaped structure that threads onto the DNA end.[1] Once bound, Ku can slide down the DNA strand, allowing more Ku molecules to thread onto the end. In higher eukaryotes, Ku forms a complex with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the full DNA-dependent protein kinase, DNA-PK.[3] Ku is thought to function as a molecular scaffold to which other proteins involved in NHEJ can bind, orienting the double-strand break for ligation.
The Ku70 and Ku80 proteins consist of three structural domains. The N-terminal domain is an alpha/beta domain. This domain only makes a small contribution to the dimer interface. The domain comprises a six stranded beta sheet of the Rossman fold.[4] The central domain of Ku70 and Ku80 is a DNA-binding beta-barrel domain. Ku makes only a few contacts with the sugar-phosphate backbone, and none with the DNA bases, but it fits sterically to major and minor groove contours forming a ring that encircles duplex DNA, cradling two full turns of the DNA molecule. By forming a bridge between the broken DNA ends, Ku acts to structurally support and align the DNA ends, to protect them from degradation, and to prevent promiscuous binding to unbroken DNA. Ku effectively aligns the DNA, while still allowing access of polymerases, nucleases and ligases to the broken DNA ends to promote end joining.[5] The C-terminal arm is an alpha helical region which embraces the central beta-barrel domain of the opposite subunit.[1] In some cases a fourth domain is present at the C-terminus, which binds to DNA-dependent protein kinase catalytic subunit.[6]
Both subunits of Ku have been experimentally knocked out in mice. These mice exhibit chromosomal instability, indicating that NHEJ is important for genome maintenance.[7][8]
In many organisms, Ku has additional functions at telomeres in addition to its role in DNA repair.[9]
Abundance of Ku80 seems to be related to species longevity.[10]
# Aging
Mutant mice defective in Ku70, or Ku80, or double mutant mice deficient in both Ku70 and Ku80 exhibit early aging.[11] The mean lifespans of the three mutant mouse strains were similar to each other, at about 37 weeks, compared to 108 weeks for the wild-type control. Six specific signs of aging were examined, and the three mutant mice were found to display the same aging signs as the control mice, but at a much earlier age. Cancer incidence was not increased in the mutant mice. These results suggest that Ku function is important for longevity assurance and that the NHEJ pathway of DNA repair (mediated by Ku) has a key role in repairing DNA double-strand breaks that would otherwise cause early aging.[12] (Also see DNA damage theory of aging.)
# Plants
Ku70 and Ku80 have also been experimentally characterized in plants, where they appear to play a similar role to that in other eukaryotes. In rice, suppression of either protein has been shown to promote homologous recombination (HR)[13] This effect was exploited to improve gene targeting (GT) efficiency in Arabidopsis thaliana. In the study, the frequency of HR-based GT using a zinc-finger nuclease (ZFN) was increased up to sixteen times in ku70 mutants[14] This result has promising implications for genome editing across eukaryotes as DSB repair mechanisms are highly conserved. A substantial difference is that in plants, Ku is also involved in maintaining an alternate telomere morphology characterized by blunt-ends or short (≤ 3-nt) 3’ overhangs.[15] This function is independent of the role of Ku in DSB repair, as removing the ability of the Ku complex to translocate along DNA has been shown to preserve blunt-ended telomeres while impeding DNA repair.[16]
# Name
The name 'Ku' is derived from the surname of the Japanese patient in which it was discovered.[17] | https://www.wikidoc.org/index.php/Ku_(protein) | |
cad59053abf985d5d23da974bff205842886d271 | wikidoc | Kunjin virus | Kunjin virus
# Overview
Kunjin virus (KUNV) is a zoonotic virus of the family Flaviviridae and the genus Flavivirus. It is a subtype of West Nile virus endemic to Oceania.
# History
The virus was first isolated from Culex annulirostris mosquitoes in Australia in 1960.
The name of Kunjin virus derives from an Aboriginal clan living on the Mitchell River close to where the virus was first isolated in Kowanyama, northern Queensland.
# Virology
Kunjin virus is a zoonotic virus of the family Flaviviridae and the genus Flavivirus. It is an arbovirus which is transmitted by mosquitoes and is part of the Japanese encephalitis serological complex. It is antigenically and genetically very similar to West Nile virus and in 1999 was reclassified as a subtype of WNV. Its genome is positive-sense single stranded RNA made up of 10,644 nucleotides.
# Symptoms and Prognosis
Infection with the virus often causes no symptoms, but it can lead to either an encephalitic disease or a non-encephalitic disease. Non-encephalitic Kunjin virus disease can cause symptoms including acute febrile illness, headache, arthralgia, myalgia, fatigue and rash. Kunjin virus encephalitis features acute febrile meningoencephalitis.
Both forms of Kunjin virus disease are milder than the diseases caused by West Nile virus and Murray Valley encephalitis virus.
# Transmission and control
Kunjin virus is transmitted by mosquito vectors, especially the Culex annulirostris. They pass the virus to waterbird reservoir hosts; a major example is the nankeen night heron. It is also passed to horses and humans. The virus been isolated in mosquitoes in South East Asia but in humans, only in Australia. It has been found all over Australia and is particularly prevalent in areas near wetlands and rivers.
The control of Kunjin virus is achieved in the same ways as other mosquito-borne diseases. These include individuals using insect repellent, wearing long-sleeved clothes and avoiding areas where mosquitoes are particularly prevalent. Habitat control by government agencies can take the form of reducing the amount of water available for mosquitoes to breed in, and the use of insecticides. There is no available vaccine against Kunjin virus.
# Use in medicine
In 2005, scientists at the Queensland Institute of Medical Research and the University of Queensland found that modified Kunjin virus particles injected into mice were able to deliver a gene into the immune system targeting cancer cells. This research may lead to vaccines for cancer and HIV. | Kunjin virus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Kunjin virus (KUNV) is a zoonotic virus of the family Flaviviridae and the genus Flavivirus. It is a subtype of West Nile virus endemic to Oceania.
# History
The virus was first isolated from Culex annulirostris mosquitoes in Australia in 1960.[1][2]
The name of Kunjin virus derives from an Aboriginal clan living on the Mitchell River close to where the virus was first isolated in Kowanyama, northern Queensland.[1][3]
# Virology
Kunjin virus is a zoonotic virus of the family Flaviviridae and the genus Flavivirus. It is an arbovirus which is transmitted by mosquitoes and is part of the Japanese encephalitis serological complex.[4] It is antigenically and genetically very similar to West Nile virus and in 1999 was reclassified as a subtype of WNV.[3][5] Its genome is positive-sense single stranded RNA made up of 10,644 nucleotides.[3][4]
# Symptoms and Prognosis
Infection with the virus often causes no symptoms, but it can lead to either an encephalitic disease or a non-encephalitic disease.[6] Non-encephalitic Kunjin virus disease can cause symptoms including acute febrile illness, headache, arthralgia, myalgia, fatigue and rash.[1][6] Kunjin virus encephalitis features acute febrile meningoencephalitis.[1]
Both forms of Kunjin virus disease are milder than the diseases caused by West Nile virus and Murray Valley encephalitis virus.[5][6]
# Transmission and control
Kunjin virus is transmitted by mosquito vectors, especially the Culex annulirostris.[3] They pass the virus to waterbird reservoir hosts; a major example is the nankeen night heron.[3] It is also passed to horses and humans.[7] The virus been isolated in mosquitoes in South East Asia but in humans, only in Australia.[6] It has been found all over Australia and is particularly prevalent in areas near wetlands and rivers.[8]
The control of Kunjin virus is achieved in the same ways as other mosquito-borne diseases. These include individuals using insect repellent, wearing long-sleeved clothes and avoiding areas where mosquitoes are particularly prevalent.[1] Habitat control by government agencies can take the form of reducing the amount of water available for mosquitoes to breed in, and the use of insecticides.[9] There is no available vaccine against Kunjin virus.[1]
# Use in medicine
In 2005, scientists at the Queensland Institute of Medical Research and the University of Queensland found that modified Kunjin virus particles injected into mice were able to deliver a gene into the immune system targeting cancer cells.[10][11] This research may lead to vaccines for cancer and HIV.[10][11] | https://www.wikidoc.org/index.php/Kunjin_virus | |
e608c80fb2105664fe4f70d091497ad3231cdc04 | wikidoc | Kupffer cell | Kupffer cell
# Overview
Kupffer cells, also known as Browicz-Kupffer cells, are specialized macrophages located in the liver that form part of the reticuloendothelial system (aka: mononuclear phagocyte system). The cells were first observed by Karl Wilhelm von Kupffer in 1876. The scientist called them "sternzellen" (star cells or stellate cells) but thought falsely that they were an integral part of the endothelium of the liver blood vessels and that they originated from it. In 1898, after several years of research, Tadeusz Browicz, a polish sciencist, identified them correctly as macrophages.
Their development begins in the bone marrow with the genesis of promonocytes and monoblasts into monocytes and then on to peripheral blood monocytes completing their differentiation into Kupffer cells.
The primary function of Kupffer cells is to recycle old red blood cells that no longer are functional. The red blood cell is broken down by phagocytic action and the hemoglobin molecule is split. The globin chains are reutilized while the iron containing portion or heme is further broken down into iron which is reutilized and bilirubin, which is conjugated with glucuronic acid within hepatocytes and secreted into the bile.
Helmy et al. identified a receptor present in Kupffer cells, the complement receptor of the immunoglobulin family (CRIg). Mice without CRIg could not clear complement system-coated pathogens. CRIg is conserved in mice and humans and is a critical component of the innate immune system. | Kupffer cell
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Kupffer cells, also known as Browicz-Kupffer cells, are specialized macrophages located in the liver that form part of the reticuloendothelial system (aka: mononuclear phagocyte system). The cells were first observed by Karl Wilhelm von Kupffer in 1876.[1] The scientist called them "sternzellen" (star cells or stellate cells) but thought falsely that they were an integral part of the endothelium of the liver blood vessels and that they originated from it. In 1898, after several years of research, Tadeusz Browicz, a polish sciencist, identified them correctly as macrophages. [2][3]
Their development begins in the bone marrow with the genesis of promonocytes and monoblasts into monocytes and then on to peripheral blood monocytes completing their differentiation into Kupffer cells.[4]
The primary function of Kupffer cells is to recycle old red blood cells that no longer are functional. The red blood cell is broken down by phagocytic action and the hemoglobin molecule is split. The globin chains are reutilized while the iron containing portion or heme is further broken down into iron which is reutilized and bilirubin, which is conjugated with glucuronic acid within hepatocytes and secreted into the bile.
Helmy et al. identified a receptor present in Kupffer cells, the complement receptor of the immunoglobulin family (CRIg). Mice without CRIg could not clear complement system-coated pathogens. CRIg is conserved in mice and humans and is a critical component of the innate immune system.[5] | https://www.wikidoc.org/index.php/Kupffer_cell | |
1ca3634dcf1f6bd0b44b116fb018ada993d1647d | wikidoc | Kynureninase | Kynureninase
Kynureninase or L-Kynurenine hydrolase (KYNU) (EC 3.7.1.3) is a PLP dependent enzyme that catalyses the cleavage of kynurenine (Kyn) into anthranilic acid (Ant). It can also act on 3hKyn (to produce 3hAnt) and some other (3-arylcarbonyl)-alanines. Humans express one kynureninase enzyme that is encoded by the KYNU gene located on chromosome 2.
KYNU is part of the pathway for the catabolism of Trp and the biosynthesis of NAD cofactors from tryptophan (Trp).
Kynureninase catalyzes the following reaction:
- L-kynurenine + H2O = anthranilate + L-alanine
# Structure
Kynureninase belongs to the class V group of aspartate aminotransferase superfamily of structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes. To date, two structures of human kynureninase have determined by X-ray diffraction with resolutions of 2.0 and 1.7 Å. Forty percent of the amino acids are arranged in an alpha helical and twelve percent are arranged in beta sheets. Docking of the kynurenine substrate into the active site suggests that Asn-333 and His-102 are involved in substrate binding.
# Function
In KYNU reaction, PLP facilitates Cβ-Cγ bond cleavage. The reaction follows the same steps as the transamination reaction but does not hydrolyze the tautomerized Schiff base. The proposed reaction mechanism involves an attack of an enzyme nucleophile on the carbonyl carbon (Cγ) of the tautomerized 3hKyn-PLP Schiff base. This is followed by Cβ-Cγ bond cleavage to generate an acyl-enzyme intermediate together with a tautomerized Ala-PLP adduct. Hydrolysis of the acyl-enzyme then yields 3hAnt. | Kynureninase
Kynureninase or L-Kynurenine hydrolase (KYNU) (EC 3.7.1.3) is a PLP dependent enzyme that catalyses the cleavage of kynurenine (Kyn) into anthranilic acid (Ant). It can also act on 3hKyn (to produce 3hAnt) and some other (3-arylcarbonyl)-alanines. Humans express one kynureninase enzyme that is encoded by the KYNU gene located on chromosome 2.[2][3]
KYNU is part of the pathway for the catabolism of Trp and the biosynthesis of NAD cofactors from tryptophan (Trp).
Kynureninase catalyzes the following reaction:
- L-kynurenine + H2O = anthranilate + L-alanine
# Structure
Kynureninase belongs to the class V group of aspartate aminotransferase superfamily of structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes. To date, two structures of human kynureninase have determined by X-ray diffraction with resolutions of 2.0 and 1.7 Å.[1][4] Forty percent of the amino acids are arranged in an alpha helical and twelve percent are arranged in beta sheets. Docking of the kynurenine substrate into the active site suggests that Asn-333 and His-102 are involved in substrate binding.[1]
# Function
In KYNU reaction, PLP facilitates Cβ-Cγ bond cleavage. The reaction follows the same steps as the transamination reaction but does not hydrolyze the tautomerized Schiff base. The proposed reaction mechanism involves an attack of an enzyme nucleophile on the carbonyl carbon (Cγ) of the tautomerized 3hKyn-PLP Schiff base. This is followed by Cβ-Cγ bond cleavage to generate an acyl-enzyme intermediate together with a tautomerized Ala-PLP adduct. Hydrolysis of the acyl-enzyme then yields 3hAnt. | https://www.wikidoc.org/index.php/Kynureninase | |
01cc656adce1a254f85156cc2276d37c86a62e3e | wikidoc | L1 (protein) | L1 (protein)
L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200-220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.
Mutations in the L1 protein are the cause of three neurological syndromes known by the acronym CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus).
# Tissue and cellular distribution
L1 protein is located all over the nervous system on the surface of neurons. It is placed along the cellular membrane so that one end of the protein remains inside the nerve cell while the other end stays on the outer surface of the neurone. This position allows the protein to activate chemical signals which spread through the neurone.
There are a wide variety of cells which express the protein L1, not only neuronal cells but also some non-neuronal ones. Cells which are known nowadays to express the protein L1 are: immature oligodendrocytes and Schwann cells, which are non-neuronal cells that provide support and protection for neurons and form myelin; T cells which are lymphocytes involved in cell-mediated immunity; other types of lymphocytes such as B cells and Monocytes. It is also expressed in intestinal epithelial progenitor cells, cerebellum neurons such as Cerebellum granule cell and Purkinje cells. Finally, it is expressed in multiple tumor cells for example Melanoma and lung carcinoma cells.
# Gene
The human L1CAM gene is found in X chromosome regions that are implicated in different neuromuscular diseases, and near the one associated with mental retardation. L1CAM gene is located in the long arm of X chromosome in Xq28 position.
# Structure
The L1 cell adhesion molecule (L1CAM) is a cell surface glycoprotein found in humans (and other forms of life as mice, for example) which has a 1253 amino acid protein sequence. The extracellular portion is formed of six immunoglobulin domains followed by five fibronectin type III domains which are connected to a small intracellular domain by a transmembrane helix. The human protein is very similar to the one that is found in mice (they are 92% identical at amino acid level, this enabling the scientists to study its structure. There are other CAM proteins like Ng-CAM (found in chicken) which has lower similarities to the human one (they are 40% identical at the amino acid level). The comparative of the sequences from human, mouse, chick and Drosophila and its good conservation, indicates that the L1 immunoglobulin domain 2 and fibronectin type III domain 2 probably are functionally important.
# Function
L1 is an important protein for the development of the nervous system affecting both cell adhesion and motility.
## Cell adhesion
L1 has a static function as a cell adhesion molecule which connects different cells. It is involved in the adhesion between neurons and in the growth and association of neurites called neurite fasciculation.
## Cell motility
Motility promoting functions are related to the regulation of the movement of nerve cells during neural development. L1 is present in developing neurons and plays an important role in guiding new neurons into the correct positions and helping axons grow and make connections with other neurons. L1 is also involved in synaptic plasticity, which is the ability of synapses to strengthen or weaken, and it also plays a role in regeneration after trauma.
Some studies have proved that L1 has a role in tumor growth, tumor cell invasion, metastasis of melanoma, ovarian and collon cancer due to an overexpression of the protein L1 that improves cell motion of the malignant cells.
The domains of this protein promote homophilic interactions, where adhesion molecules on one cell interact with identical molecules on the other cell. And also heterophilic interactions, where an adhesion molecule on one cell works as a receptor that connects with a different molecule on the other cell. These interactions promote cell adhesion and regulation of signal transduction.
In addition, L1 participates in myelination processes, which are involved in the proliferation of myelin through the nervous system (specifically the progressive myelination of nerve axon fibers), by mediating the elongation of Schwann cells along the axon.
## Nervous system
L1 is involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, cerebellar granule cell migration, neurite outgrowth on Schwann cells and interactions among epithelial cells of intestinal crypts. As a consequence, mutations in the L1CAM gene cause the Nervous System to malfunction. The main disorders linked to this mutation are known by the acronym CRASH or can be also referred as L1 syndrome. This includes disorders such as HSAS, MASA syndrome, agenesis of the corpus callosum and spastic paraplegia. Lower limb spasticity, mental retardation, hydrocephalus and flexion deformity of the thumbs are some of the symptoms expressed mostly in male individuals who suffer from this condition. Although the pathological mechanisms leading to L1syndrome are still unknown, about 200 mutations of the L1CAM gene have been identified and then associated with the syndrom. These mutations mostly affect structurally important key residues in the extracellular region of L1 causing alterations in the protein binding properties, which correlate to the impairment of neuronal physiological mechanisms such as cell adhesion or specific interacting with other molecules. Ankyrin interaction with L1CAM is an example of a protein binding that fails in CRASH patients due to a mutation that causes leucine and histidine to replace serine and tyrosine respectively, in the SFIGQY motif, where aknkyrin should be binded in the L1CAM family cytoplasmic terminus. Ankyrin-L1CAM interaction is involved in the growth cone initiation, consequently, a failure in this interaction causes neurites to not reach synaptic target.
Furthermore, evidence shows there is a correlation between fetal alcohol spectrum disorder and L1 protein since ethanol inhibits L1-mediated adhesion and neurite outgrowth. Hirschsprung's disease has also been linked to a L1CAM malfunction.
# Transcription and synthesis
The gene that regulates L1CAM transcription is found in chromosome X. The L1CAM gene is 24,657 bp in length, and is made up of 28 exons. The alternative splicing of this gene leads to multiple transcript variants (there are 7 different transcripts of the gene), including some that have an alternate exon that is considered to be specific to neurons. L1 transcription is known to take place in human fetal brain and in neuroblastoma and retinoblastoma cell lines. L1 is also expressed in the rhabdomyosarcoma cell lines RD and A-204. Two forms of L1 can be found in humans, with the difference that one has a 12-bp cytoplasmic segment and the other lacks of it. The regulation of L1CAM expression in transcription is not fully comprehended. Two sites were verified in endometrial carcinoma cell lines and seem to be used in a specific manner depending of the cell type. There are two transcription beginning sites, located in two different exons (in front of a non-translated exon 0 and next to the first protein-coding exon 1). SLUG (SNAI2), a transcription factor, upregulates the expression of L1CAM.
# Sequences and different isoforms
L1CAM has three different isoforms, that differ in their amino acid sequency, because of alternative splicing (a process that allows obtaining different mRNA mature molecules from one primary transcript of mRNA). L1CAM isoform 1 is known as the canonical sequence. The main difference between them is where they can be found, for example, the full-length isoform (isoform 1), is the one usually found in neural cells, while the short one or nonneural isoform (isoform 2), is predominant in the other cell types.
# Interactions
L1 (protein) has been shown to interact with NUMB.
## Ig-like domain interactions
L1CAM is capable of folding into a horseshoe configuration by the establishment of homophilic interactions within Ig-like domains of the same protein (the first and the second Ig motifs folding back onto the 4th and 3rd motifs). This conformation is essential for L1CAM being able to interact with other molecules and subsequently performing some of its most important functions.
Ig-like domains are implicated in many homophilic interactions with other L1CAM proteins located in adjacent cells. L1CAM molecules interact via the Ig (1-4)-like domains, allowing cell to cell adhesion. They are also important in the formation of heterophilic interactions with NCAM, TAG-1, F11 and receptor tyrosine kinases (specially during the development of the nervous system).
The six Ig motif of the L1 protein contains an Arg-Gly-Asp sequence which allows binding with diverse surface cell integrins. This interaction leads to a signaling cascade which activates focal adhesion kinases (FAK) which are then converted to its active state and form the FAK/SRC complex. The latest functions as an activator of mitogen-activated protein kinases. Another function derived from integrin binding is the activation of NF-κB which results in making cells more motile and invasive.
## Fibronectin domain interactions
Fibronectin domains of L1 protein are also capable of binding cell surface integrins. They interact with fibroblast growth factor receptor 1, which suggests it may be linked to the modulating of neuronal differentiation.
## Cytoplasmic tail interactions
The most important binding partners of the cytoplasmic tail of L1 proteins are ankyrins. The interaction is held in high-affinity binding sites located within the so-called “ank repeats” also known as membrane-binding domains. This interaction allows L1 protein connect with the cell's cytoskeleton. Also, L1 protein cytoplasmic tail can bind adaptor 2 (ADP), a key component pf clathrin mediated endocytosis.
The fact this region contains some phosphorylation sites suggests L1 may be subject to regulation by kinases.
# Implications in cancer metastasis
L1CAM protein expression is normally restricted to neurons. However, it has been noticed there's L1CAM overexpression in all types of cancer cells, which has been associated with poor prognosis, tumor progression and metastasis. This up-regulation may not be necessarily associated with mutations in L1 transcription factors. It has been seen this protein plays a key role in inflammatory reactions as the one's taking place in the tissue surrounding a tumor. This could explain why this protein gets suddenly overproduced in tumor cells. L1CAM's diverse functions make tumor cells more aggressive and resistant. Their migratory and motility related functions may result key in cell epithelial–mesenchymal transition (EMT) allowing cells to lose cell to cell static junctions and apico-basal polarity leading to them becoming migratory and independent. Also, its capacity to form adhesive interactions within different cell types may result in an advantage for tumor cells when it comes to co-opt and invade the surrounding tissues or capillaries.
Once tumor cells become anchorage-independent and migratory, due to L1 up-regulation, they leave the tissue where they belong and migrate through the capillaries to other organs. One frequent destination of tumor cells is the brain. So to settle in the brain, tumor cells have to succeed in crossing the blood brain barrier (BBB) where they get exposed to the plasmin secreted by astrocytes. Plasmin breaks L1CAM and inhibits the malignant cell's migrating powers. However, recent studies have noted these cancer cells overproduce anti-PA serpins, which are the usual inhibitors of plasmin, allowing them to cross the BBB and succeed in metastasis.
# Possible therapies involving L1CAM
Because L1CAM is considered to be a key factor in metastasis, it has been suggested that blocking this protein may inhibit cancer cells migration and tumor progression. Antibody therapy directed against L1CAM in mice models of cancer block tumor growth but enhance EMT. Liposome-encapsulated small interfering RNA has also proved to be an effective inhibitor for L1CAM expression as its function is to degrade a specific range of mRNA base pairs (in this case, the ones encoding for L1CAM sequence of amino acids) after transcription, so that the protein cannot be synthetised. Nevertheless, these possible therapies involving L1CAM as a target in human cancer are still in preclinical research. | L1 (protein)
L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200-220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation.[1] It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.
Mutations in the L1 protein are the cause of three neurological syndromes known by the acronym CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus).[2]
# Tissue and cellular distribution
L1 protein is located all over the nervous system on the surface of neurons. It is placed along the cellular membrane so that one end of the protein remains inside the nerve cell while the other end stays on the outer surface of the neurone. This position allows the protein to activate chemical signals which spread through the neurone.[3]
There are a wide variety of cells which express the protein L1, not only neuronal cells but also some non-neuronal ones. Cells which are known nowadays to express the protein L1 are: immature oligodendrocytes and Schwann cells, which are non-neuronal cells that provide support and protection for neurons and form myelin; T cells which are lymphocytes involved in cell-mediated immunity; other types of lymphocytes such as B cells and Monocytes. It is also expressed in intestinal epithelial progenitor cells, cerebellum neurons such as Cerebellum granule cell and Purkinje cells. Finally, it is expressed in multiple tumor cells for example Melanoma and lung carcinoma cells.[1]
# Gene
The human L1CAM gene is found in X chromosome regions that are implicated in different neuromuscular diseases, and near the one associated with mental retardation. L1CAM gene is located in the long arm of X chromosome in Xq28 position.[4][5]
# Structure
The L1 cell adhesion molecule (L1CAM) is a cell surface glycoprotein found in humans (and other forms of life as mice, for example) which has a 1253 amino acid protein sequence. The extracellular portion is formed of six immunoglobulin domains followed by five fibronectin type III domains which are connected to a small intracellular domain by a transmembrane helix. The human protein is very similar to the one that is found in mice (they are 92% identical at amino acid level, this enabling the scientists to study its structure. There are other CAM proteins like Ng-CAM (found in chicken) which has lower similarities to the human one (they are 40% identical at the amino acid level). The comparative of the sequences from human, mouse, chick and Drosophila and its good conservation, indicates that the L1 immunoglobulin domain 2 and fibronectin type III domain 2 probably are functionally important.[6][7]
# Function
L1 is an important protein for the development of the nervous system affecting both cell adhesion and motility.
## Cell adhesion
L1 has a static function as a cell adhesion molecule which connects different cells. It is involved in the adhesion between neurons and in the growth and association of neurites called neurite fasciculation.[8]
## Cell motility
Motility promoting functions are related to the regulation of the movement of nerve cells during neural development. L1 is present in developing neurons and plays an important role in guiding new neurons into the correct positions and helping axons grow and make connections with other neurons. L1 is also involved in synaptic plasticity, which is the ability of synapses to strengthen or weaken, and it also plays a role in regeneration after trauma.
Some studies have proved that L1 has a role in tumor growth, tumor cell invasion, metastasis of melanoma, ovarian and collon cancer [9] due to an overexpression of the protein L1 that improves cell motion of the malignant cells.
The domains of this protein promote homophilic interactions, where adhesion molecules on one cell interact with identical molecules on the other cell. And also heterophilic interactions, where an adhesion molecule on one cell works as a receptor that connects with a different molecule on the other cell.[10][11] These interactions promote cell adhesion and regulation of signal transduction.
In addition, L1 participates in myelination processes, which are involved in the proliferation of myelin through the nervous system (specifically the progressive myelination of nerve axon fibers), by mediating the elongation of Schwann cells along the axon.
## Nervous system
L1 is involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, cerebellar granule cell migration, neurite outgrowth on Schwann cells and interactions among epithelial cells of intestinal crypts.[12] As a consequence, mutations in the L1CAM gene cause the Nervous System to malfunction. The main disorders linked to this mutation are known by the acronym CRASH or can be also referred as L1 syndrome. This includes disorders such as HSAS, MASA syndrome, agenesis of the corpus callosum and spastic paraplegia. Lower limb spasticity, mental retardation, hydrocephalus and flexion deformity of the thumbs are some of the symptoms expressed mostly in male individuals who suffer from this condition.[13][14][15] Although the pathological mechanisms leading to L1syndrome are still unknown, about 200 mutations of the L1CAM gene have been identified and then associated with the syndrom. These mutations mostly affect structurally important key residues in the extracellular region of L1 causing alterations in the protein binding properties, which correlate to the impairment of neuronal physiological mechanisms such as cell adhesion or specific interacting with other molecules.[16] Ankyrin interaction with L1CAM is an example of a protein binding that fails in CRASH patients[17] due to a mutation that causes leucine and histidine to replace serine and tyrosine respectively, in the SFIGQY motif, where aknkyrin should be binded in the L1CAM family cytoplasmic terminus.[18][19] Ankyrin-L1CAM interaction is involved in the growth cone initiation, consequently, a failure in this interaction causes neurites to not reach synaptic target.
Furthermore, evidence shows there is a correlation between fetal alcohol spectrum disorder and L1 protein since ethanol inhibits L1-mediated adhesion and neurite outgrowth.[20] Hirschsprung's disease has also been linked to a L1CAM malfunction.[21]
# Transcription and synthesis
The gene that regulates L1CAM transcription is found in chromosome X. The L1CAM gene is 24,657 bp in length, and is made up of 28 exons. The alternative splicing of this gene leads to multiple transcript variants (there are 7 different transcripts of the gene),[22] including some that have an alternate exon that is considered to be specific to neurons.[23] L1 transcription is known to take place in human fetal brain and in neuroblastoma and retinoblastoma cell lines. L1 is also expressed in the rhabdomyosarcoma cell lines RD and A-204. Two forms of L1 can be found in humans, with the difference that one has a 12-bp cytoplasmic segment and the other lacks of it.[24] The regulation of L1CAM expression in transcription is not fully comprehended. Two sites were verified in endometrial carcinoma cell lines and seem to be used in a specific manner depending of the cell type. There are two transcription beginning sites, located in two different exons (in front of a non-translated exon 0 and next to the first protein-coding exon 1).[25] SLUG (SNAI2), a transcription factor, upregulates the expression of L1CAM.[26]
# Sequences and different isoforms
L1CAM has three different isoforms, that differ in their amino acid sequency, because of alternative splicing (a process that allows obtaining different mRNA mature molecules from one primary transcript of mRNA). L1CAM isoform 1 is known as the canonical sequence.[27] The main difference between them is where they can be found, for example, the full-length isoform (isoform 1), is the one usually found in neural cells, while the short one or nonneural isoform (isoform 2), is predominant in the other cell types.[28]
# Interactions
L1 (protein) has been shown to interact with NUMB.[30]
## Ig-like domain interactions
L1CAM is capable of folding into a horseshoe configuration by the establishment of homophilic interactions within Ig-like domains of the same protein (the first and the second Ig motifs folding back onto the 4th and 3rd motifs). This conformation is essential for L1CAM being able to interact with other molecules and subsequently performing some of its most important functions.
Ig-like domains are implicated in many homophilic interactions with other L1CAM proteins located in adjacent cells. L1CAM molecules interact via the Ig (1-4)-like domains, allowing cell to cell adhesion. They are also important in the formation of heterophilic interactions with NCAM, TAG-1, F11 and receptor tyrosine kinases (specially during the development of the nervous system).
The six Ig motif of the L1 protein contains an Arg-Gly-Asp sequence which allows binding with diverse surface cell integrins. This interaction leads to a signaling cascade which activates focal adhesion kinases (FAK) which are then converted to its active state and form the FAK/SRC complex. The latest functions as an activator of mitogen-activated protein kinases. Another function derived from integrin binding is the activation of NF-κB which results in making cells more motile and invasive.[1]
## Fibronectin domain interactions
Fibronectin domains of L1 protein are also capable of binding cell surface integrins. They interact with fibroblast growth factor receptor 1, which suggests it may be linked to the modulating of neuronal differentiation.[1]
## Cytoplasmic tail interactions
The most important binding partners of the cytoplasmic tail of L1 proteins are ankyrins. The interaction is held in high-affinity binding sites located within the so-called “ank repeats” also known as membrane-binding domains.[1] This interaction allows L1 protein connect with the cell's cytoskeleton. Also, L1 protein cytoplasmic tail can bind adaptor 2 (ADP), a key component pf clathrin mediated endocytosis.
The fact this region contains some phosphorylation sites suggests L1 may be subject to regulation by kinases.[1]
# Implications in cancer metastasis
L1CAM protein expression is normally restricted to neurons. However, it has been noticed there's L1CAM overexpression in all types of cancer cells, which has been associated with poor prognosis, tumor progression and metastasis.[31] This up-regulation may not be necessarily associated with mutations in L1 transcription factors. It has been seen this protein plays a key role in inflammatory reactions as the one's taking place in the tissue surrounding a tumor. This could explain why this protein gets suddenly overproduced in tumor cells. L1CAM's diverse functions make tumor cells more aggressive and resistant. Their migratory and motility related functions may result key in cell epithelial–mesenchymal transition (EMT) allowing cells to lose cell to cell static junctions and apico-basal polarity leading to them becoming migratory and independent. Also, its capacity to form adhesive interactions within different cell types may result in an advantage for tumor cells when it comes to co-opt and invade the surrounding tissues or capillaries.
Once tumor cells become anchorage-independent and migratory, due to L1 up-regulation, they leave the tissue where they belong and migrate through the capillaries to other organs. One frequent destination of tumor cells is the brain. So to settle in the brain, tumor cells have to succeed in crossing the blood brain barrier (BBB) where they get exposed to the plasmin secreted by astrocytes. Plasmin breaks L1CAM and inhibits the malignant cell's migrating powers. However, recent studies have noted these cancer cells overproduce anti-PA serpins, which are the usual inhibitors of plasmin, allowing them to cross the BBB and succeed in metastasis.[31]
# Possible therapies involving L1CAM
Because L1CAM is considered to be a key factor in metastasis, it has been suggested that blocking this protein may inhibit cancer cells migration and tumor progression. Antibody therapy directed against L1CAM in mice models of cancer block tumor growth but enhance EMT.[32] Liposome-encapsulated small interfering RNA has also proved to be an effective inhibitor for L1CAM expression as its function is to degrade a specific range of mRNA base pairs (in this case, the ones encoding for L1CAM sequence of amino acids) after transcription, so that the protein cannot be synthetised.[33] Nevertheless, these possible therapies involving L1CAM as a target in human cancer are still in preclinical research.[34] | https://www.wikidoc.org/index.php/L1_(protein) | |
79a21849aead4a4026c65955d179eba8cfc5d98b | wikidoc | LDL receptor | LDL receptor
The Low-Density Lipoprotein (LDL) Receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100, which is embedded in the outer phospholipid layer of LDL particles. The receptor also recognizes the apoE protein found in chylomicron remnants and VLDL remnants (IDL). In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. It belongs to the Low density lipoprotein receptor gene family. It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.
Michael S. Brown and Joseph L. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine for their identification of LDL-R and its relation to cholesterol metabolism and familial hypercholesterolemia. The LDLR gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
# Structure
## Gene
The LDLR gene resides on chromosome 19 at the band 19p13.2 and is split into 18 exons. Exon 1 contains a signal sequence that localises the receptor to the endoplasmic reticulum for transport to the cell surface. Beyond this, exons 2-6 code the ligand binding region; 7-14 code the epidermal growth factor (EGF) domain; 15 codes the oligosaccharide rich region; 16 (and some of 17) code the membrane spanning region; and 18 (with the rest of 17) code the cytosolic domain.
This gene produces 6 isoforms through alternative splicing.
## Protein
This protein belongs to the LDLR family and is made up of a number of functionally distinct domains, including 3 EGF-like domains, 7 LDL-R class A domains, and 6 LDL-R class B repeats.
The N-terminal domain of the LDL receptor, which is responsible for ligand binding, is composed of seven sequence repeats (~50% identical). Each repeat, referred to as a class A repeat or LDL-A, contains roughly 40 amino acids, including 6 cysteine residues that form disulfide bonds within the repeat. Additionally, each repeat has highly conserved acidic residues which it uses to coordinate a single calcium ion in an octahedral lattice. Both the disulfide bonds and calcium coordination are necessary for the structural integrity of the domain during the receptor's repeated trips to the highly acidic interior of the endosome. The exact mechanism of interaction between the class A repeats and ligand (LDL) is unknown, but it is thought that the repeats act as "grabbers" to hold the LDL. Binding of ApoB requires repeats 2-7 while binding ApoE requires only repeat 5 (thought to be the ancestral repeat).
Next to the ligand binding domain is an EGF precursor homology domain (EGFP domain). This shows approximately 30% homology with the EGF precursor gene. There are three "growth factor" repeats; A, B and C. A and B are closely linked while C is separated by the YWTD repeat region, which adopts a beta-propeller conformation (LDL-R class B domain). It is thought that this region is responsible for the pH-dependent conformational shift that causes bound LDL to be released in the endosome.
A third domain of the protein is rich in O-linked oligosaccharides but appears to show little function. Knockout experiments have confirmed that no significant loss of activity occurs without this domain. It has been speculated that the domain may have ancestrally acted as a spacer to push the receptor beyond the extracellular matrix.
The single transmembrane domain of 22 (mostly) non-polar residues crosses the plasma membrane in a single alpha helix.
The cytosolic C-terminal domain contains ~50 amino acids, including a signal sequence important for localizing the receptors to clathrin-coated pits and for triggering receptor-mediated endocytosis after binding. Portions of the cytosolic sequence have been found in other lipoprotein receptors, as well as in more distant receptor relatives.
## Mutations
Mutations in the gene encoding the LDL receptor are known to cause familial hypercholesterolaemia.
There are 5 broad classes of mutation of the LDL receptor:
- Class 1 mutations affect the synthesis of the receptor in the endoplasmic reticulum (ER).
- Class 2 mutations prevent proper transport to the Golgi body needed for modifications to the receptor.
e.g. a truncation of the receptor protein at residue number 660 leads to domains 3,4 and 5 of the EGF precursor domain being missing. This precludes the movement of the receptor from the ER to the Golgi, and leads to degradation of the receptor protein.
- e.g. a truncation of the receptor protein at residue number 660 leads to domains 3,4 and 5 of the EGF precursor domain being missing. This precludes the movement of the receptor from the ER to the Golgi, and leads to degradation of the receptor protein.
- Class 3 mutations stop the binding of LDL to the receptor.
e.g. repeat 6 of the ligand binding domain (N-terminal, extracellular fluid) is deleted.
- e.g. repeat 6 of the ligand binding domain (N-terminal, extracellular fluid) is deleted.
- Class 4 mutations inhibit the internalization of the receptor-ligand complex.
e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; C residue converted to a Y, residue number 807). This domain recruits clathrin and other proteins responsible for the endocytosis of LDL, therefore this mutation inhibits LDL internalization.
- e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; C residue converted to a Y, residue number 807). This domain recruits clathrin and other proteins responsible for the endocytosis of LDL, therefore this mutation inhibits LDL internalization.
- Class 5 mutations give rise to receptors that cannot recycle properly. This leads to a relatively mild phenotype as receptors are still present on the cell surface (but all must be newly synthesised).
# Function
LDL receptor mediates the endocytosis of cholesterol-rich LDL and thus maintains the plasma level of LDL. This occurs in all nucleated cells, but mainly in the liver which removes ~70% of LDL from the circulation. LDL receptors are clustered in clathrin-coated pits, and coated pits pinch off from the surface to form coated endocytic vesicles that carry LDL into the cell. After internalization, the receptors dissociate from their ligands when they are exposed to lower pH in endosomes. After dissociation, the receptor folds back on itself to obtain a closed conformation and recycles to the cell surface. The rapid recycling of LDL receptors provides an efficient mechanism for delivery of cholesterol to cells. It was also reported that by association with lipoprotein in the blood, viruses such as hepatitis C virus, Flaviviridae viruses and bovine viral diarrheal virus could enter cells indirectly via LDLR-mediated endocytosis. LDLR has been identified as the primary mode of entry for the Vesicuar stomatitis virus in mice and humans. In addition, LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction. Synthesis of receptors in the cell is regulated by the level of free intracellular cholesterol; if it is in excess for the needs of the cell then the transcription of the receptor gene will be inhibited. LDL receptors are translated by ribosomes on the endoplasmic reticulum and are modified by the Golgi apparatus before travelling in vesicles to the cell surface.
# Clinical significance
In humans, LDL is directly involved in the development of atherosclerosis,which is the process responsible for the majority of cardiovascular diseases, due to accumulation of LDL-cholesterol in the blood. Hyperthyroidism may be associated with hypocholesterolemia via upregulation of the LDL receptor, and hypothyroidism with the converse. A vast number of studies have described the relevance of LDL receptors in the pathophysiology of atherosclerosis, metabolomics syndrome, and steatohepatitis Previously, rare mutations in LDL-genes have been shown to contribute to myocardial infarction risk in individual families, whereas common variants at more than 45 loci have been associated with myocardial infarction risk in the population. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III. Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. Overall, LDLR has a high clinical relevance in blood lipids.
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the LDLR gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..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} | LDL receptor
The Low-Density Lipoprotein (LDL) Receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide)[1] that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100, which is embedded in the outer phospholipid layer of LDL particles. The receptor also recognizes the apoE protein found in chylomicron remnants and VLDL remnants (IDL). In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19.[2][3][4] It belongs to the Low density lipoprotein receptor gene family.[5] It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.[6]
Michael S. Brown and Joseph L. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine for their identification of LDL-R[7] and its relation to cholesterol metabolism and familial hypercholesterolemia.[8] The LDLR gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[9]
# Structure
## Gene
The LDLR gene resides on chromosome 19 at the band 19p13.2 and is split into 18 exons.[4] Exon 1 contains a signal sequence that localises the receptor to the endoplasmic reticulum for transport to the cell surface. Beyond this, exons 2-6 code the ligand binding region; 7-14 code the epidermal growth factor (EGF) domain; 15 codes the oligosaccharide rich region; 16 (and some of 17) code the membrane spanning region; and 18 (with the rest of 17) code the cytosolic domain.
This gene produces 6 isoforms through alternative splicing.[10]
## Protein
This protein belongs to the LDLR family and is made up of a number of functionally distinct domains, including 3 EGF-like domains, 7 LDL-R class A domains, and 6 LDL-R class B repeats.[10]
The N-terminal domain of the LDL receptor, which is responsible for ligand binding, is composed of seven sequence repeats (~50% identical). Each repeat, referred to as a class A repeat or LDL-A, contains roughly 40 amino acids, including 6 cysteine residues that form disulfide bonds within the repeat. Additionally, each repeat has highly conserved acidic residues which it uses to coordinate a single calcium ion in an octahedral lattice. Both the disulfide bonds and calcium coordination are necessary for the structural integrity of the domain during the receptor's repeated trips to the highly acidic interior of the endosome. The exact mechanism of interaction between the class A repeats and ligand (LDL) is unknown, but it is thought that the repeats act as "grabbers" to hold the LDL. Binding of ApoB requires repeats 2-7 while binding ApoE requires only repeat 5 (thought to be the ancestral repeat).
Next to the ligand binding domain is an EGF precursor homology domain (EGFP domain). This shows approximately 30% homology with the EGF precursor gene. There are three "growth factor" repeats; A, B and C. A and B are closely linked while C is separated by the YWTD repeat region, which adopts a beta-propeller conformation (LDL-R class B domain). It is thought that this region is responsible for the pH-dependent conformational shift that causes bound LDL to be released in the endosome.
A third domain of the protein is rich in O-linked oligosaccharides but appears to show little function. Knockout experiments have confirmed that no significant loss of activity occurs without this domain. It has been speculated that the domain may have ancestrally acted as a spacer to push the receptor beyond the extracellular matrix.
The single transmembrane domain of 22 (mostly) non-polar residues crosses the plasma membrane in a single alpha helix.
The cytosolic C-terminal domain contains ~50 amino acids, including a signal sequence important for localizing the receptors to clathrin-coated pits and for triggering receptor-mediated endocytosis after binding. Portions of the cytosolic sequence have been found in other lipoprotein receptors, as well as in more distant receptor relatives.[11][12][13]
## Mutations
Mutations in the gene encoding the LDL receptor are known to cause familial hypercholesterolaemia.
There are 5 broad classes of mutation of the LDL receptor:
- Class 1 mutations affect the synthesis of the receptor in the endoplasmic reticulum (ER).
- Class 2 mutations prevent proper transport to the Golgi body needed for modifications to the receptor.
e.g. a truncation of the receptor protein at residue number 660 leads to domains 3,4 and 5 of the EGF precursor domain being missing. This precludes the movement of the receptor from the ER to the Golgi, and leads to degradation of the receptor protein.
- e.g. a truncation of the receptor protein at residue number 660 leads to domains 3,4 and 5 of the EGF precursor domain being missing. This precludes the movement of the receptor from the ER to the Golgi, and leads to degradation of the receptor protein.
- Class 3 mutations stop the binding of LDL to the receptor.
e.g. repeat 6 of the ligand binding domain (N-terminal, extracellular fluid) is deleted.
- e.g. repeat 6 of the ligand binding domain (N-terminal, extracellular fluid) is deleted.
- Class 4 mutations inhibit the internalization of the receptor-ligand complex.
e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; C residue converted to a Y, residue number 807). This domain recruits clathrin and other proteins responsible for the endocytosis of LDL, therefore this mutation inhibits LDL internalization.
- e.g. "JD" mutant results from a single point mutation in the NPVY domain (C-terminal, cytosolic; C residue converted to a Y, residue number 807). This domain recruits clathrin and other proteins responsible for the endocytosis of LDL, therefore this mutation inhibits LDL internalization.
- Class 5 mutations give rise to receptors that cannot recycle properly. This leads to a relatively mild phenotype as receptors are still present on the cell surface (but all must be newly synthesised).[14]
# Function
LDL receptor mediates the endocytosis of cholesterol-rich LDL and thus maintains the plasma level of LDL.[15] This occurs in all nucleated cells, but mainly in the liver which removes ~70% of LDL from the circulation. LDL receptors are clustered in clathrin-coated pits, and coated pits pinch off from the surface to form coated endocytic vesicles that carry LDL into the cell.[16] After internalization, the receptors dissociate from their ligands when they are exposed to lower pH in endosomes. After dissociation, the receptor folds back on itself to obtain a closed conformation and recycles to the cell surface.[17] The rapid recycling of LDL receptors provides an efficient mechanism for delivery of cholesterol to cells.[18][19] It was also reported that by association with lipoprotein in the blood, viruses such as hepatitis C virus, Flaviviridae viruses and bovine viral diarrheal virus could enter cells indirectly via LDLR-mediated endocytosis.[20] LDLR has been identified as the primary mode of entry for the Vesicuar stomatitis virus in mice and humans.[21] In addition, LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction.[22] Synthesis of receptors in the cell is regulated by the level of free intracellular cholesterol; if it is in excess for the needs of the cell then the transcription of the receptor gene will be inhibited. LDL receptors are translated by ribosomes on the endoplasmic reticulum and are modified by the Golgi apparatus before travelling in vesicles to the cell surface.
# Clinical significance
In humans, LDL is directly involved in the development of atherosclerosis,which is the process responsible for the majority of cardiovascular diseases, due to accumulation of LDL-cholesterol in the blood. Hyperthyroidism may be associated with hypocholesterolemia via upregulation of the LDL receptor, and hypothyroidism with the converse. A vast number of studies have described the relevance of LDL receptors in the pathophysiology of atherosclerosis, metabolomics syndrome, and steatohepatitis[23][24] Previously, rare mutations in LDL-genes have been shown to contribute to myocardial infarction risk in individual families, whereas common variants at more than 45 loci have been associated with myocardial infarction risk in the population. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides.[25] Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III.[26][27] Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. Overall, LDLR has a high clinical relevance in blood lipids.[28][29]
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the LDLR gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[30]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/LDL_receptor | |
0c46f756c23ab94123b7c8a765e15c6454fbe91e | wikidoc | LOC100287387 | LOC100287387
LOC100287387 is a protein that in humans is encoded by the gene LOC100287387. The function of the protein is not yet understood in the scientific community. The gene is located on the q arm of chromosome 2.
# Gene
The human LOC100287387 gene is located on the minus strand of the q arm of chromosome 2 at 2q37.3. It overlaps the TWIST2 gene family on the plus strand of chromosome 2. The gene is formed by three exons, with two introns near the start codon.
# mRNA
There are no alternative splicings of the LOC100287387 gene (isoforms).
# Protein
The LOC100287387 protein is formed by a 423 amino acid peptide sequence. The molecular mass is 44.4 kdal, and the isoelectric point is 10.77. There is a G-patch domain and a short domain of unknown function within the peptide sequence. There are many predicted modification sites within the amino acid sequence including cAMP- dependent phosphorylation sites (CampP), casein kinase 2 (CK2), and protein kinase C (PKC) phosphorylation sites, O-linked beta-N-acetylglucosamine sites, and a sumoylation site. The predicted secondary structure of the protein includes 8 short alpha-helices (15.6% of the protein), 14 short extended strands (12.1%), and the rest as random coils (72%).
# Expression
In humans, there is low expression of LOC100287387 in all tissues. Highest expression is in the skin and central nervous system tissue such as the pons, superior cervical ganglion, trigeminal ganglion, and globus pallidus. However, expression was inconsistent among patients.
# Regulation
The promoter region of the LOC100287387 gene contains binding sites for many transcription factors which affect transcription levels of the gene. Within the promoter region, there are three TFIIB binding sites (initiates transcription), a cysteine-serine-rich nuclear protein 1 site (an activator), a Kruppel-like zinc finger protein 219 site (repressor), a stimulating protein 1 site (activator), and many more.
# Homology
Orthologs to the human LOC100287387 gene are found only in mammals, and the protein sequence is not highly conserved. Conservation is highest in primates, and falls drastically among other mammals. Conservation between species is highest at the nuclear localization signal and towards the end of the coding sequence at the G Patch domain and DUF308 which indicates these are the most functionally important parts of the sequence.
There are no paralogs of the human gene LOC100287387.
# Function
The protein contains a nuclear localization signal, and most likely acts in the nucleus. There are no confirmed protein interactions or associations to diseases. | LOC100287387
LOC100287387 is a protein that in humans is encoded by the gene LOC100287387. The function of the protein is not yet understood in the scientific community. The gene is located on the q arm of chromosome 2.[1]
# Gene
The human LOC100287387 gene is located on the minus strand of the q arm of chromosome 2 at 2q37.3.[1] It overlaps the TWIST2 gene family on the plus strand of chromosome 2.[2] The gene is formed by three exons, with two introns near the start codon.[2]
# mRNA
There are no alternative splicings of the LOC100287387 gene (isoforms).[2]
# Protein
The LOC100287387 protein is formed by a 423 amino acid peptide sequence. The molecular mass is 44.4 kdal,[5] and the isoelectric point is 10.77.[6] There is a G-patch domain and a short domain of unknown function within the peptide sequence. There are many predicted modification sites within the amino acid sequence including cAMP- dependent phosphorylation sites (CampP), casein kinase 2 (CK2), and protein kinase C (PKC) phosphorylation sites, O-linked beta-N-acetylglucosamine sites, and a sumoylation site.[3][7] The predicted secondary structure of the protein includes 8 short alpha-helices (15.6% of the protein), 14 short extended strands (12.1%), and the rest as random coils (72%).[8]
# Expression
In humans, there is low expression of LOC100287387 in all tissues. Highest expression is in the skin and central nervous system tissue such as the pons, superior cervical ganglion, trigeminal ganglion, and globus pallidus. However, expression was inconsistent among patients.[9]
# Regulation
The promoter region of the LOC100287387 gene contains binding sites for many transcription factors which affect transcription levels of the gene. Within the promoter region, there are three TFIIB binding sites (initiates transcription), a cysteine-serine-rich nuclear protein 1 site (an activator), a Kruppel-like zinc finger protein 219 site (repressor), a stimulating protein 1 site (activator), and many more.[10]
# Homology
Orthologs to the human LOC100287387 gene are found only in mammals, and the protein sequence is not highly conserved. Conservation is highest in primates, and falls drastically among other mammals.[11] Conservation between species is highest at the nuclear localization signal and towards the end of the coding sequence at the G Patch domain and DUF308 which indicates these are the most functionally important parts of the sequence.[11]
There are no paralogs of the human gene LOC100287387.[13]
# Function
The protein contains a nuclear localization signal, and most likely acts in the nucleus.[14] There are no confirmed protein interactions or associations to diseases. | https://www.wikidoc.org/index.php/LOC100287387 | |
22ee33b1610f460ad6ecefadccb41366bfe6c85d | wikidoc | LOC101059915 | LOC101059915
LOC101059915 is a protein, which in humans is encoded by the LOC101059915 gene. It is located on the X chromosome and has restricted expression in the testis.
# Gene
The LOC101059915 gene has two aliases known as chromosome X open reading frame 49-like and BX276092.6.
## Locus and Structure
LOC101059915 is located on the X chromosome at locus Xq13.1. It is 1,831 base pairs long and the gene sequence has 6 exons. LOC101059915 also has one protein coding transcript.
## Promoter Region and Expression
The promoter region of LOC101059915 is located on the sense strand of DNA, and between base pair 71666098 and 71667904 on the X chromosome. It spans up to 1.806 bp. Expression of LOC101059915, however, is relatively low in human cells, and is primarily limited to the testis.
# Protein
## General Features and Compositional Analysis
The protein has 518 amino acids and a molecular mass of 55.1 kDa. The isoelectric point is 8.15. Compared to other human proteins LOC101059915 is glycine-, proline-rich, and serine-rich but the protein has lower levels of tyrosine.
## Domains
The domain of unknown function, DUF4641 covers almost the entire protein. It is a part of pfam15483. It is 410 amino acids long, from amino acid 85 until amino acid number 495.
## Secondary Structure
The secondary structure of LOC101059915 has been shown to consist of primarily alpha helices as determined by models made on I-TASSER and analysis using ExPASy tools.
## Post-translation modifications
LOC101055915 is predicted to contain many different post-translational modifications. This include sites for phosphorylation (NetPhos 2.0) and sumoylation (SUMOplot Analysis Program).
## Subcellular localization
The LOC101059915 protein has been predicted to be located in the cell nucleus (PSORT II).
# Homology and Evolution
## Paralogs
CXorf49 and CXorf49B are paralogs of LOC101059915. They share upwards of 78% similarity with LOC101059915 and likely went through a gene duplication event relatively recently, in evolutionary terms, due the high degree of conservation between all three sequences.
CXorf49 is especially interesting due it being shown to be involved as one of the components of a small group of the HL-60 cell proteome that are most prone to form 4-Hydroxy-2-nonenal(HNE) adducts, upon exposure to nontoxic (10 μM) HNE concentrations, along with heat shock 60 kDa protein 1.
## Orthologs
Using BLAST no orthologs for LOC101059915 are found in single celled organisms, fungi or plants whose genomes have been sequenced. For multi-cellular organisms, orthologs are found in mammals, excluding Monotremes. The table below shows a representative sample of 20 of the orthologs for LOC101059915. The table is organized based on the time of divergence from humans in millions of years (MYA). In cases where the divergence time-frame is the same the orthologs are sorted by identity (%).
## Phylogeny
The most distant ortholog for LOC101059915 is from the species Sarcrophilus harrisii which is commonly known as the Tasmanian Devil dating from more than 159.0 million years ago. | LOC101059915
LOC101059915 is a protein, which in humans is encoded by the LOC101059915 gene. It is located on the X chromosome and has restricted expression in the testis.
# Gene
The LOC101059915 gene has two aliases known as chromosome X open reading frame 49-like and BX276092.6.[1]
## Locus and Structure
LOC101059915 is located on the X chromosome at locus Xq13.1. It is 1,831 base pairs long and the gene sequence has 6 exons.[2] LOC101059915 also has one protein coding transcript.
## Promoter Region and Expression
The promoter region of LOC101059915 is located on the sense strand of DNA, and between base pair 71666098 and 71667904 on the X chromosome. It spans up to 1.806 bp.[3] Expression of LOC101059915, however, is relatively low in human cells, and is primarily limited to the testis.[4]
# Protein
## General Features and Compositional Analysis
The protein has 518 amino acids and a molecular mass of 55.1 kDa.[5] The isoelectric point is 8.15. Compared to other human proteins LOC101059915 is glycine-, proline-rich, and serine-rich but the protein has lower levels of tyrosine.[6]
## Domains
The domain of unknown function, DUF4641 covers almost the entire protein. It is a part of pfam15483.[7] It is 410 amino acids long, from amino acid 85 until amino acid number 495.[8]
## Secondary Structure
The secondary structure of LOC101059915 has been shown to consist of primarily alpha helices as determined by models made on I-TASSER and analysis using ExPASy tools.[9]
## Post-translation modifications
LOC101055915 is predicted to contain many different post-translational modifications. This include sites for phosphorylation (NetPhos 2.0[10]) and sumoylation (SUMOplot Analysis Program[11]).
## Subcellular localization
The LOC101059915 protein has been predicted to be located in the cell nucleus (PSORT II).[12]
# Homology and Evolution
## Paralogs
CXorf49 and CXorf49B are paralogs of LOC101059915. They share upwards of 78% similarity with LOC101059915 and likely went through a gene duplication event relatively recently, in evolutionary terms, due the high degree of conservation between all three sequences.
CXorf49 is especially interesting due it being shown to be involved as one of the components of a small group of the HL-60 cell proteome that are most prone to form 4-Hydroxy-2-nonenal(HNE) adducts, upon exposure to nontoxic (10 μM) HNE concentrations, along with heat shock 60 kDa protein 1.[13]
## Orthologs
Using BLAST[14] no orthologs for LOC101059915 are found in single celled organisms, fungi or plants whose genomes have been sequenced. For multi-cellular organisms, orthologs are found in mammals, excluding Monotremes. The table below shows a representative sample of 20 of the orthologs for LOC101059915. The table is organized based on the time of divergence from humans in millions of years (MYA). In cases where the divergence time-frame is the same the orthologs are sorted by identity (%).
## Phylogeny
The most distant ortholog for LOC101059915 is from the species Sarcrophilus harrisii which is commonly known as the Tasmanian Devil dating from more than 159.0 million years ago. | https://www.wikidoc.org/index.php/LOC101059915 | |
eb24eb91d83eecd99dd281892fec6698a510c1c1 | wikidoc | LOC105377021 | LOC105377021
LOC105377021 is a protein which in humans is encoded by the LOC105377021 gene. LOC105377021 exhibits expressional pathology related to breast cancer, specifically triple negative breast cancer. LOC105377021 contains a serine rich region in addition to predicted alpha helix motifs.
# Gene and mRNA
LOC105377021 localizes to Homo sapiens chromosome 3 (3p2; antisense strand), approximate to the reading frame of TRIM71. The corresponding gene has 2,473 nucleotides. There is one exon in the LOC105377021p mRNA. There is no predicted alternative splicing on the NCBI gene database.
# Protein
## Protein Primary Structure
The figure below shows the basic primary protein structure, with N-terminus and C-terminus in their respective annotations. The orange domain is a predicted nuclear localization sequence, while the blue domain is the remainder of the LOC105377021 exon.
File:LOC105377021.png
## Protein Secondary Structure
According to Ali2D (a multiple sequence alignment structural predictor for proteins), LOC105377021 is predicted to form mostly alpha helix (see red highlight, blue highlight is for Beta Sheet).
File:Secondary Structure Text Outline.png
## Protein Tertiary Structure
LOC105377021 has a prominent, C-terminus repeat of serine residues, potentially for disulfide bonding. One disulfide bond (139-148) was predicted by DISULFIDE software. Additionally, the I TASSER profile shows several alpha helices in a variety of different colors, in addition to potential turn motifs (see I TASSER 3D Prediction of LOC105377021).
## Protein Modifications and Localization
A predicted protein modification of LOC105377021 is phosphorylation, with sites throughout the protein, including the serine rich construct near the C-terminus of the protein. In addition, there is predicted evidence of O-Linked β-N-acetylglucosamine supplements in the C terminal region. There is predicted evidence for a nuclear localization sequence oriented at the N-terminal, provided by PSORT with partial support by PHOBIUS software.
# Microarray Expression Pattern and Pathology
## Basic Expression and Breast Cancer
Compared to the average expression of human protein, LOC105377021 is expressed at 0.9%, which is classified as low. In humans: cranial, intestinal, ovarian, renal, and testicular tissues corroborate this trend.
Microarray data posits the expression of LOC105377021 in certain breast cancer tissues, including metastases to lymphatic and lung tissue. There is potential evidence for higher expression of LOC105377021 during Triple Negative Breast Cancer, which overshadows normal secretion levels for said protein. The figure below shows a potential trend line for this pattern (shown in green, with the triple negative microarray on the left). As the figure legend states, the red bars refer to the left axis for sample counts, whereas the blue dots show the percentage of LOC105377021 expression within each sample (the right axis).
File:NCBI Geo Profile for Triple Negative Breast Cancer and YPLR6490.png
This photo is courtesy of NCBI Geo Profiles Accession GDS4069.
## Brain Tissue Expression
Seven key brain tissues express LOC105377021 according to an Allen Brain Atlas probe. The temporal lobe, parietal lobe, cingulate gyrus, parahippocampal gyrus, and insula are five overarching regions of the seven brain tissues where expression was highlighted. The annotated figures below serve as fairly holistic representations of cranial expression in the context of LOC105377021. Light blue shaded regions posit more dense expression of LOC105377021, where as darker green and brighter red show less and least amounts of expression respectively. All seven expression areas, including the middle temporal gyrus, the short insular gyrus, the postcentral gyrus, the cingulate gyrus, the inferior temporal gyrus, the parahippocampal gyrus, and the superior temporal gyrus are depicted in Allen Brain Atlas profiles below.
File:Four Allen Brain Atlas Annotations for LOC105377021 Brain Expression.png
File:Three Allen Brain Atlas LOC105377021 Cranial Expression Profiles.png
These photos are courtesy of the Allen Brain Atlas.
# Evolutionary Relationships and Homology
## Orthologs
The Basic Local Alignment Sequence Tool (BLAST) shows that LOC105377021 orthologs are largely homogenous and mammalian. Important orthologs are summarized into three categories: primates, aquatic mammals, and ferrets/ferret-like animals. Pongo abelii and Tursiops truncatus are the most distant and related orthologs respectively. The river dolphin is the first ortholog to detach from the 80% plus similarity cohort. The following includes a list of select orthologs found:
## Pace of Evolution
The pace of evolution of LOC105377021 upon its inception (in humans) is modeled to be slow. This speed is relative to cytochrome c 6A1 and Alpha fibrinogen using corrected divergence methods.
File:LOC105377021 Corrected Divergence Graph.png
The corrected divergences graph above shows three lines: Alpha Fibrinogen in Red, LOC Ortholog (aka LOC105377021) in blue, and Cytochrome c 6A1 in green. These lines associate with evolutionary pace in LOC105377021, as tested using a corrected divergence genomic analysis.
## Single Nucleotide Polymorphisms
The following diagram shows single nucleotide polymorphisms (SNP's) in various regions of the protein. SNP's are highlighted green, with SNP coding on the right hand coding for switches in amino acids.
File:SNP's in LOC105377021.png
# Promoter and Gene Regulation
According to Genomatix, LOC389102 (synonym to LOC105377021) is proximate to a 601 base pair promoter and a 5'UTR 129 base pairs long consecutively. Genomatix predicts several transcription factors in general. Two select factors predicted include Gli3 and E2F1. | LOC105377021
LOC105377021 is a protein which in humans is encoded by the LOC105377021 gene.[1][2] LOC105377021 exhibits expressional pathology related to breast cancer, specifically triple negative breast cancer.[3][4] LOC105377021 contains a serine rich region in addition to predicted alpha helix motifs.[5][2]
# Gene and mRNA
LOC105377021 localizes to Homo sapiens chromosome 3 (3p2; antisense strand), approximate to the reading frame of TRIM71.[2][6][7] The corresponding gene has 2,473 nucleotides.[2] There is one exon in the LOC105377021p mRNA.[2] There is no predicted alternative splicing on the NCBI gene database.[2]
# Protein
## Protein Primary Structure
The figure below shows the basic primary protein structure, with N-terminus and C-terminus in their respective annotations. The orange domain is a predicted nuclear localization sequence, while the blue domain is the remainder of the LOC105377021 exon.[8]
File:LOC105377021.png
## Protein Secondary Structure
According to Ali2D (a multiple sequence alignment structural predictor for proteins), LOC105377021 is predicted to form mostly alpha helix (see red highlight, blue highlight is for Beta Sheet).[5]
File:Secondary Structure Text Outline.png
## Protein Tertiary Structure
LOC105377021 has a prominent, C-terminus repeat of serine residues, potentially for disulfide bonding.[2] One disulfide bond (139-148) was predicted by DISULFIDE software.[12] Additionally, the I TASSER profile shows several alpha helices in a variety of different colors, in addition to potential turn motifs (see I TASSER 3D Prediction of LOC105377021).[13]
## Protein Modifications and Localization
A predicted protein modification of LOC105377021 is phosphorylation, with sites throughout the protein, including the serine rich construct near the C-terminus of the protein.[14][15] In addition, there is predicted evidence of O-Linked β-N-acetylglucosamine supplements in the C terminal region.[16][17] There is predicted evidence for a nuclear localization sequence oriented at the N-terminal, provided by PSORT with partial support by PHOBIUS software.[8][18]
# Microarray Expression Pattern and Pathology
## Basic Expression and Breast Cancer
Compared to the average expression of human protein, LOC105377021 is expressed at 0.9%, which is classified as low.[6] In humans: cranial, intestinal, ovarian, renal, and testicular tissues corroborate this trend.[6]
Microarray data posits the expression of LOC105377021 in certain breast cancer tissues, including metastases to lymphatic and lung tissue.[4] There is potential evidence for higher expression of LOC105377021 during Triple Negative Breast Cancer, which overshadows normal secretion levels for said protein.[3] The figure below shows a potential trend line for this pattern (shown in green, with the triple negative microarray on the left). As the figure legend states, the red bars refer to the left axis for sample counts, whereas the blue dots show the percentage of LOC105377021 expression within each sample (the right axis).
File:NCBI Geo Profile for Triple Negative Breast Cancer and YPLR6490.png
This photo is courtesy of NCBI Geo Profiles Accession GDS4069.
## Brain Tissue Expression
Seven key brain tissues express LOC105377021 according to an Allen Brain Atlas probe.[19] The temporal lobe, parietal lobe, cingulate gyrus, parahippocampal gyrus, and insula are five overarching regions of the seven brain tissues where expression was highlighted. The annotated figures below serve as fairly holistic representations of cranial expression in the context of LOC105377021. Light blue shaded regions posit more dense expression of LOC105377021, where as darker green and brighter red show less and least amounts of expression respectively. All seven expression areas, including the middle temporal gyrus, the short insular gyrus, the postcentral gyrus, the cingulate gyrus, the inferior temporal gyrus, the parahippocampal gyrus, and the superior temporal gyrus are depicted in Allen Brain Atlas profiles below.
File:Four Allen Brain Atlas Annotations for LOC105377021 Brain Expression.png
File:Three Allen Brain Atlas LOC105377021 Cranial Expression Profiles.png
These photos are courtesy of the Allen Brain Atlas.
# Evolutionary Relationships and Homology
## Orthologs
The Basic Local Alignment Sequence Tool (BLAST) shows that LOC105377021 orthologs are largely homogenous and mammalian.[20] Important orthologs are summarized into three categories: primates, aquatic mammals, and ferrets/ferret-like animals. Pongo abelii and Tursiops truncatus are the most distant and related orthologs respectively. The river dolphin is the first ortholog to detach from the 80% plus similarity cohort. The following includes a list of select orthologs found:
## Pace of Evolution
The pace of evolution of LOC105377021 upon its inception (in humans) is modeled to be slow. This speed is relative to cytochrome c 6A1 and Alpha fibrinogen using corrected divergence methods.
File:LOC105377021 Corrected Divergence Graph.png
The corrected divergences graph above shows three lines: Alpha Fibrinogen in Red, LOC Ortholog (aka LOC105377021) in blue, and Cytochrome c 6A1 in green. These lines associate with evolutionary pace in LOC105377021, as tested using a corrected divergence genomic analysis.
## Single Nucleotide Polymorphisms
The following diagram shows single nucleotide polymorphisms (SNP's) in various regions of the protein. SNP's are highlighted green, with SNP coding on the right hand coding for switches in amino acids.[22]
File:SNP's in LOC105377021.png
# Promoter and Gene Regulation
According to Genomatix, LOC389102 (synonym to LOC105377021) is proximate to a 601 base pair promoter and a 5'UTR 129 base pairs long consecutively.[2][23] Genomatix predicts several transcription factors in general. Two select factors predicted include Gli3 and E2F1.[23] | https://www.wikidoc.org/index.php/LOC105377021 | |
12594bb47bd8063ec31287222fd335b1a86159b8 | wikidoc | LTBP1 (gene) | LTBP1 (gene)
Latent-transforming growth factor beta-binding protein 1 is a protein that in humans is encoded by the LTBP1 gene.
The protein encoded by this gene belongs to the family of latent TGF-beta binding proteins (LTBPs). The secretion and activation of TGF-betas is regulated by their association with latency-associated proteins and with latent TGF-beta binding proteins. The product of this gene targets latent complexes of transforming growth factor beta to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Alternatively spliced transcript variants encoding different isoforms have been identified.
# Interactions
LTBP1 (gene) has been shown to interact with TGF beta 1. | LTBP1 (gene)
Latent-transforming growth factor beta-binding protein 1 is a protein that in humans is encoded by the LTBP1 gene.[1][2][3]
The protein encoded by this gene belongs to the family of latent TGF-beta binding proteins (LTBPs). The secretion and activation of TGF-betas is regulated by their association with latency-associated proteins and with latent TGF-beta binding proteins. The product of this gene targets latent complexes of transforming growth factor beta to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Alternatively spliced transcript variants encoding different isoforms have been identified.[3]
# Interactions
LTBP1 (gene) has been shown to interact with TGF beta 1.[4] | https://www.wikidoc.org/index.php/LTBP1_(gene) | |
100c4f23bdb49116fe9651e5779dff888e5fa57a | wikidoc | Labia majora | Labia majora
The labia majora (singular: labium majus) are two prominent longitudinal cutaneous folds which extend downward and backward from the mons pubis to the perineum and form the lateral boundaries of the cleft of venus, which contains the labia minora, interlabial sulci, clitoral hood, clitoral glans, frenulum clitoridis, the Hart's Line, and the vulval vestibule, which contains the external openings of the urethra and the vagina.
Each labium majus has two surfaces, an outer, pigmented and covered with strong, crisp hairs; and an inner, smooth and beset with large sebaceous follicles.
Between the two there is a considerable quantity of areolar tissue, fat, and a tissue resembling the dartos tunic of the scrotum, besides vessels, nerves, and glands.
The Labia Majora are thicker in front, where they form by their meeting the anterior commisure of the labia majora.
Posteriorly they are not really joined, but appear to become lost in the neighboring integument, ending close to, and nearly parallel with, each other.
Together with the connecting skin between them, they form the posterior commisure of the labia majora or posterior boundary of the pudendum.
The interval between the posterior commissure of the labia majora and the anus, from 2.5 to 3 cm. in length, constitutes the perineum.
The labia majora correspond to the scrotum in the male.
Between the labia majora and the inner thighs are the Labiocrural Folds.
Between the labia majora and labia minora are the interlabial sulci.
# Additional images
- Sagittal section of the lower part of a female trunk, right segment.
- Median sagittal section of female pelvis.
- Vulva anatomy
- Organs of the female reproductive system.
- Female external genitalia. | Labia majora
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The labia majora (singular: labium majus) are two prominent longitudinal cutaneous folds which extend downward and backward from the mons pubis to the perineum and form the lateral boundaries of the cleft of venus, which contains the labia minora, interlabial sulci, clitoral hood, clitoral glans, frenulum clitoridis, the Hart's Line, and the vulval vestibule, which contains the external openings of the urethra and the vagina.
Each labium majus has two surfaces, an outer, pigmented and covered with strong, crisp hairs; and an inner, smooth and beset with large sebaceous follicles.
Between the two there is a considerable quantity of areolar tissue, fat, and a tissue resembling the dartos tunic of the scrotum, besides vessels, nerves, and glands.
The Labia Majora are thicker in front, where they form by their meeting the anterior commisure of the labia majora.
Posteriorly they are not really joined, but appear to become lost in the neighboring integument, ending close to, and nearly parallel with, each other.
Together with the connecting skin between them, they form the posterior commisure of the labia majora or posterior boundary of the pudendum.
The interval between the posterior commissure of the labia majora and the anus, from 2.5 to 3 cm. in length, constitutes the perineum.
The labia majora correspond to the scrotum in the male.
Between the labia majora and the inner thighs are the Labiocrural Folds.
Between the labia majora and labia minora are the interlabial sulci.
# Additional images
- Sagittal section of the lower part of a female trunk, right segment.
- Median sagittal section of female pelvis.
- Vulva anatomy
- Organs of the female reproductive system.
- Female external genitalia. | https://www.wikidoc.org/index.php/Labia_majora | |
c6a835a2919d7f6a47268274e3938a95eaa796aa | wikidoc | Lachman test | Lachman test
# Overview
A Lachman test is a medical test used for examining the Anterior Cruciate Ligament (ACL) in the knee for patients where there is a suspicion of a torn ACL.
To do this, lay the patient supine on a bed. Put the patient's knee in about 20-30 degrees flexion. The examiner should place one hand behind the tibia and the other on the patient's thigh. It is important that the examiner's thumb be on the tibial tuberosity. On pulling anteriorly on the tibia, an intact ACL should prevent forward translational movement of the tibia on the femur ("firm endpoint").
Anterior translation of the tibia associated with a soft or a mushy endpoint indicates a positive test. More than about 2 mm of anterior translation compared to the uninvolved knee suggests a torn ACL ("soft endpoint"), as does 10 mm of total anterior translation. An instrument called a "KT-1000" can be used to determine the magnitude of movement in mm.
The Lachman test is recognized by most authorities as the most reliable and sensitive clinical test for the determination of anterior cruciate ligament integrity, superior to the Anterior Drawer test commonly used in the past.
This test is named after orthopaedic surgeon, John Lachman, M.D.. A graduate of both Temple University and Temple University School of Medicine , Dr. Lachman also completed his orthopaedic residency at Temple under John Royal Moore, M.D., the first professor and chairman of the Department of Orthopaedic Surgery. Remaining on the faculty at Temple following his residency, in 1956 he succeeded Dr. Moore as professor and chairman. | Lachman test
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A Lachman test is a medical test used for examining the Anterior Cruciate Ligament (ACL) in the knee for patients where there is a suspicion of a torn ACL.
To do this, lay the patient supine on a bed. Put the patient's knee in about 20-30 degrees flexion. The examiner should place one hand behind the tibia and the other on the patient's thigh. It is important that the examiner's thumb be on the tibial tuberosity. On pulling anteriorly on the tibia, an intact ACL should prevent forward translational movement of the tibia on the femur ("firm endpoint").
Anterior translation of the tibia associated with a soft or a mushy endpoint indicates a positive test. More than about 2 mm of anterior translation compared to the uninvolved knee suggests a torn ACL ("soft endpoint"), as does 10 mm of total anterior translation. An instrument called a "KT-1000" can be used to determine the magnitude of movement in mm.
The Lachman test is recognized by most authorities as the most reliable and sensitive clinical test for the determination of anterior cruciate ligament integrity, superior to the Anterior Drawer test commonly used in the past.
This test is named after orthopaedic surgeon, John Lachman, M.D.. A graduate of both Temple University and Temple University School of Medicine , Dr. Lachman also completed his orthopaedic residency at Temple under John Royal Moore, M.D., the first professor and chairman of the Department of Orthopaedic Surgery. Remaining on the faculty at Temple following his residency, in 1956 he succeeded Dr. Moore as professor and chairman. | https://www.wikidoc.org/index.php/Lachman_maneuver | |
ae98d1c4d013dfdd489e5f77f204b041845fd1a1 | wikidoc | Lahey Clinic | Lahey Clinic
# Overview
The Lahey Clinic is a not-for-profit teaching hospital in Burlington, Massachusetts. It was founded in 1923 by Dr. Frank H. Lahey.
# History
When Dr. Frank Howard Lahey founded a group practice in 1923, his plan was to create a clinic where many specialties would coexist under one roof. This idea became the Lahey Clinic and it was built at 605 Commonwealth Ave., in Boston where it would remain for another 55 years.
Lahey's original team—anesthesiologist Lincoln Sise, operating nurse Blanche Wallace, surgical assistant Howard Clute, and gastroenterologist Sara Jordan—were pioneers in their fields.
Physicians saw only outpatients at Lahey Clinic in the early years. In fact, much of the day was spent traveling between the New England Baptist Hospital, New England Deaconess, and Peter Bent Brigham hospitals to perform surgeries and visit inpatients.
Medical centers were not common in the United States in the 1920s. If there were problems that the family doctor could not handle, the patient would be referred to a specialist or transported to a hospital. Lahey’s team was often called out to outlying Greater Boston towns for emergencies—to towns and cities in New Hampshire, Vermont and Maine.
By the 1930s and ‘40s, the Clinic was known worldwide for its phenomenal surgical outcomes, and state-of-the-art treatment of thyroid, gastrointestinal and gall bladder disorders. In 1940, an article was written in Time Magazine describing the Clinic’s history and Dr. Lahey’s election as the new president of the American Medical Association.
The reputation that Lahey Clinic has for innovative technology, pioneer medical treatment and leading-edge research was built upon Dr. Lahey's belief that the group practice should also be a center for research and learning. From the beginning, the Clinic offered residents and fellows a chance to polish their skills under the careful supervision of some of the nation's leading physicians.
By the time the Clinic moved 11 miles northwest to its current location in Burlington in November 1980, the practice had expanded to include services offered by more than 30 departments. Many of these departments had begun with a single physician who worked to promote his or her specialty. The Gastroenterology and Anesthesiology Departments, in particular, arose from the practices of Jordan and Sise, who in the 1920s were among the first physicians in the United States to specialize in these growing fields.
# About Lahey Clinic
At Lahey Clinic, more than 430 physicians and 4,400 nurses, therapists and other support staff work together to provide compassionate care and superior patient outcomes. The Clinic's multidisciplinary approach allows patients access to physicians from several medical specialties, who cooperate to develop personalized treatment plans for each patient.
Lahey Clinic Medical Center is a teaching hospital of Tufts University School of Medicine. In addition, many of its physicians hold teaching assignments at Harvard Medical School and Boston University School of Medicine. The Clinic maintains residency and fellowship programs for more than 130 new physicians in multiple subspecialties.
As a research center, Lahey Clinic offers patients access to clinical trials of new therapies for diseases such as cancer, diabetes, heart disease and cataracts. Research programs at Lahey Clinic encompass more than 200 clinical trial protocols and participation in numerous national and international studies.
# Specialties
Lahey Clinic provides access to many medical specialties.
The Heart & Vascular Center is one of the largest in the region and is recognized as a Solucient 100 Top Hospital. Through partnerships with local hospitals, Lahey physicians provide advanced cardiology services such as angioplasty and electrophysiology.
The Cerebrovascular Disease Center is among the most advanced in the region for the treatment of strokes and brain aneurysms. The Liver Transplantation Team was the first in New England to perform adult live-donor transplant procedures. In addition, surgeons are using minimally invasive laparoscopic methods, reducing the surgical recovery time for conditions such as kidney disease and bladder cancer. Robotic surgical techniques are also emerging in urology and gynecological surgery. For the past six years, Lahey Clinic was cited in U.S. News & World Report's America's Best Hospitals issue for excellence in treating urological diseases.
Through the Sophia Gordon Cancer Center at Lahey Clinic, a complete range of medical and surgical specialty departments are involved in the care of cancer patients. They sponsor regular tumor conferences to exchange information and, together as a team, manage patients with the most complex diagnoses.
# Facilities
Lahey Clinic Medical Center in Burlington encompasses an ambulatory care center serving more than 3,000 patients each day and a 317-bed hospital. Lahey Clinic Medical Center, North Shore, in Peabody, serves more than 800 outpatients each day and includes a 10-bed hospital. Both feature 24-hour emergency departments, and an American College of Surgeons verified Level II Trauma Center is based at the Burlington facility.
Lahey Clinic also has 12 community group practices that feature adult internists, pediatricians and family practice specialists. These practices enable Lahey Clinic to serve communities such as Amesbury on the North Shore, Lexington in Boston's northwestern suburbs, and Haverhill on the New Hampshire border.
# Recognitions
Lahey Clinic was named among the top cardiovascular teaching hospitals in the country by Solucient, a leading source of health care business research. Lahey also received the Premier Award for Quality for excellent care in the area of heart failure. In July 2006, U.S. News & World Report named Lahey Clinic in its “America’s Best Hospitals” issue for the ninth year in a row. Lahey was listed among the best in the country for excellence in urologic diseases.
Lahey received the American Stroke Association’s Get with the Guidelines-Stroke Initial Performance Achievement Award. Lahey is one of 68 centers classified as Primary Stroke Services by the Massachusetts Department of Public Health. Lahey Clinic has accreditation from the United Network for Organ Sharing (UNOS) to perform live-donor liver transplants. Lahey’s liver team has performed more than 128 live-donor liver transplant surgeries since the program’s inception. | Lahey Clinic
Template:Infobox Hospital
# Overview
The Lahey Clinic is a not-for-profit teaching hospital in Burlington, Massachusetts. It was founded in 1923 by Dr. Frank H. Lahey.
# History
When Dr. Frank Howard Lahey founded a group practice in 1923, his plan was to create a clinic where many specialties would coexist under one roof. This idea became the Lahey Clinic and it was built at 605 Commonwealth Ave., in Boston where it would remain for another 55 years.
Lahey's original team—anesthesiologist Lincoln Sise, operating nurse Blanche Wallace, surgical assistant Howard Clute, and gastroenterologist Sara Jordan—were pioneers in their fields.
Physicians saw only outpatients at Lahey Clinic in the early years. In fact, much of the day was spent traveling between the New England Baptist Hospital, New England Deaconess, and Peter Bent Brigham hospitals to perform surgeries and visit inpatients.
Medical centers were not common in the United States in the 1920s. If there were problems that the family doctor could not handle, the patient would be referred to a specialist or transported to a hospital. [1] Lahey’s team was often called out to outlying Greater Boston towns for emergencies—to towns and cities in New Hampshire, Vermont and Maine.
By the 1930s and ‘40s, the Clinic was known worldwide for its phenomenal surgical outcomes, and state-of-the-art treatment of thyroid, gastrointestinal and gall bladder disorders. In 1940, an article was written in Time Magazine describing the Clinic’s history and Dr. Lahey’s election as the new president of the American Medical Association.[2]
The reputation that Lahey Clinic has for innovative technology, pioneer medical treatment and leading-edge research was built upon Dr. Lahey's belief that the group practice should also be a center for research and learning. From the beginning, the Clinic offered residents and fellows a chance to polish their skills under the careful supervision of some of the nation's leading physicians.
By the time the Clinic moved 11 miles northwest to its current location in Burlington in November 1980, the practice had expanded to include services offered by more than 30 departments. Many of these departments had begun with a single physician who worked to promote his or her specialty. The Gastroenterology and Anesthesiology Departments, in particular, arose from the practices of Jordan and Sise, who in the 1920s were among the first physicians in the United States to specialize in these growing fields.
# About Lahey Clinic
At Lahey Clinic, more than 430 physicians and 4,400 nurses, therapists and other support staff work together to provide compassionate care and superior patient outcomes.[3] The Clinic's multidisciplinary approach allows patients access to physicians from several medical specialties, who cooperate to develop personalized treatment plans for each patient.
Lahey Clinic Medical Center is a teaching hospital of Tufts University School of Medicine.[4] In addition, many of its physicians hold teaching assignments at Harvard Medical School and Boston University School of Medicine. The Clinic maintains residency and fellowship programs for more than 130 new physicians in multiple subspecialties. [3]
As a research center, Lahey Clinic offers patients access to clinical trials of new therapies for diseases such as cancer, diabetes, heart disease and cataracts. Research programs at Lahey Clinic encompass more than 200 clinical trial protocols and participation in numerous national and international studies. [5]
# Specialties
Lahey Clinic provides access to many medical specialties.
The Heart & Vascular Center is one of the largest in the region and is recognized as a Solucient 100 Top Hospital. [6] Through partnerships with local hospitals, Lahey physicians provide advanced cardiology services such as angioplasty and electrophysiology.
The Cerebrovascular Disease Center is among the most advanced in the region for the treatment of strokes and brain aneurysms. The Liver Transplantation Team was the first in New England to perform adult live-donor transplant procedures. In addition, surgeons are using minimally invasive laparoscopic methods, reducing the surgical recovery time for conditions such as kidney disease and bladder cancer. Robotic surgical techniques are also emerging in urology and gynecological surgery. For the past six years, Lahey Clinic was cited in U.S. News & World Report's America's Best Hospitals issue for excellence in treating urological diseases. [7]
Through the Sophia Gordon Cancer Center at Lahey Clinic, a complete range of medical and surgical specialty departments are involved in the care of cancer patients. They sponsor regular tumor conferences to exchange information and, together as a team, manage patients with the most complex diagnoses.
# Facilities
Lahey Clinic Medical Center in Burlington encompasses an ambulatory care center serving more than 3,000 patients each day and a 317-bed hospital.[3] Lahey Clinic Medical Center, North Shore, in Peabody, serves more than 800 outpatients each day and includes a 10-bed hospital. Both feature 24-hour emergency departments, and an American College of Surgeons verified Level II Trauma Center is based at the Burlington facility.
Lahey Clinic also has 12 community group practices that feature adult internists, pediatricians and family practice specialists. These practices enable Lahey Clinic to serve communities such as Amesbury on the North Shore, Lexington in Boston's northwestern suburbs, and Haverhill on the New Hampshire border.
# Recognitions
Lahey Clinic was named among the top cardiovascular teaching hospitals in the country by Solucient, a leading source of health care business research.[6] Lahey also received the Premier Award for Quality for excellent care in the area of heart failure.[8] In July 2006, U.S. News & World Report named Lahey Clinic in its “America’s Best Hospitals” issue for the ninth year in a row. Lahey was listed among the best in the country for excellence in urologic diseases. [7]
Lahey received the American Stroke Association’s Get with the Guidelines-Stroke Initial Performance Achievement Award.[9] Lahey is one of 68 centers classified as Primary Stroke Services by the Massachusetts Department of Public Health. Lahey Clinic has accreditation from the United Network for Organ Sharing (UNOS) to perform live-donor liver transplants. Lahey’s liver team has performed more than 128 live-donor liver transplant surgeries since the program’s inception. | https://www.wikidoc.org/index.php/Lahey_Clinic | |
c551b28975fe8bf52473fded5638a9903bc082b2 | wikidoc | Lamellipodia | Lamellipodia
The lamellipodium (pl. Lamellipodia) is a cytoskeletal actin projection on the mobile edge of the cell. It contains a two-dimensional actin mesh; the whole structure pulls the cell across a substrate (Alberts, et al, 2002). Within the lamellipodia are ribs of actin called microspikes, which, when they spread beyond the lamellipodium frontier, are called filopodia (Small, et all, 2002). The lamellipodium is born of actin nucleation in the plasma membrane of the cell (Alberts, et al, 2002) and is the primary area of actin incorporation or microfilament formation of the cell.
Lamellipodia are found primarily in very mobile cells, in particular the keratinocytes of fish and frogs, which are involved in the quick repair of wounds, crawling at a speeds of 10-20μm/minute over epithelial surfaces. A lamellipodium separated from the main part of a cell by scratching across the cell with a pipette tip can continue to crawl freely about on its own.
Lamellipodia are a characteristic feature at the front, leading edge, of motile cells. They are believed to be the actual motor which pulls the cell forward during the process of cell migration. The tip of the lamellipodium is the site where exocytosis occurs in migrating mammalian cells as part of their clathrin-mediated endocytic cycle. This, together with actin-polymerisation there, helps extend the lamella forward and thus advance the cell's front. It thus acts as a steering device for cells in the process of chemotaxis. It is also the site from which particles or aggregates attached to the cell surface migrate in a process known as cap formation.
Structurally, the plus ends of the microfilaments (localized actin monomers in an ATP-bound form) face the "seeking" edge of the cell, while the minus ends (localized actin monomers in an ADP-bound form) face the lamella behind (Cramer, 1997). This creates treadmilling throughout the lamellipodium, which aids in the retrograde flow of particles throughout (ibid.). Arp2/3 complexes are present at microfilament-microfilament junctions in lamellipodia, and help create the actin meshwork. Arp 2/3 can only join onto previously existing microfilaments, but once bound it creates a site for the extension of new microfilaments, which creates branching (Weed, et al, 2000). Another molecule that is often found in polymerizing actin with Arp2/3 is cortactin, which appears to link tyrosine kinase signalling to cytoskeletal reorganization in the lamellipodium and its associated structures (ibid.).
Rac and Cdc42 are two Rho-family GTPases which are normally cytosolic but can also be found in the cell membrane under certain conditions (Small, et al, 2002). When Cdc42 is activated, it can interact with Wiskott-Aldrich syndrome protein (WASp) family receptors, in particular N-WASp, which then activates Arp2/3. This stimulates actin branching and increases cell motility (Small, et al, 2002). Rac1 induces cortactin to localize to the cell membrane, where it simultaneously binds F-actin and Arp2/3. The result is a structural reorganization of the lamellipodium and ensuing cell motility (Weed, et al, 2000). | Lamellipodia
The lamellipodium (pl. Lamellipodia) is a cytoskeletal actin projection on the mobile edge of the cell. It contains a two-dimensional actin mesh; the whole structure pulls the cell across a substrate (Alberts, et al, 2002). Within the lamellipodia are ribs of actin called microspikes, which, when they spread beyond the lamellipodium frontier, are called filopodia (Small, et all, 2002). The lamellipodium is born of actin nucleation in the plasma membrane of the cell (Alberts, et al, 2002) and is the primary area of actin incorporation or microfilament formation of the cell.
Lamellipodia are found primarily in very mobile cells, in particular the keratinocytes of fish and frogs, which are involved in the quick repair of wounds, crawling at a speeds of 10-20μm/minute over epithelial surfaces. A lamellipodium separated from the main part of a cell by scratching across the cell with a pipette tip can continue to crawl freely about on its own.
Lamellipodia are a characteristic feature at the front, leading edge, of motile cells. They are believed to be the actual motor which pulls the cell forward during the process of cell migration. The tip of the lamellipodium is the site where exocytosis occurs in migrating mammalian cells as part of their clathrin-mediated endocytic cycle. This, together with actin-polymerisation there, helps extend the lamella forward and thus advance the cell's front. It thus acts as a steering device for cells in the process of chemotaxis. It is also the site from which particles or aggregates attached to the cell surface migrate in a process known as cap formation.
Structurally, the plus ends of the microfilaments (localized actin monomers in an ATP-bound form) face the "seeking" edge of the cell, while the minus ends (localized actin monomers in an ADP-bound form) face the lamella behind (Cramer, 1997). This creates treadmilling throughout the lamellipodium, which aids in the retrograde flow of particles throughout (ibid.). Arp2/3 complexes are present at microfilament-microfilament junctions in lamellipodia, and help create the actin meshwork. Arp 2/3 can only join onto previously existing microfilaments, but once bound it creates a site for the extension of new microfilaments, which creates branching (Weed, et al, 2000). Another molecule that is often found in polymerizing actin with Arp2/3 is cortactin, which appears to link tyrosine kinase signalling to cytoskeletal reorganization in the lamellipodium and its associated structures (ibid.).
Rac and Cdc42 are two Rho-family GTPases which are normally cytosolic but can also be found in the cell membrane under certain conditions (Small, et al, 2002). When Cdc42 is activated, it can interact with Wiskott-Aldrich syndrome protein (WASp) family receptors, in particular N-WASp, which then activates Arp2/3. This stimulates actin branching and increases cell motility (Small, et al, 2002). Rac1 induces cortactin to localize to the cell membrane, where it simultaneously binds F-actin and Arp2/3. The result is a structural reorganization of the lamellipodium and ensuing cell motility (Weed, et al, 2000). | https://www.wikidoc.org/index.php/Lamellipodia | |
2351efe99ec15b2df5176750977a995f6bff8e8e | wikidoc | Lamium album | Lamium album
Lamium album (White Deadnettle) is a flowering plant in the family Lamiaceae, native throughout Europe and western Asia, growing in a variety of habitats from open grassland to woodland, generally on moist, fertile soils.
It is a herbaceous perennial plant growing to 50-100 cm tall, with green, four-angled stems. The leaves are 3-8 cm long and 2-5 cm broad, triangular with a rounded base, softly hairy, and with a serrated margin and a petiole up to 5 cm long; they appear superficially similar to those of the Stinging nettle Urtica dioica but do not sting, hence the common name "dead nettle". The flowers are white, produced in whorls ('verticillasters') on the upper part of the stem, the individual flowers 1.5-2.5 cm long.
## Cultivation and uses
The young leaves are edible, and can be used in salads or cooked as a vegetable. The plant also has a number of uses in herbal medicine.
Bees are attracted to the flowers which contain nectar or pollen, hence the plant is sometimes called the Bee Nettle.
It was introduced to North America, where it is widely naturalised.
# Notes | Lamium album
Lamium album (White Deadnettle) is a flowering plant in the family Lamiaceae, native throughout Europe and western Asia, growing in a variety of habitats from open grassland to woodland, generally on moist, fertile soils.
It is a herbaceous perennial plant growing to 50-100 cm tall, with green, four-angled stems. The leaves are 3-8 cm long and 2-5 cm broad, triangular with a rounded base, softly hairy, and with a serrated margin and a petiole up to 5 cm long; they appear superficially similar to those of the Stinging nettle Urtica dioica but do not sting, hence the common name "dead nettle". The flowers are white, produced in whorls ('verticillasters') on the upper part of the stem, the individual flowers 1.5-2.5 cm long.
## Cultivation and uses
The young leaves are edible, and can be used in salads or cooked as a vegetable. The plant also has a number of uses in herbal medicine.
Bees are attracted to the flowers which contain nectar or pollen, hence the plant is sometimes called the Bee Nettle. [1]
It was introduced to North America, where it is widely naturalised.
# Notes
- ↑ http://www.botanical.com/botanical/mgmh/n/nettle03.html
# External links
- Flora Europaea: Lamium album
- Plants for a Future: Lamium album
- File:Lamium album closeup.jpg
- File:Lamium album leaf.jpg
- File:Lamium album plants.jpg
- File:Lamium album.JPG
- File:Lamium album(01).jpg
- File:Small Lamium album plants and a stone.JPG
- File:Lamium album 2.jpg
- File:Lamium album.jpg
- File:Lamium-album-total.JPG
- File:Lamium album no flowers.jpg
cs:Hluchavka bílá
de:Weiße Taubnessel
hsb:Běła cycawka
lt:Baltažiedė notrelė
nl:Witte dovenetel
sk:Hluchavka biela
sv:Vitplister
uk:Глуха кропива біла
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Lamium_album | |
3357ebb872230ca3eab9488d101fef2b4ca9e7ce | wikidoc | Lansoprazole | Lansoprazole
# 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
Lansoprazole is a gastrointestinal, anti-ulcer agent that is FDA approved for the treatment of duodenal ulcer disease, erosive esophagitis, erosive esophagitis- maintanance, short-term treatment of active gastric ulcer, gastric ulcer - NSAID-associated gastropathy, gastroesophageal reflux disease, Zollinger-Ellison syndrome and for prophylaxis of gastric ulcer. Common adverse reactions include abdominal pain, constipation, diarrhea, nausea, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Helicobacter pylori gastrointestinal tract infection, Dual therapy: dual therapy is not recommended due to the increasing resistance rates in Helicobacter pylori infections
- Dosing Information
- Treatment of active ulcer, 15 mg ORALLY once daily up to 4 weeks
- Maintenance of healed ulcer, 15 mg ORALLY once daily
- Dosing Information
- 30 mg ORALLY twice daily in combination with amoxicillin 1 gram ORALLY twice daily and clarithromycin 500 mg ORALLY twice daily for 10 to 14 days
- 30 mg ORALLY twice daily in combination with metronidazole 500 mg ORALLY twice daily and clarithromycin 500 mg ORALLY twice daily for 10 to 14 days
- Dosing Information
- 30 mg ORALLY once daily for 8 to 16 weeks; another 8 weeks for recurrence may be considered
- Dosing Information
- 15 mg ORALLY once daily
- Dosing Information
- 30 mg ORALLY once daily up to 8 weeks
- Dosing Information
- 15 mg ORALLY once daily up to 12 weeks
- Dosing Information
- 30 mg ORALLY once daily for 8 weeks
- Dosing Information
- 15 mg ORALLY once daily up to 8 weeks
- Dosing Information
- 60 mg ORALLY once daily up to 90 mg twice daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lansoprazole in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Helicobacter pylori gastrointestinal tract infection, Quadruple therapy: (quadruple therapy) lansoprazole 30 mg ORALLY twice daily, metronidazole 250 mg ORALLY four times a day, bismuth subsalicylate 525 mg ORALLY four times a day and tetracycline 500 mg ORALLY four times a day for 10 to 14 days
### Heartburn
- Dosing Information
- 15 mg ORALLY once a day for 14 days
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- 1 to 11 years of age, weight 30 kg or less, 15 mg ORALLY once daily for up to 12 weeks, may increase dose up to 30 mg twice daily if symptoms persist after 2 or more weeks of treatment
- 1 to 11 years of age, weight more than 30 kg, 30 mg ORALLY once daily for up to 12 weeks, may increase dose up to 30 mg twice daily if symptoms persist after 2 or more weeks of treatment
- 12 years of age and older, 30 mg ORALLY once daily for up to 8 weeks
- Dosing Information
- Dosing Information
- 1 to 11 years of age, weight greater than 30 kg, 30 mg ORALLY once daily for up to 12 wk, may increase dose up to 30 mg twice daily if symptoms persist after 2 or more weeks of treatment
- 12 years of age and older, 15 mg once daily for up to 8 weeks
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lansoprazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lansoprazole in pediatric patients.
# Contraindications
- Condition1
# Warnings
Allergy alert: Do not use if you are allergic to lansoprazole
Do not use
- if you have trouble or pain swallowing food, vomiting with blood, or bloody or black stools. These may be signs of a serious condition. See your doctor.
Ask a doctor before use if you have
- liver disease
- had heartburn over 3 months. This may be a sign of a more serious condition.
- heartburn with lightheadedness, sweating or dizziness
- chest pain or shoulder pain with shortness of breath; sweating; pain spreading to arms, neck or shoulders; or lightheadedness
- frequent chest pain
- frequent wheezing, particularly with heartburn
- unexplained weight loss
- nausea or vomiting
- stomach pain
Ask a doctor or pharmacist before use if you are taking
- warfarin (blood-thinning medicine)
- prescription antifungal or anti-yeast medicines
- digoxin (heart medicine)
- theophylline (asthma medicine)
- tacrolimus (immune system medicine)
- atazanavir (medicine for HIV infection)
Stop use and ask a doctor if
- your heartburn continues or worsens
- you need to take this product for more than 14 days
- you need to take more than 1 course of treatment every 4 months
- you get diarrhea
If pregnant or breast-feeding,
- ask a health professional before use.
Keep out of reach of children.
- In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Lansoprazole Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Lansoprazole Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Lansoprazole Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lansoprazole in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Lansoprazole during labor and delivery.
### Nursing Mothers
- There is no FDA guidance on the use of Lansoprazole with respect to nursing mothers.
### Pediatric Use
- There is no FDA guidance on the use of Lansoprazole with respect to pediatric patients.
### Geriatic Use
- There is no FDA guidance on the use of Lansoprazole with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Lansoprazole with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Lansoprazole with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Lansoprazole in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Lansoprazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Lansoprazole in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Lansoprazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Lansoprazole Administration in the drug label.
### Monitoring
- There is limited information regarding Monitoring of Lansoprazole in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Lansoprazole in the drug label.
# Overdosage
There is limited information regarding Lansoprazole overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
## Structure
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Lansoprazole in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Lansoprazole in the drug label.
## Nonclinical Toxicology
- There is limited information regarding Nonclinical Toxicology of Lansoprazole in the drug label.
# Clinical Studies
- There is limited information regarding Clinical Studies of Lansoprazole in the drug label.
# How Supplied
## Storage
There is limited information regarding Lansoprazole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Adults 18 years of age and older
- this product is to be used once a day (every 24 hours), every day for 14 days
- it may take 1 to 4 days for full effect, although some people get complete relief of symptoms within 24 hours
14-Day Course of Treatment
- swallow 1 capsule with a glass of water before eating in the morning
- take every day for 14 days
- do not take more than 1 capsule a day
- swallow whole. Do not crush or chew capsules.
- do not use for more than 14 days unless directed by your doctor
Repeated 14-Day Courses (if needed)
- you may repeat a 14-day course every 4 months
- do not take for more than 14 days or more often than every 4 months unless directed by a doctor
- children under 18 years of age: ask a doctor before use. Heartburn in children may sometimes be caused by a serious condition.
Other information
- read the directions, warnings and package insert before use
- keep the carton and package insert. They contain important information.
- store at 20-25°C (68-77°F)
- keep product out of high heat and humidity
- protect product from moisture
# Precautions with Alcohol
- Alcohol-Lansoprazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Prevacid,
Prevacid I.V.,
Prevacid SoluTab,
First - Lansoprazole
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Lansoprazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Lansoprazole is a gastrointestinal, anti-ulcer agent that is FDA approved for the treatment of duodenal ulcer disease, erosive esophagitis, erosive esophagitis- maintanance, short-term treatment of active gastric ulcer, gastric ulcer - NSAID-associated gastropathy, gastroesophageal reflux disease, Zollinger-Ellison syndrome and for prophylaxis of gastric ulcer. Common adverse reactions include abdominal pain, constipation, diarrhea, nausea, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Helicobacter pylori gastrointestinal tract infection, Dual therapy: dual therapy is not recommended due to the increasing resistance rates in Helicobacter pylori infections
- Dosing Information
- Treatment of active ulcer, 15 mg ORALLY once daily up to 4 weeks
- Maintenance of healed ulcer, 15 mg ORALLY once daily
- Dosing Information
- 30 mg ORALLY twice daily in combination with amoxicillin 1 gram ORALLY twice daily and clarithromycin 500 mg ORALLY twice daily for 10 to 14 days
- 30 mg ORALLY twice daily in combination with metronidazole 500 mg ORALLY twice daily and clarithromycin 500 mg ORALLY twice daily for 10 to 14 days
- Dosing Information
- 30 mg ORALLY once daily for 8 to 16 weeks; another 8 weeks for recurrence may be considered
- Dosing Information
- 15 mg ORALLY once daily
- Dosing Information
- 30 mg ORALLY once daily up to 8 weeks
- Dosing Information
- 15 mg ORALLY once daily up to 12 weeks
- Dosing Information
- 30 mg ORALLY once daily for 8 weeks
- Dosing Information
- 15 mg ORALLY once daily up to 8 weeks
- Dosing Information
- 60 mg ORALLY once daily up to 90 mg twice daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lansoprazole in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Helicobacter pylori gastrointestinal tract infection, Quadruple therapy: (quadruple therapy) lansoprazole 30 mg ORALLY twice daily, metronidazole 250 mg ORALLY four times a day, bismuth subsalicylate 525 mg ORALLY four times a day and tetracycline 500 mg ORALLY four times a day for 10 to 14 days
### Heartburn
- Dosing Information
- 15 mg ORALLY once a day for 14 days
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- 1 to 11 years of age, weight 30 kg or less, 15 mg ORALLY once daily for up to 12 weeks, may increase dose up to 30 mg twice daily if symptoms persist after 2 or more weeks of treatment
- 1 to 11 years of age, weight more than 30 kg, 30 mg ORALLY once daily for up to 12 weeks, may increase dose up to 30 mg twice daily if symptoms persist after 2 or more weeks of treatment
- 12 years of age and older, 30 mg ORALLY once daily for up to 8 weeks
- Dosing Information
- Dosing Information
- 1 to 11 years of age, weight greater than 30 kg, 30 mg ORALLY once daily for up to 12 wk, may increase dose up to 30 mg twice daily if symptoms persist after 2 or more weeks of treatment
- 12 years of age and older, 15 mg once daily for up to 8 weeks
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lansoprazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lansoprazole in pediatric patients.
# Contraindications
- Condition1
# Warnings
Allergy alert: Do not use if you are allergic to lansoprazole
Do not use
- if you have trouble or pain swallowing food, vomiting with blood, or bloody or black stools. These may be signs of a serious condition. See your doctor.
Ask a doctor before use if you have
- liver disease
- had heartburn over 3 months. This may be a sign of a more serious condition.
- heartburn with lightheadedness, sweating or dizziness
- chest pain or shoulder pain with shortness of breath; sweating; pain spreading to arms, neck or shoulders; or lightheadedness
- frequent chest pain
- frequent wheezing, particularly with heartburn
- unexplained weight loss
- nausea or vomiting
- stomach pain
Ask a doctor or pharmacist before use if you are taking
- warfarin (blood-thinning medicine)
- prescription antifungal or anti-yeast medicines
- digoxin (heart medicine)
- theophylline (asthma medicine)
- tacrolimus (immune system medicine)
- atazanavir (medicine for HIV infection)
Stop use and ask a doctor if
- your heartburn continues or worsens
- you need to take this product for more than 14 days
- you need to take more than 1 course of treatment every 4 months
- you get diarrhea
If pregnant or breast-feeding,
- ask a health professional before use.
Keep out of reach of children.
- In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Lansoprazole Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Lansoprazole Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Lansoprazole Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lansoprazole in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Lansoprazole during labor and delivery.
### Nursing Mothers
- There is no FDA guidance on the use of Lansoprazole with respect to nursing mothers.
### Pediatric Use
- There is no FDA guidance on the use of Lansoprazole with respect to pediatric patients.
### Geriatic Use
- There is no FDA guidance on the use of Lansoprazole with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Lansoprazole with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Lansoprazole with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Lansoprazole in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Lansoprazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Lansoprazole in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Lansoprazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Lansoprazole Administration in the drug label.
### Monitoring
- There is limited information regarding Monitoring of Lansoprazole in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Lansoprazole in the drug label.
# Overdosage
There is limited information regarding Lansoprazole overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
-
## Structure
-
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Lansoprazole in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Lansoprazole in the drug label.
## Nonclinical Toxicology
- There is limited information regarding Nonclinical Toxicology of Lansoprazole in the drug label.
# Clinical Studies
- There is limited information regarding Clinical Studies of Lansoprazole in the drug label.
# How Supplied
-
## Storage
There is limited information regarding Lansoprazole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Adults 18 years of age and older
- this product is to be used once a day (every 24 hours), every day for 14 days
- it may take 1 to 4 days for full effect, although some people get complete relief of symptoms within 24 hours
14-Day Course of Treatment
- swallow 1 capsule with a glass of water before eating in the morning
- take every day for 14 days
- do not take more than 1 capsule a day
- swallow whole. Do not crush or chew capsules.
- do not use for more than 14 days unless directed by your doctor
Repeated 14-Day Courses (if needed)
- you may repeat a 14-day course every 4 months
- do not take for more than 14 days or more often than every 4 months unless directed by a doctor
- children under 18 years of age: ask a doctor before use. Heartburn in children may sometimes be caused by a serious condition.
Other information
- read the directions, warnings and package insert before use
- keep the carton and package insert. They contain important information.
- store at 20-25°C (68-77°F)
- keep product out of high heat and humidity
- protect product from moisture
# Precautions with Alcohol
- Alcohol-Lansoprazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Prevacid,
Prevacid I.V.,
Prevacid SoluTab,
First - Lansoprazole
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lansoprazole | |
ccd530a981cfac83c0488091c7ff7419b05038d5 | wikidoc | Lantibiotics | Lantibiotics
Lantibiotics are a class of peptide antibiotics that contain polycyclic thioether amino acids as well as the unsaturated amino acids dehydroalanine and 2-aminoisobutyric acid. These characteristic cyclic thioether amino acids are composed of either lanthionine or methyllanthionine. Lantibiotics are produced by a large number of Gram positive bacteria such as Streptococcus and Streptomyces to attack other gram positive bacteria and as such they are considered a member of the bacteriocins.
Lantibiotics are well studied because of the commercial use of these bacteria in the food industry for making dairy products such as cheese. Bacteriocins are classified according to their extent of posttranslational modification. The lantibiotics are a class of more extensively modified bacteriocins, also called Class I. Bacteriocins for which disulfide bonds are the only modification to the peptide are Class II bacteriocins. Most bacteriocins are biologically active single-chain peptides. Some are only active as partners with a second peptide (see Class IIb, below).
Nisin and epidermin are members of a family of lantibiotics that bind to a cell wall precursor lipid component of target bacteria and disrupt cell wall production. The duramycin family of lantibiotics binds phosphoethanolamine in the membranes of its target cells and seem to disrupt several physiological functions.
# History
The name Lantibiotics was introduced in 1988 as an abbreviation for "Lanthionine-containing peptide antibiotics". The first structures of these antimicrobial agents were produced by pioneering work by Gross and Morell in the late sixties and early seventies, thus marking the formal introduction of Lantibiotics. Since then Lantibiotics such as Nisin have been used auspiciously for food preservation and have yet to encounter significant bacterial resistance. These attributes of lantibiotics have led to more detailed research into their structures and biosynthetic pathways.
# Classification
- Type A Lantibiotics are long flexible molecules - eg Nisin, subtilin, epidermin. Subgroup AI includes Mutacin II, subgroup AII includes Mutacin I & III.
- Type B Lantibiotics are globular - eg mersacidin, actagardine, cinnamycin.
# Biosynthesis
The biosynthesis is interesting . They are synthesised with a leader polypeptide sequence which is only removed during the transport of the molecule out of the synthesising cell.
# Mechanism of action
Lantibiotics show substantial specificity for some components (eg lipid II) of bacterial cell membranes especially of Gram positive bacteria. Type A kill rapidly by pore formation, type B inhibit peptidoglycan biosynthesis. See Brotz and Sahl. JAC (2000) 46, 1-6 for discussion of mechanism of action. They are active in very low concentrations.
# Application
Lantibiotics are produced by Gram-positive bacteria and show strong antimicrobial action towards a wide range of other Gram-positive bacteria. As such they have become attractive candidates for use in food preservation (by inhibiting pathogens that cause food spoilage) and the pharmaceutical industry (to prevent or fight infections in humans or animals). See C. van Kraaij et al, Nat. Prod. Rep. (1999), 16, 583 - 584 for more detailed disccusion of the pharmaceutical application of lantibiotics. | Lantibiotics
Lantibiotics are a class of peptide antibiotics that contain polycyclic thioether amino acids as well as the unsaturated amino acids dehydroalanine and 2-aminoisobutyric acid. These characteristic cyclic thioether amino acids are composed of either lanthionine or methyllanthionine. Lantibiotics are produced by a large number of Gram positive bacteria such as Streptococcus and Streptomyces to attack other gram positive bacteria and as such they are considered a member of the bacteriocins.
Lantibiotics are well studied because of the commercial use of these bacteria in the food industry for making dairy products such as cheese. Bacteriocins are classified according to their extent of posttranslational modification. The lantibiotics are a class of more extensively modified bacteriocins, also called Class I. Bacteriocins for which disulfide bonds are the only modification to the peptide are Class II bacteriocins. Most bacteriocins are biologically active single-chain peptides. Some are only active as partners with a second peptide (see Class IIb, below).
Nisin and epidermin are members of a family of lantibiotics that bind to a cell wall precursor lipid component of target bacteria and disrupt cell wall production. The duramycin family of lantibiotics binds phosphoethanolamine in the membranes of its target cells and seem to disrupt several physiological functions.
# History
[1]The name Lantibiotics was introduced in 1988 as an abbreviation for "Lanthionine-containing peptide antibiotics". The first structures of these antimicrobial agents were produced by pioneering work by Gross and Morell in the late sixties and early seventies, thus marking the formal introduction of Lantibiotics. Since then Lantibiotics such as Nisin have been used auspiciously for food preservation and have yet to encounter significant bacterial resistance. These attributes of lantibiotics have led to more detailed research into their structures and biosynthetic pathways.
# Classification
- Type A Lantibiotics are long flexible molecules - eg Nisin, subtilin, epidermin. Subgroup AI includes Mutacin II, subgroup AII includes Mutacin I & III.
- Type B Lantibiotics are globular - eg mersacidin, actagardine, cinnamycin.
# Biosynthesis
The biosynthesis is interesting <details to be added>. They are synthesised with a leader polypeptide sequence which is only removed during the transport of the molecule out of the synthesising cell.
# Mechanism of action
Lantibiotics show substantial specificity for some components (eg lipid II) of bacterial cell membranes especially of Gram positive bacteria. Type A kill rapidly by pore formation, type B inhibit peptidoglycan biosynthesis. See Brotz and Sahl. JAC (2000) 46, 1-6 for discussion of mechanism of action. They are active in very low concentrations.
# Application
[2]Lantibiotics are produced by Gram-positive bacteria and show strong antimicrobial action towards a wide range of other Gram-positive bacteria. As such they have become attractive candidates for use in food preservation (by inhibiting pathogens that cause food spoilage) and the pharmaceutical industry (to prevent or fight infections in humans or animals). See C. van Kraaij et al, Nat. Prod. Rep. (1999), 16, 583 - 584 for more detailed disccusion of the pharmaceutical application of lantibiotics. | https://www.wikidoc.org/index.php/Lantibiotics | |
62e6d0a41060c8dc8a6d958bfff3a1175b33b5e3 | wikidoc | Propiomazine | Propiomazine
# Overview
Propiomazine (Largon, Propavan, Indorm, Serentin, Dorevane, Dorevan) is an antihistamine blocking H1 receptors. It is used to treat insomnia, and to produce sleepiness or drowsiness and to relieve anxiety before or during surgery or other procedures and in combination with analgetics also during labor. Propiomazine is a phenothiazine, but is not used as a neuroleptic because it does not block dopamine receptors well.
# Mechanism of action
Propiomazine is an antagonist at types 1, 2, and 4 dopamine receptors, serotonin (5-HT) receptor types 2A and 2C, muscarinic receptors 1 through 5, alpha(1)-receptors, and histamine H1-receptors. Propiomazine's antipsychotic effect is due to antagonism at dopamine and serotonin type 2 receptors, with greater activity at serotonin 5-HT2 receptors than at dopamine type-2 receptors. This may explain the lack of extrapyramidal effects. Propiomazine does not appear to block dopamine within the tubero-infundibular tract, explaining the lower incidence of hyperprolactinemia than with typical antipsychotic agents or risperidone.
# Side effects
Rare, serious side effects include convulsions (seizures); difficult or unusually fast breathing; fast or irregular heartbeat or pulse; fever (high); high or low blood pressure; loss of bladder control; muscle stiffness (severe); unusual increase in sweating; unusually pale skin; and unusual tiredness or weakness.
Drowsiness is a usual side effect. | Propiomazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Propiomazine (Largon, Propavan, Indorm, Serentin, Dorevane, Dorevan) is an antihistamine blocking H1 receptors. It is used to treat insomnia, and to produce sleepiness or drowsiness and to relieve anxiety before or during surgery or other procedures and in combination with analgetics also during labor. Propiomazine is a phenothiazine, but is not used as a neuroleptic because it does not block dopamine receptors well.
# Mechanism of action
Propiomazine is an antagonist at types 1, 2, and 4 dopamine receptors, serotonin (5-HT) receptor types 2A and 2C, muscarinic receptors 1 through 5, alpha(1)-receptors, and histamine H1-receptors. Propiomazine's antipsychotic effect is due to antagonism at dopamine and serotonin type 2 receptors, with greater activity at serotonin 5-HT2 receptors than at dopamine type-2 receptors. This may explain the lack of extrapyramidal effects. Propiomazine does not appear to block dopamine within the tubero-infundibular tract, explaining the lower incidence of hyperprolactinemia than with typical antipsychotic agents or risperidone.
# Side effects
Rare, serious side effects include convulsions (seizures); difficult or unusually fast breathing; fast or irregular heartbeat or pulse; fever (high); high or low blood pressure; loss of bladder control; muscle stiffness (severe); unusual increase in sweating; unusually pale skin; and unusual tiredness or weakness.
Drowsiness is a usual side effect. | https://www.wikidoc.org/index.php/Largon | |
28efed46fd1790418eb72905c177fe5b69023733 | wikidoc | Laryngospasm | Laryngospasm
# Overview
In medicine, laryngospasm is an uncontrolled/involuntary muscular contraction (spasm) of the laryngeal cords. The condition typically lasts less than 30 or 60 seconds, and causes a partial blocking of breathing in, while breathing out remains easier. It may be triggered when the vocal cords or the area of the trachea below the cords detects the entry of water, mucus, blood, or other substance. It is characterized by stridor and or retractions. Some people suffer from frequent laryngospasms, whether awake or asleep. In an ear, nose and throat practice, it is typically seen in people who have silent reflux disease. It is also a well known, infrequent, but serious post-surgery complication.
# Etiology
It is a complication associated with anesthesia. The spasm can happen often without any provocation, but tends to occur after tracheal extubation. Drugs like Penicillin G potassium, Oxacillin can cause laryngospasm.
# Treatment
Laryngospasm in the operating room is treated by hyperextending the patient's neck and administering assisted ventilation with 100% oxygen. In more serious cases it may require the administration of an intravenous muscle relaxant and reintubation.
In ear, nose and throat practices, it is treated by examining the patient in the office and reassuring the patient that laryngospasm resolves. Sometimes reflux medication is used to reduce the acidity in the stomach. | Laryngospasm
Editor-in-Chief: Santosh Patel M.D., FRCA [1]
# Overview
In medicine, laryngospasm is an uncontrolled/involuntary muscular contraction (spasm) of the laryngeal cords. The condition typically lasts less than 30 or 60 seconds, and causes a partial blocking of breathing in, while breathing out remains easier. It may be triggered when the vocal cords or the area of the trachea below the cords detects the entry of water, mucus, blood, or other substance. It is characterized by stridor and or retractions. Some people suffer from frequent laryngospasms, whether awake or asleep. In an ear, nose and throat practice, it is typically seen in people who have silent reflux disease. It is also a well known, infrequent, but serious post-surgery complication.
# Etiology
It is a complication associated with anesthesia. The spasm can happen often without any provocation, but tends to occur after tracheal extubation. Drugs like Penicillin G potassium, Oxacillin can cause laryngospasm.
# Treatment
Laryngospasm in the operating room is treated by hyperextending the patient's neck and administering assisted ventilation with 100% oxygen. In more serious cases it may require the administration of an intravenous muscle relaxant and reintubation.
In ear, nose and throat practices, it is treated by examining the patient in the office and reassuring the patient that laryngospasm resolves. Sometimes reflux medication is used to reduce the acidity in the stomach.
# External links
- Template:GPnotebook
- emerg/802 at eMedicine "Ketamine: Emergency Applications" - discusses laryngospasm.
- Information for patients with laryngospasm - voicedoctor.net
Template:Respiratory pathology
sv:Laryngospasm
de:Stimmritzenkrampf
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Laryngeal_spasm | |
92c0b7a4115af00263552b6109c71fd551cc48b5 | wikidoc | Laryngectomy | Laryngectomy
# Overview
Laryngectomy is the surgical removal of the larynx and separation of the airway from the mouth, nose, and esophagus. The laryngectomee breathes through an opening in the neck, a stoma. It is done in cases of laryngeal cancer. However, many laryngeal cancer cases are now treated only with radiation and chemotherapy or other laser procedures, and laryngectomy is performed when those treatments fail to conserve the larynx.
Voice functions are generally replaced with a voice prosthesis placed in the tracheo esophageal puncture created by the surgeon. The voice prosthesis vibrates the esophageal tissue in lieu of the larynx. A second method is the use of an electrolarynx. An electrolarynx is an external device that is placed against the neck and creates vibration that the speaker then articulates. The sound has been characterized as mechanical and robotic. A third method is called esophageal speech. The speaker pushes air into the esophagus and then pushes it back up, articulating speech sounds to speak. This method is time-consuming and difficult to learn and is seldom used by laryngectomees. A fourth method is the use of the UltraVoice speaking device which is built into an upper denture or retainer and worn inside the patient's mouth. The speech from the Ultravoice has computer controlled prosody which changes the pitch creating a more natural sound than the electrolarynx.
Laryngectomees number about 60,000 in the United States. Perhaps 10,000 laryngeal cancer cases are treated annually, but only about 3,000 people are laryngectomized. Because it is a relatively rare cancer and because the post-operative care is complex in achieving a functional result, laryngeal cancer patients should be treated at or at least consult a major federally designated cancer center, where the fields of surgery, radiology, chemotherapy, speech-language pathology are integrated in head and neck departments.
Laryngectomies may be applied to dogs as a debarking procedure.
nl:Laryngectomie
de:Laryngektomie | Laryngectomy
Template:Interventions infobox
# Overview
Laryngectomy is the surgical removal of the larynx and separation of the airway from the mouth, nose, and esophagus. The laryngectomee breathes through an opening in the neck, a stoma. It is done in cases of laryngeal cancer. However, many laryngeal cancer cases are now treated only with radiation and chemotherapy or other laser procedures, and laryngectomy is performed when those treatments fail to conserve the larynx.
Voice functions are generally replaced with a voice prosthesis placed in the tracheo esophageal puncture created by the surgeon. The voice prosthesis vibrates the esophageal tissue in lieu of the larynx. A second method is the use of an electrolarynx. An electrolarynx is an external device that is placed against the neck and creates vibration that the speaker then articulates. The sound has been characterized as mechanical and robotic. A third method is called esophageal speech. The speaker pushes air into the esophagus and then pushes it back up, articulating speech sounds to speak. This method is time-consuming and difficult to learn and is seldom used by laryngectomees. A fourth method is the use of the UltraVoice speaking device which is built into an upper denture or retainer and worn inside the patient's mouth. The speech from the Ultravoice has computer controlled prosody which changes the pitch creating a more natural sound than the electrolarynx.
Laryngectomees number about 60,000 in the United States. Perhaps 10,000 laryngeal cancer cases are treated annually, but only about 3,000 people are laryngectomized. Because it is a relatively rare cancer and because the post-operative care is complex in achieving a functional result, laryngeal cancer patients should be treated at or at least consult a major federally designated cancer center, where the fields of surgery, radiology, chemotherapy, speech-language pathology are integrated in head and neck departments.
Laryngectomies may be applied to dogs as a debarking procedure.
Template:Respiratory system surgeries and other procedures
nl:Laryngectomie
de:Laryngektomie
Template:WS
Template:Jb1 | https://www.wikidoc.org/index.php/Laryngectomy | |
f61e824ab802dc7357b42e5061464096449a4559 | wikidoc | Lasker Award | Lasker Award
The Albert Lasker Medical Research Awards have been awarded annually since 1946 to living persons who have made major contributions to medical science. They are administered by the Lasker Foundation, founded by advertising pioneer Albert Lasker and his wife Mary Woodward Lasker (later an influential medical research activist). The awards are sometimes referred to as "America's Nobels." As of 2005, 71 recipients have gone on to win the Nobel Prize in Physiology or Medicine. James W. Fordyce is the current President of the Foundation.
The four main awards are:
- Albert Lasker Award for Basic Medical Research
- Albert Lasker Award for Clinical Medical Research
- Mary Woodard Lasker Award for Public Service (renamed in 2000 from Albert Lasker Public Service Award)
- Albert Lasker Special Achievement Award (1994-)
# Recent awards
Generally the Lasker Award is given in three categories – Basic Medical Research, Clinical Medical Research, and the Special Achievement Award. Recent winners include the following:
- Basic – Robert G. Roeder, Rockefeller University
- Clinical – Marc Feldmann and Ravinder N. Maini
- Basic – Pierre Chambon, Ronald M. Evans and Elwood V. Jensen
- Clinical – Charles Kelman, New York Medical College
- Basic – Ernest A. McCulloch and James E. Till
- Clinical – Alec John Jeffreys and Edwin Mellor Southern
Winners of the 2006 Lasker Awards were announced September 16, 2006. Among announcements were the following awards: (Reuters), (laskerfoundation.org)
- The Albert Lasker Award for Basic Medical Research, for work on telomerase and genome integrity, went to:
Elizabeth Blackburn (University of California, San Francisco),
Carol W. Greider (Johns Hopkins University School of Medicine), and
Jack Szostak (Harvard Medical School and the Howard Hughes Medical Institute)
- Elizabeth Blackburn (University of California, San Francisco),
- Carol W. Greider (Johns Hopkins University School of Medicine), and
- Jack Szostak (Harvard Medical School and the Howard Hughes Medical Institute)
- Albert Lasker Award for Clinical Medical Research:
Aaron T. Beck (University of Pennsylvania School of Medicine) for developing cognitive therapy.
- Aaron T. Beck (University of Pennsylvania School of Medicine) for developing cognitive therapy.
- Albert Lasker Special Achievement Award:
Joseph G. Gall (Carnegie Institution of Washington) for his work as an early leader of modern cell biology, particularly for the development of in situ hybridization, and as an early champion of women in science.
- Joseph G. Gall (Carnegie Institution of Washington) for his work as an early leader of modern cell biology, particularly for the development of in situ hybridization, and as an early champion of women in science.
On September 15, 2007, the Albert and Mary Lasker Foundation announced the 2007 Lasker Award winners which included 2 surgeons:
- Drs. Alain Carpentier, 74, Georges Pompidou hospital in Paris;
- Albert Starr, 81, of the Providence Health System in Portland, Oregon;
- Dr. Ralph Steinman, 64, of Rockefeller University in Manhattan;
- and Dr. Anthony Fauci, 66, an internationally known immunologist.
Dr. Steinman and Dr. Fauci will each receive $150,000 and Dr. Starr and Dr. Carpentier will each receive $75,000. | Lasker Award
The Albert Lasker Medical Research Awards have been awarded annually since 1946 to living persons who have made major contributions to medical science. They are administered by the Lasker Foundation, founded by advertising pioneer Albert Lasker and his wife Mary Woodward Lasker (later an influential medical research activist). The awards are sometimes referred to as "America's Nobels." As of 2005, 71 recipients have gone on to win the Nobel Prize in Physiology or Medicine. James W. Fordyce is the current President of the Foundation.
The four main awards are:
- Albert Lasker Award for Basic Medical Research
- Albert Lasker Award for Clinical Medical Research
- Mary Woodard Lasker Award for Public Service (renamed in 2000 from Albert Lasker Public Service Award)
- Albert Lasker Special Achievement Award (1994-)
# Recent awards
Generally the Lasker Award is given in three categories – Basic Medical Research, Clinical Medical Research, and the Special Achievement Award. Recent winners include the following:
## 2003
- Basic – Robert G. Roeder, Rockefeller University
- Clinical – Marc Feldmann and Ravinder N. Maini
## 2004
- Basic – Pierre Chambon, Ronald M. Evans and Elwood V. Jensen
- Clinical – Charles Kelman, New York Medical College
## 2005
- Basic – Ernest A. McCulloch and James E. Till
- Clinical – Alec John Jeffreys and Edwin Mellor Southern
## 2006
Winners of the 2006 Lasker Awards were announced September 16, 2006. Among announcements were the following awards: (Reuters), (laskerfoundation.org)
- The Albert Lasker Award for Basic Medical Research, for work on telomerase and genome integrity, went to:
Elizabeth Blackburn (University of California, San Francisco),
Carol W. Greider (Johns Hopkins University School of Medicine), and
Jack Szostak (Harvard Medical School and the Howard Hughes Medical Institute)
- Elizabeth Blackburn (University of California, San Francisco),
- Carol W. Greider (Johns Hopkins University School of Medicine), and
- Jack Szostak (Harvard Medical School and the Howard Hughes Medical Institute)
- Albert Lasker Award for Clinical Medical Research:
Aaron T. Beck (University of Pennsylvania School of Medicine) for developing cognitive therapy.
- Aaron T. Beck (University of Pennsylvania School of Medicine) for developing cognitive therapy.
- Albert Lasker Special Achievement Award:
Joseph G. Gall (Carnegie Institution of Washington) for his work as an early leader of modern cell biology, particularly for the development of in situ hybridization, and as an early champion of women in science.
- Joseph G. Gall (Carnegie Institution of Washington) for his work as an early leader of modern cell biology, particularly for the development of in situ hybridization, and as an early champion of women in science.
## 2007
On September 15, 2007, the Albert and Mary Lasker Foundation announced the 2007 Lasker Award winners which included 2 surgeons:
- Drs. Alain Carpentier, 74, Georges Pompidou hospital in Paris;
- Albert Starr, 81, of the Providence Health System in Portland, Oregon;
- Dr. Ralph Steinman, 64, of Rockefeller University in Manhattan;
- and Dr. Anthony Fauci, 66, an internationally known immunologist.
Dr. Steinman and Dr. Fauci will each receive $150,000 and Dr. Starr and Dr. Carpentier will each receive $75,000.[7]
# External links
- The Lasker Foundation - Official site | https://www.wikidoc.org/index.php/Lasker_Award | |
f7bd51ddd21d3781361ffe34076f7f4f2d8d2216 | wikidoc | Lasofoxifene | Lasofoxifene
# Overview
Lasofoxifene (INN) (proposed tradename Fablyn) is a non-steroidal selective estrogen receptor modulator (SERM) which is under development by Pfizer for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy, and the result of an exclusive research collaboration with Ligand Pharmaceuticals (LGND). It also appears to have had a statistically significant effect of reducing breast cancer in women according to a study published online November 4 in The Journal of the National Cancer Institute.
In September 2005, Pfizer received a non-approvable letter from the U.S. Food and Drug Administration regarding lasofoxifene (trade name Oporia), a selective estrogen receptor modulator for the prevention of osteoporosis.
On January 2008, Ligand Pharmaceuticals, through its marketing partner, Pfizer, submitted a New Drug Application for lasofoxifene, which is expected to be marketed under the tradename Fablyn. Lasofoxifene was approved in the EU under the brand name Fablyn by the EMEA in March 2009.
Lasofoxifene is a desmethyl dihydro analog of nafoxidine.
# Treatment
In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. | Lasofoxifene
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lasofoxifene (INN) (proposed tradename Fablyn) is a non-steroidal selective estrogen receptor modulator (SERM) which is under development by Pfizer for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy,[1] and the result of an exclusive research collaboration with Ligand Pharmaceuticals (LGND). It also appears to have had a statistically significant effect of reducing breast cancer in women according to a study published online November 4 in The Journal of the National Cancer Institute.
In September 2005, Pfizer received a non-approvable letter from the U.S. Food and Drug Administration regarding lasofoxifene (trade name Oporia), a selective estrogen receptor modulator for the prevention of osteoporosis.
On January 2008, Ligand Pharmaceuticals, through its marketing partner, Pfizer, submitted a New Drug Application for lasofoxifene, which is expected to be marketed under the tradename Fablyn. Lasofoxifene was approved in the EU under the brand name Fablyn by the EMEA in March 2009.[2]
Lasofoxifene is a desmethyl dihydro analog of nafoxidine.[3]
# Treatment
In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events.[4][5] | https://www.wikidoc.org/index.php/Lasofoxifene | |
4a0265dd8e3337579ecc7d023b560e2f6604c295 | wikidoc | Latin square | Latin square
A Latin square is an n × n table filled with n different symbols in such a way that each symbol occurs exactly once in each row and exactly once in each column. Here are two examples:
\begin{bmatrix}
\end{bmatrix}
\begin{bmatrix}
\end{bmatrix}
Latin squares occur as the multiplication tables (Cayley tables) of quasigroups. They have applications in the design of experiments and in error correcting codes.
The name Latin square originates from Leonhard Euler, who used Latin characters as symbols.
A Latin square is said to be reduced (also, normalized or in standard form) if its first row and first column are in natural order. For example, the first Latin square above is reduced because both its first row and its first column are 1,2,3 (rather than 3,1,2 or any other order); The second is not reduced, as its first row is a,b,d,c rather than a,b,c,d. We can make any Latin square reduced by permuting (reordering) the rows and columns.
# Orthogonal array representation
If each entry of an n × n Latin square is written as a triple (r,c,s), where r is the row, c is the column, and s is the symbol, we obtain a set of n2 triples called the orthogonal array representation of the square. For example, the orthogonal array representation of the first Latin square displayed above is
where for example the triple (2,3,1) means that in row 2 and column 3 there is the symbol 1. The definition of a Latin square can be written in terms of orthogonal arrays as follows:
- There are n2 triples of the form (r,c,s), where 1 ≤ r, c, s ≤ n.
- All of the pairs (r,c) are different, all the pairs (r,s) are different, and all the pairs (c,s) are different.
The orthogonal array representation shows that rows, columns and symbols play rather similar roles, as will be made clear below.
# Equivalence classes of Latin squares
Many operations on a Latin square produce another Latin square (for example, turning it upside down).
If we permute the rows, permute the columns, and permute the names of the symbols of a Latin square, we obtain a new Latin square said to be isotopic to the first. Isotopism is an equivalence relation, so the set of all Latin squares is divided into subsets, called isotopy classes, such that two squares in the same class are isotopic and two squares in different classes are not isotopic.
Another type of operation is easiest to explain using the orthogonal array representation of the Latin square. If we systematically and consistently reorder the three items in each triple, another orthogonal array (and, thus, another Latin square) is obtained. For example, we can replace each triple (r,c,s) by (c,r,s) which corresponds to transposing the square (reflecting about its main diagonal), or we could replace each triple (r,c,s) by (c,s,r), which is a more complicated operation. Altogether there are 6 possibilities including "do nothing", giving us 6 Latin squares called the conjugates (also parastrophes) of the original square.
Finally, we can combine these two equivalence operations: two Latin squares are said to be paratopic, also main class isotopic, if one of them is isotopic to a conjugate of the other. This is again an equivalence relation, with the equivalence classes called main classes, species, or paratopy classes. Each main class contains up to 6 isotopy classes.
# The number of Latin squares
There is no known easily-computable formula for the number of n × n Latin squares with symbols 1,2,...,n. The most accurate upper and lower bounds known for large n are far apart. Here we will give all the known exact values. It can be seen that the numbers grow exceedingly quickly.
For each n, the number of Latin squares altogether Template:OEIS is n! (n-1)! times the number of reduced Latin squares Template:OEIS.
For each n, each isotopy class Template:OEIS contains up to (n!)3 Latin squares (the exact number varies), while each main class Template:OEIS contains either 1, 2, 3 or 6 isotopy classes.
# Examples
We give one example of a Latin square from each main class up to order 5.
\begin{bmatrix}
\end{bmatrix}
\quad
\begin{bmatrix}
\end{bmatrix}
\quad
\begin{bmatrix}
\end{bmatrix}
\begin{bmatrix}
\end{bmatrix}
\quad
\begin{bmatrix}
\end{bmatrix}
\begin{bmatrix}
\end{bmatrix}
\quad
\begin{bmatrix}
\end{bmatrix}
They present, respectively, the multiplication tables of the following groups:
- {0} - the trivial 1-element group
- \mathbb{Z}_2 - the binary group
- \mathbb{Z}_3 - cyclic group of order 3
- \mathbb{Z}_2 \times \mathbb{Z}_2 - the Klein four-group
- \mathbb{Z}_4 - cyclic group of order 4
- \mathbb{Z}_5 - cyclic group of order 5
- the last one is an example of a quasigroup, or rather a loop, which is not associative
# Latin squares and error correcting codes
Sets of Latin squares that are orthogonal to each other has found an application as error correcting codes in situations where communication is disturbed by more types of noise than simple white noise, such as when attempting to transmit broadband internet over powerlines.
Firstly, the message is sent by using several frequencies, or channels, a common method that makes the signal less vulnerable to noise at any one specific frequency. A letter in the message to be sent is encoded by sending a series of signals at different frequencies at successive time intervals. In the example below, the letters A to L are encoded by sending signals at four different frequencies, in four time slots. The letter C for instance, is encoded by first sending at frequency 3, then 4, 1 and 2.
\begin{matrix}
A\\
B\\
C\\
D\\
\end{matrix}
\begin{bmatrix}
\quad
\begin{matrix}
E\\
F\\
G\\
H\\
\end{matrix}
\begin{bmatrix}
\end{bmatrix}
\quad
\begin{matrix}
I\\
J\\
K\\
L\\
\end{matrix}
\begin{bmatrix}
\end{bmatrix}
The encoding of the twelve letters are formed from three Latin squares that are orthogonal to each other. Now imagine that there's added noise in channels 1 and 2 during the whole transmission. The letter A would then be picked up as:
\begin{matrix}
\end{matrix}
Because of the noise, we can no longer tell if the two first slots were 1,1 1,2 2,1 or 2,2 but the 1,2 case is the only one that yields a sequence matching a letter in the above table, the letter A.
Similarly, we may imagine a burst of static over all frequencies in the third slot:
\begin{matrix}
\end{matrix}
Again, we are able to infer from the table of encodings that it must have been the letter A being transmitted. The number of errors this code can spot is one less than the number of time slots. It has also been proved that if the number of frequencies is a prime or a power of a prime, the orthogonal Latin squares produce the most effective error detecting codes.
# Latin squares and mathematical puzzles
The problem of determining if a partially filled square can be completed to form a Latin square is NP-complete.
The popular Sudoku puzzles are a special case of Latin squares; any solution to a Sudoku puzzle is a Latin square. Sudoku imposes the additional restriction that 3×3 subgroups must also contain the digits 1–9 (in the standard version).
# Heraldry
The Latin square also figures in the blazon of the arms of the Statistical Society of Canada. Also, it appears in the logo of the International Biometric Society. | Latin square
A Latin square is an n × n table filled with n different symbols in such a way that each symbol occurs exactly once in each row and exactly once in each column. Here are two examples:
\begin{bmatrix}
\end{bmatrix}
\begin{bmatrix}
\end{bmatrix}
Latin squares occur as the multiplication tables (Cayley tables) of quasigroups. They have applications in the design of experiments and in error correcting codes.
The name Latin square originates from Leonhard Euler, who used Latin characters as symbols.
A Latin square is said to be reduced (also, normalized or in standard form) if its first row and first column are in natural order. For example, the first Latin square above is reduced because both its first row and its first column are 1,2,3 (rather than 3,1,2 or any other order); The second is not reduced, as its first row is a,b,d,c rather than a,b,c,d. We can make any Latin square reduced by permuting (reordering) the rows and columns.
# Orthogonal array representation
If each entry of an n × n Latin square is written as a triple (r,c,s), where r is the row, c is the column, and s is the symbol, we obtain a set of n2 triples called the orthogonal array representation of the square. For example, the orthogonal array representation of the first Latin square displayed above is
where for example the triple (2,3,1) means that in row 2 and column 3 there is the symbol 1. The definition of a Latin square can be written in terms of orthogonal arrays as follows:
- There are n2 triples of the form (r,c,s), where 1 ≤ r, c, s ≤ n.
- All of the pairs (r,c) are different, all the pairs (r,s) are different, and all the pairs (c,s) are different.
The orthogonal array representation shows that rows, columns and symbols play rather similar roles, as will be made clear below.
# Equivalence classes of Latin squares
Many operations on a Latin square produce another Latin square (for example, turning it upside down).
If we permute the rows, permute the columns, and permute the names of the symbols of a Latin square, we obtain a new Latin square said to be isotopic to the first. Isotopism is an equivalence relation, so the set of all Latin squares is divided into subsets, called isotopy classes, such that two squares in the same class are isotopic and two squares in different classes are not isotopic.
Another type of operation is easiest to explain using the orthogonal array representation of the Latin square. If we systematically and consistently reorder the three items in each triple, another orthogonal array (and, thus, another Latin square) is obtained. For example, we can replace each triple (r,c,s) by (c,r,s) which corresponds to transposing the square (reflecting about its main diagonal), or we could replace each triple (r,c,s) by (c,s,r), which is a more complicated operation. Altogether there are 6 possibilities including "do nothing", giving us 6 Latin squares called the conjugates (also parastrophes) of the original square.
Finally, we can combine these two equivalence operations: two Latin squares are said to be paratopic, also main class isotopic, if one of them is isotopic to a conjugate of the other. This is again an equivalence relation, with the equivalence classes called main classes, species, or paratopy classes. Each main class contains up to 6 isotopy classes.
# The number of Latin squares
There is no known easily-computable formula for the number of n × n Latin squares with symbols 1,2,...,n. The most accurate upper and lower bounds known for large n are far apart. Here we will give all the known exact values. It can be seen that the numbers grow exceedingly quickly.
For each n, the number of Latin squares altogether Template:OEIS is n! (n-1)! times the number of reduced Latin squares Template:OEIS.
For each n, each isotopy class Template:OEIS contains up to (n!)3 Latin squares (the exact number varies), while each main class Template:OEIS contains either 1, 2, 3 or 6 isotopy classes.
# Examples
We give one example of a Latin square from each main class up to order 5.
\begin{bmatrix}
\end{bmatrix}
\quad
\begin{bmatrix}
\end{bmatrix}
\quad
\begin{bmatrix}
\end{bmatrix}
\begin{bmatrix}
\end{bmatrix}
\quad
\begin{bmatrix}
\end{bmatrix}
\begin{bmatrix}
\end{bmatrix}
\quad
\begin{bmatrix}
\end{bmatrix}
They present, respectively, the multiplication tables of the following groups:
- {0} - the trivial 1-element group
- <math>\mathbb{Z}_2</math> - the binary group
- <math>\mathbb{Z}_3</math> - cyclic group of order 3
- <math>\mathbb{Z}_2 \times \mathbb{Z}_2</math> - the Klein four-group
- <math>\mathbb{Z}_4</math> - cyclic group of order 4
- <math>\mathbb{Z}_5</math> - cyclic group of order 5
- the last one is an example of a quasigroup, or rather a loop, which is not associative
# Latin squares and error correcting codes
Sets of Latin squares that are orthogonal to each other has found an application as error correcting codes in situations where communication is disturbed by more types of noise than simple white noise, such as when attempting to transmit broadband internet over powerlines. [1] [2] [3]
Firstly, the message is sent by using several frequencies, or channels, a common method that makes the signal less vulnerable to noise at any one specific frequency. A letter in the message to be sent is encoded by sending a series of signals at different frequencies at successive time intervals. In the example below, the letters A to L are encoded by sending signals at four different frequencies, in four time slots. The letter C for instance, is encoded by first sending at frequency 3, then 4, 1 and 2.
\begin{matrix}
A\\
B\\
C\\
D\\
\end{matrix}
\begin{bmatrix}
\quad
\begin{matrix}
E\\
F\\
G\\
H\\
\end{matrix}
\begin{bmatrix}
1 & 3 & 4 & 2\\
2 & 4 & 3 & 1\\
3 & 1 & 2 & 4\\
4 & 2 & 1 & 3\\
\end{bmatrix}
\quad
\begin{matrix}
I\\
J\\
K\\
L\\
\end{matrix}
\begin{bmatrix}
1 & 4 & 2 & 3\\
2 & 3 & 1 & 4\\
3 & 2 & 4 & 1\\
4 & 1 & 3 & 2\\
\end{bmatrix}
The encoding of the twelve letters are formed from three Latin squares that are orthogonal to each other. Now imagine that there's added noise in channels 1 and 2 during the whole transmission. The letter A would then be picked up as:
<math>\begin{matrix}
12 & 12 & 123 & 124\\
\end{matrix}</math>
Because of the noise, we can no longer tell if the two first slots were 1,1 1,2 2,1 or 2,2 but the 1,2 case is the only one that yields a sequence matching a letter in the above table, the letter A.
Similarly, we may imagine a burst of static over all frequencies in the third slot:
<math>\begin{matrix}
1 & 2 & 1234 & 4 \\
\end{matrix}</math>
Again, we are able to infer from the table of encodings that it must have been the letter A being transmitted. The number of errors this code can spot is one less than the number of time slots. It has also been proved that if the number of frequencies is a prime or a power of a prime, the orthogonal Latin squares produce the most effective error detecting codes.
# Latin squares and mathematical puzzles
The problem of determining if a partially filled square can be completed to form a Latin square is NP-complete.[4]
The popular Sudoku puzzles are a special case of Latin squares; any solution to a Sudoku puzzle is a Latin square. Sudoku imposes the additional restriction that 3×3 subgroups must also contain the digits 1–9 (in the standard version).
# Heraldry
The Latin square also figures in the blazon of the arms of the Statistical Society of Canada.[1] Also, it appears in the logo of the International Biometric Society.[2] | https://www.wikidoc.org/index.php/Latin_square | |
b4e4123ce8a5fc18c556c303f74e265ed0fe53c0 | wikidoc | Laurel water | Laurel water
Laurel water is distilled from the fresh leaves of the cherry laurel and contains the poison prussic acid (hydrocyanic acid) along with other products carried over in the process.
# Pharmacological usage
The water (Latin aqua laurocerasi) has been used for asthma, cough, indigestion and dyspepsia, and as a sedative narcotic, but since it is effectively a solution of hydrogen cyanide, of uncertain strength, it would be extremely dangerous to attempt medication with laurel water. The Roman emperor Nero used cherry laurel water to poison the wells of his enemies.
# Footnotes
- ↑ "laurel water - definition by dict.die.net". Retrieved 2007-01-10..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}
- ↑ "botanical.com - A Modern Herbal". Retrieved 2007-01-10. Text " Laurel, Cherry - Herb Profile and Information" ignored (help)
- ↑ Anderson, Faye. "Security and Water". Retrieved 2007-01-10. | Laurel water
Laurel water is distilled from the fresh leaves of the cherry laurel and contains the poison prussic acid (hydrocyanic acid) along with other products carried over in the process.[1]
# Pharmacological usage
The water (Latin aqua laurocerasi) has been used for asthma, cough, indigestion and dyspepsia, and as a sedative narcotic,[2] but since it is effectively a solution of hydrogen cyanide, of uncertain strength, it would be extremely dangerous to attempt medication with laurel water. The Roman emperor Nero used cherry laurel water to poison the wells of his enemies.[3]
# Footnotes
- ↑ "laurel water - definition by dict.die.net". Retrieved 2007-01-10..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}
- ↑ "botanical.com - A Modern Herbal". Retrieved 2007-01-10. Text " Laurel, Cherry - Herb Profile and Information" ignored (help)
- ↑ Anderson, Faye. "Security and Water". Retrieved 2007-01-10.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Laurel_water | |
9d4f4df6e7b93913477d08e954a8e02d850edfde | wikidoc | Lavender oil | Lavender oil
Lavender oil is an essential oil obtained by distillation from the flower spikes of certain species of lavender. Two forms are distinguished, Lavender Flower Oil, a colorless oil, insoluble in water, having a density of 0.885 (g/mL); and Lavender Spike Oil, a distillate from the herb Lavandula latifolia, having density 0.905. Lavender Flower Oil is a designation of the National Formulary and the British Pharmacopoeia. It is not a pure compound; it is a complex mixture of natural products. Lavender oil should never be taken internally.
# Therapeutic uses
Lavender oil, which has long been used in the production of perfume, can also be used in aromatherapy. The scent has a calming effect which may aid in relaxation and the reduction of anxiety. It may also help to relieve pain from tension headache when breathed in as vapor or diluted and rubbed on the skin. When added to a vaporizer, lavender oil may aid in the treatment of cough and respiratory infection.
Lavender oil may also be used as a mosquito repellent when worn as perfume or when added to lotions or hair products.
# Medicinal uses
According to advocates of alternative medicine, lavender oil can be used as first aid and to treat a variety of common ailments.
The diluted or undiluted oil may be used as an antiseptic and pain reliever to be applied to minor burns and insect bites and stings. For the treatment of sunburn and sunstroke, 10 drops of oil can be diluted in 25 mL of carrier oil. (Note: This is not an effective sunblock.) When added to chamomile, lavender oil may be effective on eczema.
To create a massage oil which may be effective in the relief of joint and muscle pain, 1 mL of oil can be added to 1 oz. of carrier oil and rubbed liberally on the affected area. To create a chest rub for relief of asthmatic and bronchitic spasm, 1 mL of lavender oil and 5 drops of chamomile oil can be added to 10 mL of carrier oil.
As a treatment for head lice, 5-10 drops of oil can be diluted in water to produce a hair rinse, while a few drops of undiluted oil can be added to a fine comb to eliminate nits.
As far as serious ailments, researchers at the University of Wisconsin-Madison have found that lavender oil may have played a role in the reduction of advanced mammary tumors in lab rats. Research is on-going for potential breast, ovarian, pancreatic, liver, and prostate cancer treatments.
# Contraindications
Lavender oil has recently been implicated in gynecomastia, the abnormal development of breasts in young boys. Denver endocrinologist Clifford Bloch discovered the link after several boys presented with enlarged breasts. Subsequently, Derek Henley and Kenneth Korach of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., discovered in lavender and tea tree oil the presence of compounds which both suppress male hormones and mimic female hormones.
Because sex hormone levels are normally low prior to puberty, young boys and girls are particularly sensitive to estrogenic and androgenic compounds. The discovery of the gynecomastia link in boys has led some researchers to suspect lavender and tea tree oils, which are present in various personal care products including shampoos and lotions, may also contribute to the increased incidence of early breast development in girls.
Discontinuation of use of these products resulted in rapid reversal of gynecomastia in Bloch’s young patients.
However, the conclusion that the gynecomastia was actually caused by the essential oils in these products are currently being disputed by the Artisan Perfumers Guild and Cropwatch due to insufficient evidence.
# Composition
The primary components of lavender oil are linalyl acetate (51%) and linalool (35%) . Other components include α-pinene, limonene, 1,8-cineole, cis- and trans-ocimene, 3-octanone, camphor, caryophyllene, terpinen-4-ol and lavendulyl acetate . | Lavender oil
Lavender oil is an essential oil obtained by distillation from the flower spikes of certain species of lavender. Two forms are distinguished, Lavender Flower Oil, a colorless oil, insoluble in water, having a density of 0.885 (g/mL); and Lavender Spike Oil, a distillate from the herb Lavandula latifolia, having density 0.905. Lavender Flower Oil is a designation of the National Formulary and the British Pharmacopoeia. It is not a pure compound; it is a complex mixture of natural products. Lavender oil should never be taken internally.
# Therapeutic uses
Lavender oil, which has long been used in the production of perfume, can also be used in aromatherapy. The scent has a calming effect which may aid in relaxation and the reduction of anxiety. It may also help to relieve pain from tension headache when breathed in as vapor or diluted and rubbed on the skin. When added to a vaporizer, lavender oil may aid in the treatment of cough and respiratory infection.
Lavender oil may also be used as a mosquito repellent when worn as perfume or when added to lotions or hair products.
# Medicinal uses
According to advocates of alternative medicine, lavender oil can be used as first aid and to treat a variety of common ailments.[1]
The diluted or undiluted oil may be used as an antiseptic and pain reliever to be applied to minor burns and insect bites and stings. For the treatment of sunburn and sunstroke, 10 drops of oil can be diluted in 25 mL of carrier oil. (Note: This is not an effective sunblock.) When added to chamomile, lavender oil may be effective on eczema.
To create a massage oil which may be effective in the relief of joint and muscle pain, 1 mL of oil can be added to 1 oz. of carrier oil and rubbed liberally on the affected area. To create a chest rub for relief of asthmatic and bronchitic spasm, 1 mL of lavender oil and 5 drops of chamomile oil can be added to 10 mL of carrier oil.
As a treatment for head lice, 5-10 drops of oil can be diluted in water to produce a hair rinse, while a few drops of undiluted oil can be added to a fine comb to eliminate nits.
As far as serious ailments, researchers at the University of Wisconsin-Madison have found that lavender oil may have played a role in the reduction of advanced mammary tumors in lab rats. Research is on-going for potential breast, ovarian, pancreatic, liver, and prostate cancer treatments.[citation needed]
# Contraindications
Lavender oil has recently been implicated in gynecomastia, the abnormal development of breasts in young boys. Denver endocrinologist Clifford Bloch discovered the link after several boys presented with enlarged breasts. Subsequently, Derek Henley and Kenneth Korach of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., discovered in lavender and tea tree oil the presence of compounds which both suppress male hormones and mimic female hormones.
Because sex hormone levels are normally low prior to puberty, young boys and girls are particularly sensitive to estrogenic and androgenic compounds. The discovery of the gynecomastia link in boys has led some researchers to suspect lavender and tea tree oils, which are present in various personal care products including shampoos and lotions, may also contribute to the increased incidence of early breast development in girls.
Discontinuation of use of these products resulted in rapid reversal of gynecomastia in Bloch’s young patients.[2][3]
However, the conclusion that the gynecomastia was actually caused by the essential oils in these products are currently being disputed by the Artisan Perfumers Guild and Cropwatch due to insufficient evidence.
# Composition
The primary components of lavender oil are linalyl acetate (51%) and linalool (35%) [4]. Other components include α-pinene, limonene, 1,8-cineole, cis- and trans-ocimene, 3-octanone, camphor, caryophyllene, terpinen-4-ol and lavendulyl acetate [5]. | https://www.wikidoc.org/index.php/Lavender_oil | |
0958dc01cc0d340cc607a5bfb81781428d6aa7ce | wikidoc | Lead sulfide | Lead sulfide
Lead sulfide is an ionic compound of lead and sulfur, having two possible proportions:
- Lead(II) sulfide, the ionic compound containing one lead atom and one sulfur atom.
- Lead(IV) sulfide, the ionic compound containing one lead atom and two sulfur atoms.
- The natural mineral galena | Lead sulfide
Lead sulfide is an ionic compound of lead and sulfur, having two possible proportions:
- Lead(II) sulfide, the ionic compound containing one lead atom and one sulfur atom.
- Lead(IV) sulfide, the ionic compound containing one lead atom and two sulfur atoms.
- The natural mineral galena
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Lead_sulfide | |
f8f8bf93db84d2225da1684dbfad9300df910384 | wikidoc | Ovarian vein | Ovarian vein
The ovarian vein, the female gonadal vein, carries deoxygenated blood from its corresponding ovary to inferior vena cava or one of its tributaries. It is the female equivalent of the testicular vein, and is the venous counterpart of the ovarian artery. It can be found in the suspensory ligament of the ovary.
It a paired vein, with one supplying each ovary.
- The right ovarian vein generally joins the inferior vena cava.
- The left ovarian vein, unlike the right, often joins the left renal vein instead of the inferior vena cava.
# Pathology
Thrombosis of ovarian vein is associated with postpartum endometritis, pelvic inflammatory disease, diverticulitis, appendicitis, and gynecologic surgery.
# Additional images
- Uterus and right broad ligament, seen from behind. | Ovarian vein
Template:Infobox Vein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The ovarian vein, the female gonadal vein, carries deoxygenated blood from its corresponding ovary to inferior vena cava or one of its tributaries. It is the female equivalent of the testicular vein, and is the venous counterpart of the ovarian artery. It can be found in the suspensory ligament of the ovary.
It a paired vein, with one supplying each ovary.
- The right ovarian vein generally joins the inferior vena cava.
- The left ovarian vein, unlike the right, often joins the left renal vein instead of the inferior vena cava.
# Pathology
Thrombosis of ovarian vein is associated with postpartum endometritis, pelvic inflammatory disease, diverticulitis, appendicitis, and gynecologic surgery.
# Additional images
- Uterus and right broad ligament, seen from behind.
# External links
- Template:SUNYAnatomyLabs - "Posterior Abdominal Wall: Tributaries to the Inferior Vena Cava"
Template:Veins
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Left_ovarian_vein | |
fc5afc7b8ce49950f9cd4756b5852408ea096ae7 | wikidoc | Lenalidomide | Lenalidomide
# 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
Lenalidomide is a Immune Modulator that is FDA approved for the treatment of Multiple myeloma(MM), Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS), Mantle cell lymphoma (MCL). There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, neutropenia, constipation, diarrhea, muscle cramp, anemia, pyrexia, peripheral edema, nausea, back pain, upper respiratory tract infection, dyspnea, dizziness, thrombocytopenia, tremor and rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy.
- REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
- REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.
- REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials
### Dosage
- The recommended starting dose of REVLIMID is 25 mg once daily on Days 1-21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg once daily on Days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily orally on Days 1-4 every 28 days. Treatment is continued or modified based upon clinical and laboratory findings.
- Dose modification guidelines, as summarized below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID.
- For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has resolved to ≤ Grade 2.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lenalidomide in adult patients.
### Non–Guideline-Supported Use
- Chronic lymphoid leukemia, Relapsed or refractory
- Multiple myeloma, In combination with dexamethasone, first-line therapy
- Myelofibrosis
- Non-Hodgkin's lymphoma, Aggressive disease, relapsed or refractory
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lenalidomide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lenalidomide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lenalidomide in pediatric patients.
# Contraindications
- REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant. 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
- REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide
# Warnings
- REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy.
- REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”)
- Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.
- Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy.
- Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles.
- Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm.
- Patients must not donate blood during treatment with REVLIMID 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 REVLIMID.
- Because of the embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program).
- Required components of the REVLIMID REMS™ program include the following:
- Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements.
- Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
- Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements.
- Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.
- REVLIMID can cause significant neutropenia and thrombocytopenia. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction.
- Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days.
- In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone.
- In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.
- Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies.
- Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking)
- In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed multiple myeloma who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.7 months. Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID.
- In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 , consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013.
- Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.
- Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.
- Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
- Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.
- REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.
- Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
- Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.
- Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.
# Adverse Reactions
## Clinical Trials Experience
- Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).
- In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse events and Grade 3/4 adverse events were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.
- TABLES 2, 3, and 4 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.
- Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse events between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.
- Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively. Discontinuations due to DVT adverse reactions were reported at comparable rates between groups.
- Pulmonary embolism (PE) was reported as a serious adverse drug reaction including Grade 3/4 (3.7%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% in the placebo/dexamethasone group. Discontinuations due to PE adverse reactions were reported at comparable rates between groups.
- Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group.
- Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/ dexamethasone group and 0.3% in the placebo/dexamethasone group.
- In these clinical studies of REVLIMID in patients with multiple myeloma, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported:
- pancytopenia
- autoimmune hemolytic anemia
- bradycardia
- myocardial infarction
- angina pectoris
- hirsutism
- blindness
- ocular hypertension
- gastrointestinal hemorrhage
- glossodynia
- malaise
- liver function tests abnormal
- alanine aminotransferase increased
- cerebral ischemia
- mood swings
- hallucination
- loss of libido
- erectile dysfunction
- cough
- hoarseness
- exanthem
- skin hyperpigmentation
- A total of 148 patients received at least 1 dose of 10 mg REVLIMID in the del 5q MDS clinical study. At least one adverse event was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID. The most frequently reported adverse events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.
- Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events. The next most common adverse events observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 5 summarizes the adverse events that were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. TABLE 6 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID. In the single-arm studies conducted, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.
- In other clinical studies of REVLIMID in MDS patients, the following serious adverse events (regardless of relationship to study drug treatment) not described in TABLE 5 or 6 were reported:
- warm type hemolytic anemia
- splenic infarction
- bone marrow depression
- coagulopathy
- hemolysis
- hemolytic anemia
- refractory anemia
- cardiac failure congestive
- atrial fibrillation
- angina pectoris
- cardiac arrest
- cardiac failure
- cardio-respiratory arrest
- cardiomyopathy
- myocardial infarction
- myocardial ischemia
- atrial fibrillation aggravated
- bradycardia
- cardiogenic shock
- pulmonary edema
- supraventricular arrhythmia
- tachyarrhythmia
- ventricular dysfunction
- vertigo
- Basedow’s disease
- gastrointestinal hemorrhage
- colitis ischemic
- intestinal perforation
- rectal hemorrhage
- colonic polyp
- diverticulitis
- dysphagia
- gastritis
- gastroenteritis
- gastroesophageal reflux disease
- obstructive inguinal hernia
- irritable bowel syndrome
- melena
- pancreatitis due to biliary obstruction
- pancreatitis
- perirectal abscess
- small intestinal obstruction
- upper gastrointestinal hemorrhage
- disease progression
- fall
- abnormal gait
- intermittent pyrexia
- nodule
- rigors
- sudden death
- hyperbilirubinemia
- cholecystitis
- acute cholecystitis
- hepatic failure
- hypersensitivity
- infection
- bacteremia
- central line infection
- clostridial infection
- ear infection
- Enterobacter sepsis
- fungal infection
- herpes viral infection NOS
- influenza,
- kidney infection
- Klebsiella sepsis
- lobar pneumonia
- localized infection
- oral infection
- Pseudomonas infection
- septic shock
- sinusitis acute
- sinusitis
- Staphylococcal infection
- urosepsis
- femur fracture
- transfusion reaction
- cervical vertebral fracture
- femoral neck fracture
- fractured pelvis
- hip fracture
- overdose
- post procedural hemorrhage
- rib fracture
- road traffic accident
- spinal compression fracture
- blood creatinine increased
- hemoglobin decreased
- liver function tests abnormal
- troponin I increased
- dehydration
- gout
- hypernatremia
- hypoglycemia
- arthritis
- arthritis aggravated
- gouty arthritis
- neck pain
- chondrocalcinosis pyrophosphate
- acute leukemia
- acute myeloid leukemia
- bronchoalveolar carcinoma
- lung cancer metastatic
- lymphoma
- prostate cancer metastatic
- cerebrovascular accident
- aphasia
- cerebellar infarction
- cerebral infarction
- depressed level of consciousness
- dysarthria
- migraine
- spinal cord compression
- subarachnoid hemorrhage
- transient ischemic attack
- confusional state
- renal failure
- hematuria
- renal failure acute
- azotemia
- calculus ureteric
- renal mass
- pelvic pain
- bronchitis
- chronic obstructive airways disease exacerbated
- respiratory failure
- dyspnea exacerbated
- interstitial lung disease
- lung infiltration
- wheezing
- acute febrile neutrophilic dermatosis
- deep vein thrombosis
- hypotension
- aortic disorder
- ischemia
- thrombophlebitis superficial
- thrombosis
- In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years.
- Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events.
- The following adverse events which have occurred in other indications and not described above have been reported (5-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma.
- Chills
- Pain in extremity
- Nervous system disorders
- Dysguesia
- headache
- peripheral neuropathy
- Respiratory tract infection
- sinusitis
- nasopharyngitis
- Dry skin
- night sweats
- The following serious adverse events not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma.
- Chronic obstructive pulmonary disease
- Clostridium difficile colitis
- sepsis
- Basal cell carcinoma
- Supraventricular tachycardia
## Postmarketing Experience
- The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.
# Drug Interactions
- Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions.
- In vitro studies demonstrated that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2.
- In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp).
- When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID.
- Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin.
- Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue.
- Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.
- Lenalidomide caused thalidomide-type limb defects in monkey offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
- In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.
- In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lenalidomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lenalidomide 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 and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 have not been established.
### Geriatic Use
- REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age.
- Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients.
- REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age.
- Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.
- REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients.
- Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.
### Gender
There is no FDA guidance on the use of Lenalidomide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lenalidomide with respect to specific racial populations.
### Renal Impairment
- Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis
### Hepatic Impairment
- No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route.
### Females of Reproductive Potential and Males
- REVLIMID can cause fetal harm when administered during pregnancy. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy.
- Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.
- Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.
- Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
### Immunocompromised Patients
There is no FDA guidance one the use of Lenalidomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed.
### Monitoring
- Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter.
- Monitor for and advise patients about signs and symptoms of thromboembolism.
- Monitor patients at risk of Tumor Lysis Syndromes (i.e., those with high tumor burden) and take appropriate precautions
- monitor liver function
# IV Compatibility
There is limited information regarding IV Compatibility of Lenalidomide in the drug label.
# Overdosage
- There is no specific experience in the management of lenalidomide overdose in patients; although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose studies, some patients were exposed to up to 400 mg.
- In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose, supportive care is advised.
# Pharmacology
## Mechanism of Action
- Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including multiple myeloma. Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.
## Structure
- REVLIMID, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:
## Pharmacodynamics
- The effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in a randomized, thorough QT study with placebo and positive controls. At a dose two times the maximum recommended dose, lenalidomide does not prolong the QTc interval to any clinically relevant extent. The largest upper bound of the 2-sided 90% CI for the mean differences between lenalidomide and placebo was below 10 ms.
## Pharmacokinetics
- Lenalidomide is rapidly absorbed following oral administration. Following single and multiple doses of REVLIMID in patients with MM or MDS the maximum plasma concentrations occurred between 0.5 and 6 hours post-dose. The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and Cmax values increasing proportionally with dose. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.
- Systemic exposure (AUC) of lenalidomide in MM and MDS patients with normal or mild renal function (CLcr ≥ 60 mL/min) is approximately 60% higher as compared to young healthy male subjects.
- Administration of a single 25 mg dose of REVLIMID with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in Cmax. In the trials where the efficacy and safety were established for REVLIMID, the drug was administered without regard to food intake. REVLIMID can be administered with or without food.
- Population pharmacokinetic analyses show that the oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.
- In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%.
- Lenalidomide -undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.
- Elimination is primarily renal. Following a single oral administration of -lenalidomide (25 mg) to healthy subjects, approximately 90% and 4% of the radioactive dose is eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose is excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate.
- The mean half-life of lenalidomide is 3 hours in healthy subjects and 3 to 5 hours in patients with MM, MDS or MCL.
- Co-administration of single or multiple doses of dexamethasone (40 mg) has no clinically relevant effect on the multiple dose pharmacokinetics of REVLIMID (25 mg).
- The pharmacokinetics of lenalidomide were studied in patients with renal impairment due to nonmalignant conditions. In this study, 5 patients with mild renal impairment (creatinine clearance 57-74 mL/min), 6 patients with moderate renal impairment (creatinine clearance 33-46 mL/min), 6 patients with severe renal impairment (creatinine clearance 17-29 mL/min), and 6 patients with end stage renal disease requiring dialysis were administered a single oral 25-mg dose of REVLIMID. As a control group comparator, 7 healthy subjects of similar age with normal renal function (creatinine clearance 83-145 mL/min) were also administered a single oral 25-mg dose of REVLIMID. As creatinine clearance decreased from mild to severe impairment, half-life increased and drug clearance decreased linearly. Patients with moderate and severe renal impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) given a single, 25-mg dose of lenalidomide has an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 40% of the administered dose was removed from the body during a single dialysis session.
- In MM patients, those patients with mild renal impairment had an AUC 56% greater than those with normal renal function.
- Adjustment of the starting dose of REVLIMID is recommended in patients with moderate or severe (CLcr < 60 mL/min) renal impairment and in patients on dialysis.
- No dedicated clinical studies have been conducted to evaluate pharmacokinetics of lenalidomide in the elderly. Population pharmacokinetic analyses included patients with ages ranging from 39 to 85 years old and show that age does not influence the disposition of lenalidomide.
- Population pharmacokinetic analyses included patients with mild hepatic impairment (N = 16, total bilirubin >1 to ≤ 1.5 x ULN or AST > ULN) and show that mild hepatic impairment does not influence the disposition of lenalidomide. There are no data available for patients with moderate to severe hepatic impairment.
- No pharmacokinetic data are available in patients below the age of 18 years.
- Population pharmacokinetic analyses show that body weight (33-135 kg), gender, race, and type of hematological malignancies (MM, MDS or MCL) do not have a clinically relevant effect on lenalidomide clearance in adult patients.
## Nonclinical Toxicology
- Carcinogenicity studies with lenalidomide have not been conducted.
- Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.
- A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.
# Clinical Studies
- Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and safety of REVLIMID. These multicenter, multinational, double-blind, placebo-controlled studies compared REVLIMID plus oral pulse high-dose dexamethasone therapy to dexamethasone therapy alone in patients with multiple myeloma who had received at least one prior treatment. These studies enrolled patients with absolute neutrophil counts (ANC) ≥ 1000/mm3, platelet counts ≥ 75,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL
- In both studies, patients in the REVLIMID/dexamethasone group took 25 mg of REVLIMID orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22 to 28 of each 28-day cycle. Patients in the placebo/dexamethasone group took 1 placebo capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy.
- The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue until disease progression.
- In both studies, dose adjustments were allowed based on clinical and laboratory findings. Sequential dose reductions to 15 mg daily, 10 mg daily and 5 mg daily were allowed for toxicity .
- Table 8 summarizes the baseline patient and disease characteristics in the two studies. In both studies, baseline demographic and disease-related characteristics were comparable between the REVLIMID/dexamethasone and placebo/dexamethasone groups.
- The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease.
- Preplanned interim analyses of both studies showed that the combination of REVLIMID/dexamethasone was significantly superior to dexamethasone alone for TTP. The studies were unblinded to allow patients in the placebo/dexamethasone group to receive treatment with the REVLIMID/dexamethasone combination. For both studies, the extended follow-up survival data with crossovers were analyzed. In study 1, the median survival time was 39.4 months (95%CI: 32.9, 47.4) in REVLIMID/dexamethasone group and 31.6 months (95%CI: 24.1, 40.9) in placebo/dexamethasone group, with a hazard ratio of 0.79 (95% CI: 0.61-1.03). In study 2, the median survival time was 37.5 months (95%CI: 29.9, 46.6) in REVLIMID/dexamethasone group and 30.8 months (95%CI: 23.5, 40.3) in placebo/dexamethasone group, with a hazard ratio of 0.86 (95% CI: 0.65-1.14).
- The efficacy and safety of REVLIMID were evaluated in patients with transfusion-dependent anemia in low- or intermediate-1- risk MDS with a 5q (q31-33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at a dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an open-label, single-arm, multi-center study. The major study was not designed nor powered to prospectively compare the efficacy of the 2 dosing regimens. Sequential dose reductions to 5 mg daily and 5 mg every other day, as well as dose delays, were allowed for toxicity.
- This major study enrolled 148 patients who had RBC transfusion dependent anemia. RBC transfusion dependence was defined as having received ≥ 2 units of RBCs within 8 weeks prior to study treatment. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 500/mm3, platelet counts ≥ 50,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL. Granulocyte colony-stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia. Baseline patient and disease-related characteristics are summarized in Table 10.
- The frequency of RBC transfusion independence was assessed using criteria modified from the International Working Group (IWG) response criteria for MDS. RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period.
- Transfusion independence was seen in 99/148 (67%) patients (95% CI ). The median duration from the date when RBC transfusion independence was first declared (i.e., the last day of the 56-day RBC transfusion-free period) to the date when an additional transfusion was received after the 56-day transfusion-free period among the 99 responders was 44 weeks (range of 0 to >67 weeks). Ninety percent of patients who achieved a transfusion benefit did so by completion of three months in the study.
- RBC transfusion independence rates were unaffected by age or gender.
- The dose of REVLIMID was reduced or interrupted at least once due to an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose reduction or interruption was 21 days (mean, 35.1 days; range, 2-253 days), and the median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2-265 days). A second dose reduction or interruption due to adverse events was required in 50 (33.8%) of the 148 patients. The median interval between the first and second dose reduction or interruption was 51 days (mean, 59.7 days; range, 15-205 days) and the median duration of the second dose interruption was 21 days (mean, 26 days; range, 2-148 days).
- A multicenter, single-arm, open-label trial of single-agent lenalidomide was conducted to evaluate the safety and efficacy of lenalidomide in patients with mantle cell lymphoma who have relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. Patients with a creatinine clearance >60 mL/min were given lenalidomide at a dose of 25 mg once daily for 21 days every 28 days. Patients with a creatinine clearance ≥30 mL/min and <60 mL/min were given lenalidomide at a dose of 10 mg once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.
- The trial included patients who were at least 18 years of age with biopsy-proven MCL with measurable disease by CT scan. Patients were required to have received prior treatment with an anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination. Patients were required to have documented refractory disease (defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen), or relapsed disease (defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen). At enrollment patients were to have an absolute neutrophil counts (ANC) ≥1500/ mm3, platelet counts ≥ 60,000/mm3, serum SGOT/AST or SGPT/ALT ≤3x upper limit of normal (ULN) unless there was documented evidence of liver involvement by lymphoma, serum total bilirubin ≤1.5 x ULN except in cases of Gilbert’s syndrome or documented liver involvement by lymphoma, and calculated creatinine clearance (Cockcroft-Gault formula) ≥30 mL/min.
- The median age was 67 years (43-83), 81% were male and 96% were Caucasian. The table below summarizes the baseline disease-related characteristics and prior anti-lymphoma therapy in the Mantle Cell Lymphoma trial.
- The efficacy endpoints in the MCL trial were overall response rate (ORR) and duration of response (DOR). Response was determined based on review of radiographic scans by an independent review committee according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999). The DOR is defined as the time from the initial response (at least PR) to documented disease progression. The efficacy results for the MCL population were based on all evaluable patients who received at least one dose of study drug and are presented in Table 12. The median time to response was 2.2 months (range 1.8 to 13 months).
# How Supplied
- White and blue-green opaque hard capsules imprinted “REV” on one half and “2.5 mg” on the other half in black ink:
- White opaque capsules imprinted “REV” on one half and “5 mg” on the other half in black ink:
- Blue/green and pale yellow opaque capsules imprinted “REV” on one half and “10 mg” on the other half in black ink:
- Powder blue and white opaque capsules imprinted “REV” on one half and “15 mg” on the other half in black ink:
- Powder blue and blue-green opaque hard capsules imprinted “REV” on one half and “20 mg” on the other half in black ink.
- White opaque capsules imprinted “REV” on one half and “25 mg” on the other half in black ink:
## Storage
- Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) .
- Care should be exercised in the handling of REVLIMID. REVLIMID capsules should not be opened or crushed. If powder from REVLIMID contacts the skin, wash the skin immediately and thoroughly with soap and water. If REVLIMID contacts the mucous membranes, flush thoroughly with water.
- Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.1
- Dispense no more than a 28-day supply.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients that REVLIMID is contraindicated in pregnancy. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby.
- Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy.
Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test.
- Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.
- Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
- Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception.
- Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy.
- Advise male patients taking REVLIMID that they must not donate sperm.
All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID.
- Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program).
- Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements.
- REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product.
- Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia.
- Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation.
- Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure .
- Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID.
- Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.
- Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation.
- Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.
- Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.
- Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water.
- Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.
# Precautions with Alcohol
- Alcohol-Lenalidomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Revlimid®
# Look-Alike Drug Names
There is limited information regarding Lenalidomide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Lenalidomide
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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# Black Box Warning
# Overview
Lenalidomide is a Immune Modulator that is FDA approved for the treatment of Multiple myeloma(MM), Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS), Mantle cell lymphoma (MCL). There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, neutropenia, constipation, diarrhea, muscle cramp, anemia, pyrexia, peripheral edema, nausea, back pain, upper respiratory tract infection, dyspnea, dizziness, thrombocytopenia, tremor and rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- REVLIMID in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy.
- REVLIMID is indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
- REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.
- REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials
### Dosage
- The recommended starting dose of REVLIMID is 25 mg once daily on Days 1-21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg once daily on Days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily orally on Days 1-4 every 28 days. Treatment is continued or modified based upon clinical and laboratory findings.
- Dose modification guidelines, as summarized below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID.
- For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has resolved to ≤ Grade 2.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lenalidomide in adult patients.
### Non–Guideline-Supported Use
- Chronic lymphoid leukemia, Relapsed or refractory[1][2]
- Multiple myeloma, In combination with dexamethasone, first-line therapy[3][4]
- Myelofibrosis[5]
- Non-Hodgkin's lymphoma, Aggressive disease, relapsed or refractory[6]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lenalidomide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lenalidomide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lenalidomide in pediatric patients.
# Contraindications
- REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant. 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
- REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide
# Warnings
- REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy.
- REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”)
- Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.
- Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy.
- Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles.
- Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm.
- Patients must not donate blood during treatment with REVLIMID 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 REVLIMID.
- Because of the embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program).
- Required components of the REVLIMID REMS™ program include the following:
- Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements.
- Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
- Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements.
- Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.
- REVLIMID can cause significant neutropenia and thrombocytopenia. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction.
- Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days.
- In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone.
- In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.
- Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboses are increased in patients treated with REVLIMID. A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies.
- Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking)
- In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed multiple myeloma who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.7 months. Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID.
- In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013.
- Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.
- Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide.
- Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
- Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.
- REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance.
- Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
- Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.
- Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.
# Adverse Reactions
## Clinical Trials Experience
- Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).
- In the REVLIMID/dexamethasone treatment group, 269 patients (76%) had at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse events and Grade 3/4 adverse events were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.
- TABLES 2, 3, and 4 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.
- Median duration of exposure among patients treated with REVLIMID/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse events between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.
- Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively. Discontinuations due to DVT adverse reactions were reported at comparable rates between groups.
- Pulmonary embolism (PE) was reported as a serious adverse drug reaction including Grade 3/4 (3.7%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% in the placebo/dexamethasone group. Discontinuations due to PE adverse reactions were reported at comparable rates between groups.
- Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group.
- Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/ dexamethasone group and 0.3% in the placebo/dexamethasone group.
- In these clinical studies of REVLIMID in patients with multiple myeloma, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported:
- pancytopenia
- autoimmune hemolytic anemia
- bradycardia
- myocardial infarction
- angina pectoris
- hirsutism
- blindness
- ocular hypertension
- gastrointestinal hemorrhage
- glossodynia
- malaise
- liver function tests abnormal
- alanine aminotransferase increased
- cerebral ischemia
- mood swings
- hallucination
- loss of libido
- erectile dysfunction
- cough
- hoarseness
- exanthem
- skin hyperpigmentation
- A total of 148 patients received at least 1 dose of 10 mg REVLIMID in the del 5q MDS clinical study. At least one adverse event was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID. The most frequently reported adverse events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.
- Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events. The next most common adverse events observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 5 summarizes the adverse events that were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. TABLE 6 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID. In the single-arm studies conducted, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.
- In other clinical studies of REVLIMID in MDS patients, the following serious adverse events (regardless of relationship to study drug treatment) not described in TABLE 5 or 6 were reported:
- warm type hemolytic anemia
- splenic infarction
- bone marrow depression
- coagulopathy
- hemolysis
- hemolytic anemia
- refractory anemia
- cardiac failure congestive
- atrial fibrillation
- angina pectoris
- cardiac arrest
- cardiac failure
- cardio-respiratory arrest
- cardiomyopathy
- myocardial infarction
- myocardial ischemia
- atrial fibrillation aggravated
- bradycardia
- cardiogenic shock
- pulmonary edema
- supraventricular arrhythmia
- tachyarrhythmia
- ventricular dysfunction
- vertigo
- Basedow’s disease
- gastrointestinal hemorrhage
- colitis ischemic
- intestinal perforation
- rectal hemorrhage
- colonic polyp
- diverticulitis
- dysphagia
- gastritis
- gastroenteritis
- gastroesophageal reflux disease
- obstructive inguinal hernia
- irritable bowel syndrome
- melena
- pancreatitis due to biliary obstruction
- pancreatitis
- perirectal abscess
- small intestinal obstruction
- upper gastrointestinal hemorrhage
- disease progression
- fall
- abnormal gait
- intermittent pyrexia
- nodule
- rigors
- sudden death
- hyperbilirubinemia
- cholecystitis
- acute cholecystitis
- hepatic failure
- hypersensitivity
- infection
- bacteremia
- central line infection
- clostridial infection
- ear infection
- Enterobacter sepsis
- fungal infection
- herpes viral infection NOS
- influenza,
- kidney infection
- Klebsiella sepsis
- lobar pneumonia
- localized infection
- oral infection
- Pseudomonas infection
- septic shock
- sinusitis acute
- sinusitis
- Staphylococcal infection
- urosepsis
- femur fracture
- transfusion reaction
- cervical vertebral fracture
- femoral neck fracture
- fractured pelvis
- hip fracture
- overdose
- post procedural hemorrhage
- rib fracture
- road traffic accident
- spinal compression fracture
- blood creatinine increased
- hemoglobin decreased
- liver function tests abnormal
- troponin I increased
- dehydration
- gout
- hypernatremia
- hypoglycemia
- arthritis
- arthritis aggravated
- gouty arthritis
- neck pain
- chondrocalcinosis pyrophosphate
- acute leukemia
- acute myeloid leukemia
- bronchoalveolar carcinoma
- lung cancer metastatic
- lymphoma
- prostate cancer metastatic
- cerebrovascular accident
- aphasia
- cerebellar infarction
- cerebral infarction
- depressed level of consciousness
- dysarthria
- migraine
- spinal cord compression
- subarachnoid hemorrhage
- transient ischemic attack
- confusional state
- renal failure
- hematuria
- renal failure acute
- azotemia
- calculus ureteric
- renal mass
- pelvic pain
- bronchitis
- chronic obstructive airways disease exacerbated
- respiratory failure
- dyspnea exacerbated
- interstitial lung disease
- lung infiltration
- wheezing
- acute febrile neutrophilic dermatosis
- deep vein thrombosis
- hypotension
- aortic disorder
- ischemia
- thrombophlebitis superficial
- thrombosis
- In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years.
- Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events.
- The following adverse events which have occurred in other indications and not described above have been reported (5-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma.
- Chills
- Pain in extremity
- Nervous system disorders
- Dysguesia
- headache
- peripheral neuropathy
- Respiratory tract infection
- sinusitis
- nasopharyngitis
- Dry skin
- night sweats
- The following serious adverse events not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma.
- Chronic obstructive pulmonary disease
- Clostridium difficile colitis
- sepsis
- Basal cell carcinoma
- Supraventricular tachycardia
## Postmarketing Experience
- The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.
# Drug Interactions
- Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions.
- In vitro studies demonstrated that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2.
- In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp).
- When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID.
- Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin.
- Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving REVLIMID
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue.
- Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.
- Lenalidomide caused thalidomide-type limb defects in monkey offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
- In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.
- In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lenalidomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lenalidomide 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 and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 have not been established.
### Geriatic Use
- REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age.
- Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients.
- REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age.
- Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.
- REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients.
- Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.
### Gender
There is no FDA guidance on the use of Lenalidomide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lenalidomide with respect to specific racial populations.
### Renal Impairment
- Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis
### Hepatic Impairment
- No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route.
### Females of Reproductive Potential and Males
- REVLIMID can cause fetal harm when administered during pregnancy. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy.
- Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.
- Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation.
- Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
### Immunocompromised Patients
There is no FDA guidance one the use of Lenalidomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed.
### Monitoring
- Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter.
- Monitor for and advise patients about signs and symptoms of thromboembolism.
- Monitor patients at risk of Tumor Lysis Syndromes (i.e., those with high tumor burden) and take appropriate precautions
- monitor liver function
# IV Compatibility
There is limited information regarding IV Compatibility of Lenalidomide in the drug label.
# Overdosage
- There is no specific experience in the management of lenalidomide overdose in patients; although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose studies, some patients were exposed to up to 400 mg.
- In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose, supportive care is advised.
# Pharmacology
## Mechanism of Action
- Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including multiple myeloma. Immunomodulatory properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.
## Structure
- REVLIMID, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:
## Pharmacodynamics
- The effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in a randomized, thorough QT study with placebo and positive controls. At a dose two times the maximum recommended dose, lenalidomide does not prolong the QTc interval to any clinically relevant extent. The largest upper bound of the 2-sided 90% CI for the mean differences between lenalidomide and placebo was below 10 ms.
## Pharmacokinetics
- Lenalidomide is rapidly absorbed following oral administration. Following single and multiple doses of REVLIMID in patients with MM or MDS the maximum plasma concentrations occurred between 0.5 and 6 hours post-dose. The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and Cmax values increasing proportionally with dose. Multiple dosing at the recommended dose-regimen does not result in drug accumulation.
- Systemic exposure (AUC) of lenalidomide in MM and MDS patients with normal or mild renal function (CLcr ≥ 60 mL/min) is approximately 60% higher as compared to young healthy male subjects.
- Administration of a single 25 mg dose of REVLIMID with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in Cmax. In the trials where the efficacy and safety were established for REVLIMID, the drug was administered without regard to food intake. REVLIMID can be administered with or without food.
- Population pharmacokinetic analyses show that the oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.
- In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%.
- Lenalidomide -undergoes limited metabolism. Unchanged lenalidomide is the predominant circulating component in humans. Two identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.
- Elimination is primarily renal. Following a single oral administration of [14C]-lenalidomide (25 mg) to healthy subjects, approximately 90% and 4% of the radioactive dose is eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose is excreted as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate.
- The mean half-life of lenalidomide is 3 hours in healthy subjects and 3 to 5 hours in patients with MM, MDS or MCL.
- Co-administration of single or multiple doses of dexamethasone (40 mg) has no clinically relevant effect on the multiple dose pharmacokinetics of REVLIMID (25 mg).
- The pharmacokinetics of lenalidomide were studied in patients with renal impairment due to nonmalignant conditions. In this study, 5 patients with mild renal impairment (creatinine clearance 57-74 mL/min), 6 patients with moderate renal impairment (creatinine clearance 33-46 mL/min), 6 patients with severe renal impairment (creatinine clearance 17-29 mL/min), and 6 patients with end stage renal disease requiring dialysis were administered a single oral 25-mg dose of REVLIMID. As a control group comparator, 7 healthy subjects of similar age with normal renal function (creatinine clearance 83-145 mL/min) were also administered a single oral 25-mg dose of REVLIMID. As creatinine clearance decreased from mild to severe impairment, half-life increased and drug clearance decreased linearly. Patients with moderate and severe renal impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) given a single, 25-mg dose of lenalidomide has an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 40% of the administered dose was removed from the body during a single dialysis session.
- In MM patients, those patients with mild renal impairment had an AUC 56% greater than those with normal renal function.
- Adjustment of the starting dose of REVLIMID is recommended in patients with moderate or severe (CLcr < 60 mL/min) renal impairment and in patients on dialysis.
- No dedicated clinical studies have been conducted to evaluate pharmacokinetics of lenalidomide in the elderly. Population pharmacokinetic analyses included patients with ages ranging from 39 to 85 years old and show that age does not influence the disposition of lenalidomide.
- Population pharmacokinetic analyses included patients with mild hepatic impairment (N = 16, total bilirubin >1 to ≤ 1.5 x ULN or AST > ULN) and show that mild hepatic impairment does not influence the disposition of lenalidomide. There are no data available for patients with moderate to severe hepatic impairment.
- No pharmacokinetic data are available in patients below the age of 18 years.
- Population pharmacokinetic analyses show that body weight (33-135 kg), gender, race, and type of hematological malignancies (MM, MDS or MCL) do not have a clinically relevant effect on lenalidomide clearance in adult patients.
## Nonclinical Toxicology
- Carcinogenicity studies with lenalidomide have not been conducted.
- Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.
- A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.
# Clinical Studies
- Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and safety of REVLIMID. These multicenter, multinational, double-blind, placebo-controlled studies compared REVLIMID plus oral pulse high-dose dexamethasone therapy to dexamethasone therapy alone in patients with multiple myeloma who had received at least one prior treatment. These studies enrolled patients with absolute neutrophil counts (ANC) ≥ 1000/mm3, platelet counts ≥ 75,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL
- In both studies, patients in the REVLIMID/dexamethasone group took 25 mg of REVLIMID orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22 to 28 of each 28-day cycle. Patients in the placebo/dexamethasone group took 1 placebo capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy.
- The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue until disease progression.
- In both studies, dose adjustments were allowed based on clinical and laboratory findings. Sequential dose reductions to 15 mg daily, 10 mg daily and 5 mg daily were allowed for toxicity [see Dosage and Administration (2.1)].
- Table 8 summarizes the baseline patient and disease characteristics in the two studies. In both studies, baseline demographic and disease-related characteristics were comparable between the REVLIMID/dexamethasone and placebo/dexamethasone groups.
- The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease.
- Preplanned interim analyses of both studies showed that the combination of REVLIMID/dexamethasone was significantly superior to dexamethasone alone for TTP. The studies were unblinded to allow patients in the placebo/dexamethasone group to receive treatment with the REVLIMID/dexamethasone combination. For both studies, the extended follow-up survival data with crossovers were analyzed. In study 1, the median survival time was 39.4 months (95%CI: 32.9, 47.4) in REVLIMID/dexamethasone group and 31.6 months (95%CI: 24.1, 40.9) in placebo/dexamethasone group, with a hazard ratio of 0.79 (95% CI: 0.61-1.03). In study 2, the median survival time was 37.5 months (95%CI: 29.9, 46.6) in REVLIMID/dexamethasone group and 30.8 months (95%CI: 23.5, 40.3) in placebo/dexamethasone group, with a hazard ratio of 0.86 (95% CI: 0.65-1.14).
- The efficacy and safety of REVLIMID were evaluated in patients with transfusion-dependent anemia in low- or intermediate-1- risk MDS with a 5q (q31-33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at a dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an open-label, single-arm, multi-center study. The major study was not designed nor powered to prospectively compare the efficacy of the 2 dosing regimens. Sequential dose reductions to 5 mg daily and 5 mg every other day, as well as dose delays, were allowed for toxicity.
- This major study enrolled 148 patients who had RBC transfusion dependent anemia. RBC transfusion dependence was defined as having received ≥ 2 units of RBCs within 8 weeks prior to study treatment. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 500/mm3, platelet counts ≥ 50,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL. Granulocyte colony-stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia. Baseline patient and disease-related characteristics are summarized in Table 10.
- The frequency of RBC transfusion independence was assessed using criteria modified from the International Working Group (IWG) response criteria for MDS. RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period.
- Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The median duration from the date when RBC transfusion independence was first declared (i.e., the last day of the 56-day RBC transfusion-free period) to the date when an additional transfusion was received after the 56-day transfusion-free period among the 99 responders was 44 weeks (range of 0 to >67 weeks). Ninety percent of patients who achieved a transfusion benefit did so by completion of three months in the study.
- RBC transfusion independence rates were unaffected by age or gender.
- The dose of REVLIMID was reduced or interrupted at least once due to an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose reduction or interruption was 21 days (mean, 35.1 days; range, 2-253 days), and the median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2-265 days). A second dose reduction or interruption due to adverse events was required in 50 (33.8%) of the 148 patients. The median interval between the first and second dose reduction or interruption was 51 days (mean, 59.7 days; range, 15-205 days) and the median duration of the second dose interruption was 21 days (mean, 26 days; range, 2-148 days).
- A multicenter, single-arm, open-label trial of single-agent lenalidomide was conducted to evaluate the safety and efficacy of lenalidomide in patients with mantle cell lymphoma who have relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. Patients with a creatinine clearance >60 mL/min were given lenalidomide at a dose of 25 mg once daily for 21 days every 28 days. Patients with a creatinine clearance ≥30 mL/min and <60 mL/min were given lenalidomide at a dose of 10 mg once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.
- The trial included patients who were at least 18 years of age with biopsy-proven MCL with measurable disease by CT scan. Patients were required to have received prior treatment with an anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination. Patients were required to have documented refractory disease (defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen), or relapsed disease (defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen). At enrollment patients were to have an absolute neutrophil counts (ANC) ≥1500/ mm3, platelet counts ≥ 60,000/mm3, serum SGOT/AST or SGPT/ALT ≤3x upper limit of normal (ULN) unless there was documented evidence of liver involvement by lymphoma, serum total bilirubin ≤1.5 x ULN except in cases of Gilbert’s syndrome or documented liver involvement by lymphoma, and calculated creatinine clearance (Cockcroft-Gault formula) ≥30 mL/min.
- The median age was 67 years (43-83), 81% were male and 96% were Caucasian. The table below summarizes the baseline disease-related characteristics and prior anti-lymphoma therapy in the Mantle Cell Lymphoma trial.
- The efficacy endpoints in the MCL trial were overall response rate (ORR) and duration of response (DOR). Response was determined based on review of radiographic scans by an independent review committee according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999). The DOR is defined as the time from the initial response (at least PR) to documented disease progression. The efficacy results for the MCL population were based on all evaluable patients who received at least one dose of study drug and are presented in Table 12. The median time to response was 2.2 months (range 1.8 to 13 months).
# How Supplied
- White and blue-green opaque hard capsules imprinted “REV” on one half and “2.5 mg” on the other half in black ink:
- White opaque capsules imprinted “REV” on one half and “5 mg” on the other half in black ink:
- Blue/green and pale yellow opaque capsules imprinted “REV” on one half and “10 mg” on the other half in black ink:
- Powder blue and white opaque capsules imprinted “REV” on one half and “15 mg” on the other half in black ink:
- Powder blue and blue-green opaque hard capsules imprinted “REV” on one half and “20 mg” on the other half in black ink.
- White opaque capsules imprinted “REV” on one half and “25 mg” on the other half in black ink:
## Storage
- Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [See USP Controlled Room Temperature].
- Care should be exercised in the handling of REVLIMID. REVLIMID capsules should not be opened or crushed. If powder from REVLIMID contacts the skin, wash the skin immediately and thoroughly with soap and water. If REVLIMID contacts the mucous membranes, flush thoroughly with water.
- Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.1
- Dispense no more than a 28-day supply.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients that REVLIMID is contraindicated in pregnancy. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby.
- Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy.
Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test.
- Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.
- Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
- Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception.
- Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy.
- Advise male patients taking REVLIMID that they must not donate sperm.
All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID.
- Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program).
- Patients must sign a Patient-Physician agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements.
- REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product.
- Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia.
- Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation.
- Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)].
- Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID.
- Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.
- Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation.
- Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.
- Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation.
- Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water.
- Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.
# Precautions with Alcohol
- Alcohol-Lenalidomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Revlimid®[7]
# Look-Alike Drug Names
There is limited information regarding Lenalidomide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lenalidomide | |
33a4f8bcd6bc10c429a027d818a7d4c17c8bb7e6 | wikidoc | Sargramostim | Sargramostim
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# Overview
Sargramostim is a colony stimulating factor that is FDA approved for the treatment of granulocytopenia following induction chemotherapy in acute myelogenous leukemia, mobilization and following transplantation of autologous peripheral blood progentior cells, myeloid reconstitution after autologous bone marrow transplantation, myeloid reconstitution after allogeneic bone marrow transplantation and bone marrow transplantation failure or engraftment delay. Common adverse reactions include chest pain, peripheral edema, pruritus, rash, hypercholesterolemia, hypomagnesemia, weight loss, abdominal pain, diarrhea, dysphagia, GI hemorrhage, hematemesis, nausea, vomiting, acute myelogenous leukemia, increased bilirrubin, arthralgia, bone pain, myalgia, asthenia, intraocular hemorrhage, anxiety, elevated BUN, pharyngitis, fever, malaise and rigor.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Neutrophil Recovery Following Chemotherapy in Acute Myelogenous Leukemia
- The recommended dose is 250 mcg/m2/day administered intravenously over a 4 hour period starting approximately on day 11 or four days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with 1500 cells/mm3 for 3 consecutive days or a maximum of 42 days. Sargramostim should be discontinued immediately if leukemic regrowth occurs. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates.
- In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3 or ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during Sargramostim therapy. Sargramostim treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.
### Mobilization of Peripheral Blood Progenitor Cells
- The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily. Dosing should continue at the same dose through the period of PBPC collection. The optimal schedule for PBPC collection has not been established. In clinical studies, collection of PBPC was usually begun by day 5 and performed daily until protocol specified targets were achieved. If WBC > 50,000 cells/mm3, the Sargramostim dose should be reduced by 50%. If adequate numbers of progenitor cells are not collected, other mobilization therapy should be considered.
### Post Peripheral Blood Progenitor Cell Transplantation
- The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily beginning immediately following infusion of progenitor cells and continuing until an ANC>1500 cells/mm3 for three consecutive days is attained.
### Myeloid Reconstitution After Autologous or Allogeneic Bone Marrow Transplantation
- The recommended dose is 250 mcg/m2/day administered IV over a 2-hour period beginning two to four hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Patients should not receive Sargramostim until the post marrow infusion ANC is less than 500 cells/mm3. Sargramostim should be continued until an ANC >1500 cells/mm3 for three consecutive days is attained. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Sargramostim should be discontinued immediately if blast cells appear or disease progression occurs.
- In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during Sargramostim therapy. Sargramostim treatment should be interrupted or the dose reduced by 50% if the ANC exceeds 20,000 cells/mm3.
### Bone Marrow Transplantation Failure or Engraftment Delay
- The recommended dose is 250 mcg/m2/day for 14 days as a 2-hour IV infusion. The dose can be repeated after 7 days off therapy if engraftment has not occurred. If engraftment still has not occurred, a third course of 500 mcg/m2/day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Sargramostim should be discontinued immediately if blast cells appear or disease progression occurs.
- In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during Sargramostim therapy. Sargramostim treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.
### Preparation of Sargramostim
- Liquid Sargramostim is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized Sargramostim is a sterile, white, preservative-free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP, or 1 mL Bacteriostatic Water for Injection, USP.
- Liquid Sargramostim may be stored for up to 20 days at 2–8°C once the vial has been entered. Discard any remaining solution after 20 days.
- Lyophilized Sargramostim (250 mcg) should be reconstituted aseptically with 1.0 mL of diluent (see below).
- The contents of vials reconstituted with different diluents should not be mixed together. Sterile Water for Injection, USP (without preservative): Lyophilized Sargramostim vials contain no antibacterial preservative, and therefore solutions prepared with Sterile Water for Injection, USP should be administered as soon as possible, and within 6 hours following reconstitution and/or dilution for IV infusion. The vial should not be re-entered or reused. Do not save any unused portion for administration more than 6 hours following reconstitution. Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol): Reconstituted solutions prepared with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) may be stored for up to 20 days at 2–8°C prior to use. Discard reconstituted solution after 20 days. Previously reconstituted solutions mixed with freshly reconstituted solutions must be administered within 6 hours following mixing. Preparations containing benzyl alcohol (including liquid Sargramostim and lyophilized Sargramostim reconstituted with Bacteriostatic Water for Injection) should not be used in neonates.
- During reconstitution of lyophilized Sargramostim the diluent should be directed at the side of the vial and the contents gently swirled to avoid foaming during dissolution. Avoid excessive or vigorous agitation; do not shake.
- Sargramostim should be used for SC injection without further dilution. Dilution for IV infusion should be performed in 0.9% Sodium Chloride Injection, USP. If the final concentration of Sargramostim is below 10 mcg/mL, Albumin (Human) at a final concentration of 0.1% should be added to the saline prior to addition of Sargramostim to prevent adsorption to the components of the drug delivery system. To obtain a final concentration of 0.1% Albumin (Human), add 1 mg Albumin (Human) per 1 mL 0.9% Sodium Chloride Injection, USP (e.g., use 1 mL 5% Albumin in 50 mL 0.9% Sodium Chloride Injection, USP).
- Store liquid Sargramostim and reconstituted lyophilized Sargramostim solutions under refrigeration at 2–8°C (36–46°F); DO NOT FREEZE.
- In the absence of compatibility and stability information, no other medication should be added to infusion solutions containing Sargramostim. Use only 0.9% Sodium Chloride Injection, USP to prepare IV infusion solutions.
- Aseptic technique should be employed in the preparation of all Sargramostim solutions. To assure correct concentration following reconstitution, care should be exercised to eliminate any air bubbles from the needle hub of the syringe used to prepare the diluent. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sargramostim in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sargramostim in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sargramostim FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sargramostim in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sargramostim in pediatric patients.
# Contraindications
Sargramostim is contraindicated:
- In patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%);
- In patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product;
- For concomitant use with chemotherapy and radiotherapy.
- Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, Sargramostim should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received Sargramostim and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without Sargramostim The patients randomized to Sargramostim had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.
# Warnings
### Pediatric Use
- Benzyl alcohol is a constituent of liquid Sargramostim and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Liquid solutions containing benzyl alcohol (including liquid Sargramostim) or lyophilized Sargramostim reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates.
### Fluid Retention
- Edema, capillary leak syndrome, pleural effusion and/or pericardial effusion have been reported in patients after Sargramostim administration. In 156 patients enrolled in placebo-controlled studies using Sargramostim at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention (Sargramostim vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed Sargramostim, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of Sargramostim may aggravate fluid retention; however, fluid retention associated with or worsened by Sargramostim has been reversible after interruption or dose reduction of Sargramostim with or without diuretic therapy. Sargramostim should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.
### Respiratory Symptoms
- Sequestration of granulocytes in the pulmonary circulation has been documented following Sargramostim infusion and dyspnea has been reported occasionally in patients treated with Sargramostim Special attention should be given to respiratory symptoms during or immediately following Sargramostim infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during Sargramostim administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. Sargramostim should be administered with caution in patients with hypoxia.
### Cardiovascular Symptoms
- Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during Sargramostim administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of Sargramostim. Sargramostim should be used with caution in patients with preexisting cardiac disease.
### Renal and Hepatic Dysfunction
- In some patients with preexisting renal dysfunction or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Sargramostim has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of Sargramostim administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal dysfunction and hepatic dysfunction were comparable between Sargramostim (250 mcg/m2/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal function and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during Sargramostim administration.
# Adverse Reactions
## Clinical Trials Experience
### Autologous and Allogeneic Bone Marrow Transplantation
- Sargramostim is generally well tolerated. In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV Sargramostim or placebo were as reported in TABLE 6.
- No significant differences were observed between Sargramostim and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Sargramostim has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition, there was no significant difference in relapse rate and 24 month survival between the Sargramostim and placebo-treated patients.
- In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV Sargramostim or placebo were as reported in TABLE 7.
- There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the Sargramostim and placebo-treated patients. Adverse events observed for the patients treated with Sargramostim in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with Sargramostim in the graft failure study.
- In uncontrolled Phase I/II studies with Sargramostim in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash.
- Reports of events occurring with marketed Sargramostim include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities.
- In patients with preexisting edema, capillary leak syndrome, pleural effusion and/or pericardial effusion, administration of Sargramostim may aggravate fluid retention. Body weight and hydration status should be carefully monitored during Sargramostim administration.
- Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients.
### Acute Myelogenous Leukemia
Adverse events reported in at least 10% of patients who received Sargramostim or placebo were as reported in TABLE 8.
- Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between Sargramostim and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the Sargramostim group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the Sargramostim and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate.
- In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the Sargramostim treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two Sargramostim treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when Sargramostim was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).15
### Antibody Formation
- Serum samples collected before and after Sargramostim treatment from 214 patients with a variety of underlying diseases have been examined for immunogenicity based on the presence of antibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving Sargramostim by continuous IV infusion (three patients) or subcutaneous injection (SC) (two patients) for 28 to 84 days in multiple courses. All five patients had impaired hematopoiesis before the administration of Sargramostim and consequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could not be assessed. Antibody studies of 75 patients with Crohn's disease receiving Sargramostim by subcutaneous injection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%) with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies are unknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of the therapeutic effect of Sargramostim secondary to formation of neutralizing antibody remain a theoretical possibility. Serious allergic and anaphylactoid reactions have been reported with Sargramostim but the rate of occurrence of antibodies in such patients has not been assessed.
### Overdosage
- The maximum amount of Sargramostim that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of Sargramostim.
- In case of overdosage, Sargramostim therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.
To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-888-4RX-Sargramostim or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
## Postmarketing Experience
There is limited information regarding Sargramostim Postmarketing Experience in the drug label.
# Drug Interactions
- Interactions between Sargramostim and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of Sargramostim, such as lithium and corticosteroids, should be used with caution.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with Sargramostim It is not known whether Sargramostim can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. Sargramostim should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sargramostim in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sargramostim during labor and delivery.
### Nursing Mothers
- It is not known whether Sargramostim is excreted in human milk. Because many drugs are excreted in human milk, Sargramostim should be administered to a nursing woman only if clearly needed.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that Sargramostim does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with Sargramostim in clinical trials at doses ranging from 60–1,000 mcg/m2/day intravenously and 4–1,500 mcg/m2/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid Sargramostim or lyophilized Sargramostim reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates
### Geriatic Use
- In the clinical trials, experience in older patients (age ≥65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with Sargramostim in this randomized study, 22 patients were age 65–70 years and 30 patients were age 55–64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65–70 yrs) vs younger patients (55–64 yrs). Greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Sargramostim with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sargramostim with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sargramostim in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sargramostim in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sargramostim in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sargramostim in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Sargramostim Administration in the drug label.
### Monitoring
There is limited information regarding Sargramostim Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Sargramostim and IV administrations.
# Overdosage
- The maximum amount of Sargramostim that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of Sargramostim.
- In case of overdosage, Sargramostim therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.
# Pharmacology
## Mechanism of Action
There is limited information regarding Sargramostim Mechanism of Action in the drug label.
## Structure
There is limited information regarding Sargramostim Structure in the drug label.
## Pharmacodynamics
### In vitro Studies of Sargramostim in Human Cells
- The biological activity of GM-CSF is species-specific. Consequently, in vitro studies have been performed on human cells to characterize the pharmacological activity of Sargramostim. In vitro exposure of human bone marrow cells to Sargramostim at concentrations ranging from 1–100 ng/mL results in the proliferation of hematopoietic progenitors and in the formation of pure granulocyte, pure macrophage and mixed granulocytemacrophage colonies. Chemotactic, anti-fungal and anti-parasitic activities of granulocytes and monocytes are increased by exposure to Sargramostim in vitro. Sargramostim increases the cytotoxicity of monocytes toward certain neoplastic cell lines and activates polymorphonuclear neutrophils to inhibit the growth of tumor cells.
## Pharmacokinetics
### General
- GM-CSF belongs to a group of growth factors termed colony stimulating factors which support survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways which include neutrophils, monocytes/macrophages and myeloid-derived dendritic cells.
- GM-CSF is also capable of activating mature granulocytes and macrophages. GM-CSF is a multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors. However, other factors are required to induce complete maturation in these two lineages. The various cellular responses (i.e., division, maturation, activation) are induced through GM-CSF binding to specific receptors expressed on the cell surface of target cells.2
### In vivo Primate Studies of Sargramostim
- Pharmacology/toxicology studies of Sargramostim were performed in cynomolgus monkeys. An acute toxicity study revealed an absence of treatment-related toxicity following a single IV bolus injection at a dose of 300 mcg/kg. Two subacute studies were performed using IV injection (maximum dose 200 mcg/kg/day × 14 days) and subcutaneous injection (SC) (maximum dose 200 mcg/kg/day × 28 days). No major visceral organ toxicity was documented. Notable histopathology findings included increased cellularity in hematologic organs and heart and lung tissues. A dose-dependent increase in leukocyte count, which consisted primarily of segmented neutrophils, occurred during the dosing period; increases in monocytes, basophils, eosinophils and lymphocytes were also noted. Leukocyte counts decreased to pretreatment values over a 1–2 week recovery period.
### Pharmacokinetics
- Pharmacokinetic profiles have been analyzed in controlled studies of 24 normal male volunteers. Liquid and lyophilized Sargramostim at the recommended dose of 250 mcg/m2, have been determined to be bioequivalent based on the statistical evaluation of AUC.5
- When Sargramostim (either liquid or lyophilized) was administered IV over two hours to normal volunteers, the mean beta half-life was approximately 60 minutes. Peak concentrations of GM-CSF were observed in blood samples obtained during or immediately after completion of Sargramostim infusion. For liquid Sargramostim the mean maximum concentration (Cmax) was 5.0 ng/mL, the mean clearance rate was approximately 420 mL/min/m2 and the mean AUC (0–inf) was 640 ng/mLmin. Corresponding results for lyophilized Sargramostim in the same subjects were mean Cmax of 5.4 ng/mL, mean clearance rate of 431 mL/min/m2, and mean AUC (0–inf) of 677 ng/mLmin. GM-CSF was last detected in blood samples obtained at three or six hours.
- When Sargramostim (either liquid or lyophilized) was administered SC to normal volunteers, GM-CSF was detected in the serum at 15 minutes, the first sample point. The mean beta half-life was approximately 162 minutes. Peak levels occurred at one to three hours post injection, and Sargramostim remained detectable for up to six hours after injection. The mean Cmax was 1.5 ng/mL. For liquid Sargramostim the mean clearance was 549 mL/min/m2 and the mean AUC (0–inf) was 549 ng/mLmin. For lyophilized Sargramostim, the mean clearance was 529 mL/min/m2 and the mean AUC (0–inf) was 501 ng/mLmin
## Nonclinical Toxicology
There is limited information regarding Sargramostim Nonclinical Toxicology in the drug label.
# Clinical Studies
### Acute Myelogenous Leukemia
- The safety and efficacy of Sargramostim in patients with AML who are younger than 55 years of age have not been determined. Based on Phase II data suggesting the best therapeutic effects could be achieved in patients at highest risk for severe infections and mortality while neutropenic, the Phase III clinical trial was conducted in older patients. The safety and efficacy of Sargramostim in the treatment of AML were evaluated in a multi-center, randomized, double-blind placebo-controlled trial of 99 newly diagnosed adult patients, 55–70 years of age, receiving induction with or without consolidation. A combination of standard doses of daunorubicin (days 1–3) and ara-C (days 1–7) was administered during induction and high dose ara-C was administered days 1–6 as a single course of consolidation, if given. Bone marrow evaluation was performed on day 10 following induction chemotherapy. If hypoplasia with <5% blasts was not achieved, patients immediately received a second cycle of induction chemotherapy. If the bone marrow was hypoplastic with <5% blasts on day 10 or four days following the second cycle of induction chemotherapy, Sargramostim (250 mcg/m2/day) or placebo was given IV over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥1500/mm3 for three consecutive days was attained or a maximum of 42 days. Sargramostim or placebo was also administered after the single course of consolidation chemotherapy if delivered (ara-C 3–6 weeks after induction following neutrophil recovery). Study drug was discontinued immediately if leukemic regrowth occurred.
- Sargramostim significantly shortened the median duration of ANC 500/mm3 by day 16, compared to day 25 for patients receiving placebo. The proportion of patients receiving one cycle (70%) or two cycles (30%) of induction was similar in both treatment groups; Sargramostim significantly shortened the median times to neutrophil recovery whether one cycle (12 versus 15 days) or two cycles (14 versus 23 days) of induction chemotherapy was administered. Median times to platelet (>20,000/mm3) and RBC transfusion independence were not significantly different between treatment groups.
- During the consolidation phase of treatment, Sargramostim did not shorten the median time to recovery of ANC to 500/mm3 (13 days) or 1000/mm3 (14.5 days) compared to placebo. There were no significant differences in time to platelet and RBC transfusion independence.
- The incidence of severe infections and deaths associated with infections was significantly reduced in patients who received Sargramostim During induction or consolidation, 27 of 52 patients receiving Sargramostim and 35 of 47 patients receiving placebo had at least one grade 3, 4 or 5 infection (p=0.02). Twenty-five patients receiving Sargramostim and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the Sargramostim arm (3 versus 11, p=0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.
- Disease outcomes were not adversely affected by the use of Sargramostim The proportion of patients achieving complete remission (CR) was higher in the Sargramostim group (69% as compared to 55% for the placebo group), but the difference was not significant (p=0.21). There was no significant difference in relapse rates; 12 of 36 patients who received Sargramostim and five of 26 patients who received placebo relapsed within 180 days of documented CR (p=0.26). The overall median survival was 378 days for patients receiving Sargramostim and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of Sargramostim treatment on response or survival.
### Mobilization and Engraftment of PBPC
- A retrospective review was conducted of data from patients with cancer undergoing collection of peripheral blood progenitor cells (PBPC) at a single transplant center. Mobilization of PBPC and myeloid reconstitution post-transplant were compared between four groups of patients (n=196) receiving Sargramostim for mobilization and a historical control group who did not receive any mobilization treatment (progenitor cells collected by leukapheresis without mobilization (n=100)). Sequential cohorts received Sargramostim The cohorts differed by dose (125 or 250 mcg/m2/day), route (IV over 24 hours or SC) and use of Sargramostim post-transplant. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000/mm3. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 × 108/kg body weight) and a minimum number of phereses (5–8) were performed. Both minimum requirements varied by treatment cohort and planned conditioning regimen. If subjects failed to reach a WBC of 10,000 cells/mm3 by day five, another cytokine was substituted for Sargramostim; these subjects were all successfully leukapheresed and transplanted. The most marked mobilization and post-transplant effects were seen in patients administered the higher dose of Sargramostim (250 mcg/m2) either IV (n=63) or SC (n=41).
- PBPCs from patients treated at the 250 mcg/m2/day dose had significantly higher number of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization. The mean value after thawing was 11.41 × 104 CFU-GM/kg for all Sargramostim-mobilized patients, compared to 0.96 × 104/kg for the non-mobilized group. A similar difference was observed in the mean number of erythrocyte burst-forming units (BFU-E) collected (23.96 × 104/kg for patients mobilized with 250 mcg/m2 doses of Sargramostim administered SC vs. 1.63 × 104/kg for non-mobilized patients).
- After transplantation, mobilized subjects had shorter times to myeloid engraftment and fewer days between transplantation and the last platelet transfusion compared to non-mobilized subjects. Neutrophil recovery (ANC >500/mm3) was more rapid in patients administered Sargramostim following PBPC transplantation with Sargramostim-mobilized cells (see TABLE 2). Mobilized patients also had fewer days to the last platelet transfusion and last RBC transfusion, and a shorter duration of hospitalization than did non-mobilized subjects.
- A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. Sargramostim was given SC at 250 mcg/m2/day once a day (n=10) or twice a day (n=21) until completion of the phereses. Phereses were begun on day 5 of Sargramostim administration and continued until the targeted MNC count of 9 × 108/kg or CD34+ cell count of 1 × 106/kg was reached. There was no difference in CD34+ cell count in patients receiving Sargramostim once or twice a day. The median time to ANC>500/mm3 was 12 days and to platelet recovery (>25,000/mm3) was 23 days.
- Survival studies comparing mobilized study patients to the nonmobilized patients and to an autologous historical bone marrow transplant group showed no differences in median survival time.
### Autologous Bone Marrow Transplantation
Following a dose-ranging Phase I/II trial in patients undergoing autologous BMT for lymphoid malignancies, three single center, randomized, placebo-controlled and double-blinded studies were conducted to evaluate the safety and efficacy of Sargramostim for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients (65 Sargramostim 63 placebo) were enrolled in these three studies. The majority of the patients had lymphoid malignancy (87 NHL, 17 ALL), 23 patients had Hodgkin's disease, and one patient had acute myeloblastic leukemia (AML). In 72 patients with NHL or ALL, the bone marrow harvest was purged prior to storage with one of several monoclonal antibodies. No chemical agent was used for in vitro treatment of the bone marrow. Preparative regimens in the three studies included cyclophosphamide (total dose 120–150 mg/kg) and total body irradiation (total dose 1,200–1,575 rads). Other regimens used in patients with Hodgkin's disease and NHL without radiotherapy consisted of three or more of the following in combination (expressed as total dose): cytosine arabinoside (400 mg/m2) and carmustine (300 mg/m2), cyclophosphamide (140–150 mg/kg), hydroxyurea (4.5 grams/m2) and etoposide (375–450 mg/m2).
- Compared to placebo, administration of Sargramostim in two studies (n=44 and 47) significantly improved the following hematologic and clinical endpoints: time to neutrophil engraftment, duration of hospitalization and infection experience or antibacterial usage. In the third study (n=37) there was a positive trend toward earlier myeloid engraftment in favor of Sargramostim This latter study differed from the other two in having enrolled a large number of patients with Hodgkin's disease who had also received extensive radiation and chemotherapy prior to harvest of autologous bone marrow. A subgroup analysis of the data from all three studies revealed that the median time to engraftment for patients with Hodgkin's disease, regardless of treatment, was six days longer when compared to patients with NHL and ALL, but that the overall beneficial Sargramostim treatment effect was the same. In the following combined analysis of the three studies, these two subgroups (NHL and ALL vs. Hodgkin's disease) are presented separately.
### Patients with Lymphoid Malignancy (Non-Hodgkin's Lymphoma and Acute Lymphoblastic Leukemia)
- Myeloid engraftment (absolute neutrophil count ANC≥500 cells/mm3) in 54 patients receiving Sargramostim was observed 6 days earlier than in 50 patients treated with placebo (see TABLE 3). Accelerated myeloid engraftment was associated with significant clinical benefits. The median duration of hospitalization was six days shorter for the Sargramostim group than for the placebo group. Median duration of infectious episodes (defined as fever and neutropenia; or two positive cultures of the same organism; or fever >38°C and one positive blood culture; or clinical evidence of infection) was three days less in the group treated with Sargramostim. The median duration of antibacterial administration in the post-transplantation period was four days shorter for the patients treated with Sargramostim than for placebo-treated patients. The study was unable to detect a significant difference between the treatment groups in rate of disease relapse 24 months post-transplantation. As a group, leukemic subjects receiving Sargramostim derived less benefit than NHL subjects. However, both the leukemic and NHL groups receiving Sargramostim engrafted earlier than controls.
### Patients with Hodgkin's Disease
- If patients with Hodgkin's disease are analyzed separately, a trend toward earlier myeloid engraftment is noted. Sargramostim-treated patients engrafted earlier (by five days) than the placebo-treated patients (p=0.189, Wilcoxon) but the number of patients was small (n=22).
### Allogeneic Bone Marrow Transplantation
- A multi-center, randomized, placebo-controlled, and double-blinded study was conducted to evaluate the safety and efficacy of Sargramostim for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 Sargramostim, 56 placebo) were enrolled in the study. Twenty-three patients (11 Sargramostim, 12 placebo) were 18 years old or younger. Sixty-seven patients had myeloid malignancies (33 AML, 34 CML), 17 had lymphoid malignancies (12 ALL, 5 NHL), three patients had Hodgkin's disease, six had multiple myeloma, nine had myelodysplastic disease, and seven patients had aplastic anemia. In 22 patients at one of the seven study sites, bone marrow harvests were depleted of T cells. Preparative regimens included cyclophosphamide, busulfan, cytosine arabinoside, etoposide, methotrexate, corticosteroids, and asparaginase. Some patients also received total body, splenic, or testicular irradiation. Primary graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and a corticosteroid.
- Accelerated myeloid engraftment was associated with significant laboratory and clinical benefits. Compared to placebo, administration of Sargramostim significantly improved the following: time to neutrophil engraftment, duration of hospitalization, number of patients with bacteremia and overall incidence of infection (see TABLE 4).
- Median time to myeloid engraftment (ANC ≥ 500 cells/mm3) in 53 patients receiving Sargramostim was 4 four days less than in 56 patients treated with placebo (see TABLE 4). The number of patients with bacteremia and infection was significantly lower in the Sargramostim group compared to the placebo group (9/53 versus 19/56 and 30/53 versus 42/56, respectively). There were a number of secondary laboratory and clinical endpoints. Of these, only the incidence of severe (grade 3/4) mucositis was significantly improved in the Sargramostim group (4/53) compared to the placebo group (16/56) at p<0.05. Sargramostim-treated patients also had a shorter median duration of post-transplant IV antibiotic infusions, and shorter median number of days to last platelet and RBC transfusions compared to placebo patients, but none of these differences reached statistical significance.
### Bone Marrow Transplantation Failure or Engraftment Delay
- A historically-controlled study was conducted in patients experiencing graft failure following allogeneic or autologous BMT to determine whether Sargramostim improved survival after BMT failure.
- Three categories of patients were eligible for this study:
patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 28 post-transplantation);
patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 21 post-transplantation) and who had evidence of an active infection; and
patients who lost their marrow graft after a transient engraftment (manifested by an average of ANC ≥ 500 cells/mm3 for at least one week followed by loss of engraftment with ANC < 500 cells/mm3 for at least one week beyond day 21 post-transplantation).
- patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 28 post-transplantation);
- patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 21 post-transplantation) and who had evidence of an active infection; and
- patients who lost their marrow graft after a transient engraftment (manifested by an average of ANC ≥ 500 cells/mm3 for at least one week followed by loss of engraftment with ANC < 500 cells/mm3 for at least one week beyond day 21 post-transplantation).
- A total of 140 eligible patients from 35 institutions were treated with Sargramostim and evaluated in comparison to 103 historical control patients from a single institution. One hundred sixty-three patients had lymphoid leukemia or myeloid leukemia, 24 patients had non-Hodgkin's lymphoma, 19 patients had Hodgkin's disease and 37 patients had other diseases, such as aplastic anemia, myelodysplasia or non-hematologic malignancy. The majority of patients (223 out of 243) had received prior chemotherapy with or without radiotherapy and/or immunotherapy prior to preparation for transplantation.
- One hundred day survival was improved in favor of the patients treated with Sargramostim after graft failure following either autologous or allogeneic BMT. In addition, the median survival was improved by greater than two-fold. The median survival of patients treated with Sargramostim after autologous failure was 474 days versus 161 days for the historical patients. Similarly, after allogeneic failure, the median survival was 97 days with Sargramostim treatment and 35 days for the historical controls. Improvement in survival was better in patients with fewer impaired organs.
- The MOF score is a simple clinical and laboratory assessment of seven major organ systems: cardiovascular, respiratory, gastrointestinal, hematologic, renal, hepatic and neurologic.10 Assessment of the MOF score is recommended as an additional method of determining the need to initiate treatment with Sargramostim in patients with graft failure or delay in engraftment following autologous or allogeneic BMT (see TABLE 5).
### Factors that Contribute to Survival
- The probability of survival was relatively greater for patients with any one of the following characteristics: autologous BMT failure or delay in engraftment, exclusion of total body irradiation from the preparative regimen, a non-leukemic malignancy or MOF score ≤ two (zero, one or two dysfunctional organ systems). Leukemic subjects derived less benefit than other subjects.
# How Supplied
Liquid Sargramostim is available in vials containing 500 mcg/mL (2.8 × 106 IU/mL) sargramostim. Lyophilized Sargramostim is available in vials containing 250 mcg (1.4 × 106 IU/vial) sargramostim.
- Each dosage form is supplied as follows:
Lyophilized Sargramostim: Carton of five vials of lyophilized Sargramostim 250 mcg (NDC 0024-5843-05)
Liquid Sargramostim: Carton of one multiple-use vial; each vial contains 1 mL of preserved 500 mcg/mL liquid Sargramostim (NDC 0024-5844-01)
- Lyophilized Sargramostim: Carton of five vials of lyophilized Sargramostim 250 mcg (NDC 0024-5843-05)
- Liquid Sargramostim: Carton of one multiple-use vial; each vial contains 1 mL of preserved 500 mcg/mL liquid Sargramostim (NDC 0024-5844-01)
- Carton of five multiple-use vials; each vial contains 1 mL of preserved 500 mcg/mL liquid Sargramostim (NDC 0024-5844-05)
## Storage
- Sargramostim should be refrigerated at 2–8°C (36–46°F). Do not freeze or shake. Do not use beyond the expiration date printed on the vial.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Sargramostim Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Sargramostim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Leukine
# Look-Alike Drug Names
There is limited information regarding Sargramostim Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Sargramostim
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Sargramostim is a colony stimulating factor that is FDA approved for the treatment of granulocytopenia following induction chemotherapy in acute myelogenous leukemia, mobilization and following transplantation of autologous peripheral blood progentior cells, myeloid reconstitution after autologous bone marrow transplantation, myeloid reconstitution after allogeneic bone marrow transplantation and bone marrow transplantation failure or engraftment delay. Common adverse reactions include chest pain, peripheral edema, pruritus, rash, hypercholesterolemia, hypomagnesemia, weight loss, abdominal pain, diarrhea, dysphagia, GI hemorrhage, hematemesis, nausea, vomiting, acute myelogenous leukemia, increased bilirrubin, arthralgia, bone pain, myalgia, asthenia, intraocular hemorrhage, anxiety, elevated BUN, pharyngitis, fever, malaise and rigor.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Neutrophil Recovery Following Chemotherapy in Acute Myelogenous Leukemia
- The recommended dose is 250 mcg/m2/day administered intravenously over a 4 hour period starting approximately on day 11 or four days following the completion of induction chemotherapy, if the day 10 bone marrow is hypoplastic with <5% blasts. If a second cycle of induction chemotherapy is necessary, Sargramostim should be administered approximately four days after the completion of chemotherapy if the bone marrow is hypoplastic with <5% blasts. Sargramostim should be continued until an ANC >1500 cells/mm3 for 3 consecutive days or a maximum of 42 days. Sargramostim should be discontinued immediately if leukemic regrowth occurs. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates.
- In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3 or ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during Sargramostim therapy. Sargramostim treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.
### Mobilization of Peripheral Blood Progenitor Cells
- The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily. Dosing should continue at the same dose through the period of PBPC collection. The optimal schedule for PBPC collection has not been established. In clinical studies, collection of PBPC was usually begun by day 5 and performed daily until protocol specified targets were achieved. If WBC > 50,000 cells/mm3, the Sargramostim dose should be reduced by 50%. If adequate numbers of progenitor cells are not collected, other mobilization therapy should be considered.
### Post Peripheral Blood Progenitor Cell Transplantation
- The recommended dose is 250 mcg/m2/day administered IV over 24 hours or SC once daily beginning immediately following infusion of progenitor cells and continuing until an ANC>1500 cells/mm3 for three consecutive days is attained.
### Myeloid Reconstitution After Autologous or Allogeneic Bone Marrow Transplantation
- The recommended dose is 250 mcg/m2/day administered IV over a 2-hour period beginning two to four hours after bone marrow infusion, and not less than 24 hours after the last dose of chemotherapy or radiotherapy. Patients should not receive Sargramostim until the post marrow infusion ANC is less than 500 cells/mm3. Sargramostim should be continued until an ANC >1500 cells/mm3 for three consecutive days is attained. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Sargramostim should be discontinued immediately if blast cells appear or disease progression occurs.
- In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during Sargramostim therapy. Sargramostim treatment should be interrupted or the dose reduced by 50% if the ANC exceeds 20,000 cells/mm3.
### Bone Marrow Transplantation Failure or Engraftment Delay
- The recommended dose is 250 mcg/m2/day for 14 days as a 2-hour IV infusion. The dose can be repeated after 7 days off therapy if engraftment has not occurred. If engraftment still has not occurred, a third course of 500 mcg/m2/day for 14 days may be tried after another 7 days off therapy. If there is still no improvement, it is unlikely that further dose escalation will be beneficial. If a severe adverse reaction occurs, the dose can be reduced by 50% or temporarily discontinued until the reaction abates. Sargramostim should be discontinued immediately if blast cells appear or disease progression occurs.
- In order to avoid potential complications of excessive leukocytosis (WBC > 50,000 cells/mm3, ANC > 20,000 cells/mm3) a CBC with differential is recommended twice per week during Sargramostim therapy. Sargramostim treatment should be interrupted or the dose reduced by half if the ANC exceeds 20,000 cells/mm3.
### Preparation of Sargramostim
- Liquid Sargramostim is formulated as a sterile, preserved (1.1% benzyl alcohol), injectable solution (500 mcg/mL) in a vial. Lyophilized Sargramostim is a sterile, white, preservative-free powder (250 mcg) that requires reconstitution with 1 mL Sterile Water for Injection, USP, or 1 mL Bacteriostatic Water for Injection, USP.
- Liquid Sargramostim may be stored for up to 20 days at 2–8°C once the vial has been entered. Discard any remaining solution after 20 days.
- Lyophilized Sargramostim (250 mcg) should be reconstituted aseptically with 1.0 mL of diluent (see below).
- The contents of vials reconstituted with different diluents should not be mixed together. Sterile Water for Injection, USP (without preservative): Lyophilized Sargramostim vials contain no antibacterial preservative, and therefore solutions prepared with Sterile Water for Injection, USP should be administered as soon as possible, and within 6 hours following reconstitution and/or dilution for IV infusion. The vial should not be re-entered or reused. Do not save any unused portion for administration more than 6 hours following reconstitution. Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol): Reconstituted solutions prepared with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) may be stored for up to 20 days at 2–8°C prior to use. Discard reconstituted solution after 20 days. Previously reconstituted solutions mixed with freshly reconstituted solutions must be administered within 6 hours following mixing. Preparations containing benzyl alcohol (including liquid Sargramostim and lyophilized Sargramostim reconstituted with Bacteriostatic Water for Injection) should not be used in neonates.
- During reconstitution of lyophilized Sargramostim the diluent should be directed at the side of the vial and the contents gently swirled to avoid foaming during dissolution. Avoid excessive or vigorous agitation; do not shake.
- Sargramostim should be used for SC injection without further dilution. Dilution for IV infusion should be performed in 0.9% Sodium Chloride Injection, USP. If the final concentration of Sargramostim is below 10 mcg/mL, Albumin (Human) at a final concentration of 0.1% should be added to the saline prior to addition of Sargramostim to prevent adsorption to the components of the drug delivery system. To obtain a final concentration of 0.1% Albumin (Human), add 1 mg Albumin (Human) per 1 mL 0.9% Sodium Chloride Injection, USP (e.g., use 1 mL 5% Albumin [Human] in 50 mL 0.9% Sodium Chloride Injection, USP).
- Store liquid Sargramostim and reconstituted lyophilized Sargramostim solutions under refrigeration at 2–8°C (36–46°F); DO NOT FREEZE.
- In the absence of compatibility and stability information, no other medication should be added to infusion solutions containing Sargramostim. Use only 0.9% Sodium Chloride Injection, USP to prepare IV infusion solutions.
- Aseptic technique should be employed in the preparation of all Sargramostim solutions. To assure correct concentration following reconstitution, care should be exercised to eliminate any air bubbles from the needle hub of the syringe used to prepare the diluent. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or the solution is discolored, the vial should not be used.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sargramostim in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sargramostim in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Sargramostim FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sargramostim in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sargramostim in pediatric patients.
# Contraindications
Sargramostim is contraindicated:
- In patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (≥ 10%);
- In patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product;
- For concomitant use with chemotherapy and radiotherapy.
- Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, Sargramostim should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours preceding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received Sargramostim and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without Sargramostim The patients randomized to Sargramostim had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.
# Warnings
### Pediatric Use
- Benzyl alcohol is a constituent of liquid Sargramostim and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. Liquid solutions containing benzyl alcohol (including liquid Sargramostim) or lyophilized Sargramostim reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates.
### Fluid Retention
- Edema, capillary leak syndrome, pleural effusion and/or pericardial effusion have been reported in patients after Sargramostim administration. In 156 patients enrolled in placebo-controlled studies using Sargramostim at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention (Sargramostim vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed Sargramostim, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of Sargramostim may aggravate fluid retention; however, fluid retention associated with or worsened by Sargramostim has been reversible after interruption or dose reduction of Sargramostim with or without diuretic therapy. Sargramostim should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure.
### Respiratory Symptoms
- Sequestration of granulocytes in the pulmonary circulation has been documented following Sargramostim infusion and dyspnea has been reported occasionally in patients treated with Sargramostim Special attention should be given to respiratory symptoms during or immediately following Sargramostim infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during Sargramostim administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. Sargramostim should be administered with caution in patients with hypoxia.
### Cardiovascular Symptoms
- Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during Sargramostim administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of Sargramostim. Sargramostim should be used with caution in patients with preexisting cardiac disease.
### Renal and Hepatic Dysfunction
- In some patients with preexisting renal dysfunction or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Sargramostim has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of Sargramostim administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal dysfunction and hepatic dysfunction were comparable between Sargramostim (250 mcg/m2/day by 2-hour IV infusion) and placebo-treated patients. Monitoring of renal function and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during Sargramostim administration.
# Adverse Reactions
## Clinical Trials Experience
### Autologous and Allogeneic Bone Marrow Transplantation
- Sargramostim is generally well tolerated. In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV Sargramostim or placebo were as reported in TABLE 6.
- No significant differences were observed between Sargramostim and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of Sargramostim has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition, there was no significant difference in relapse rate and 24 month survival between the Sargramostim and placebo-treated patients.
- In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV Sargramostim or placebo were as reported in TABLE 7.
- There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the Sargramostim and placebo-treated patients. Adverse events observed for the patients treated with Sargramostim in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with Sargramostim in the graft failure study.
- In uncontrolled Phase I/II studies with Sargramostim in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash.
- Reports of events occurring with marketed Sargramostim include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities.
- In patients with preexisting edema, capillary leak syndrome, pleural effusion and/or pericardial effusion, administration of Sargramostim may aggravate fluid retention. Body weight and hydration status should be carefully monitored during Sargramostim administration.
- Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients.
### Acute Myelogenous Leukemia
Adverse events reported in at least 10% of patients who received Sargramostim or placebo were as reported in TABLE 8.
- Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between Sargramostim and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the Sargramostim group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the Sargramostim and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate.
- In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the Sargramostim treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two Sargramostim treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when Sargramostim was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).15
### Antibody Formation
- Serum samples collected before and after Sargramostim treatment from 214 patients with a variety of underlying diseases have been examined for immunogenicity based on the presence of antibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving Sargramostim by continuous IV infusion (three patients) or subcutaneous injection (SC) (two patients) for 28 to 84 days in multiple courses. All five patients had impaired hematopoiesis before the administration of Sargramostim and consequently the effect of the development of anti-GM-CSF antibodies on normal hematopoiesis could not be assessed. Antibody studies of 75 patients with Crohn's disease receiving Sargramostim by subcutaneous injection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%) with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies are unknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of the therapeutic effect of Sargramostim secondary to formation of neutralizing antibody remain a theoretical possibility. Serious allergic and anaphylactoid reactions have been reported with Sargramostim but the rate of occurrence of antibodies in such patients has not been assessed.
### Overdosage
- The maximum amount of Sargramostim that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of Sargramostim.
- In case of overdosage, Sargramostim therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.
To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-888-4RX-Sargramostim or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
## Postmarketing Experience
There is limited information regarding Sargramostim Postmarketing Experience in the drug label.
# Drug Interactions
- Interactions between Sargramostim and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of Sargramostim, such as lithium and corticosteroids, should be used with caution.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with Sargramostim It is not known whether Sargramostim can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. Sargramostim should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sargramostim in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sargramostim during labor and delivery.
### Nursing Mothers
- It is not known whether Sargramostim is excreted in human milk. Because many drugs are excreted in human milk, Sargramostim should be administered to a nursing woman only if clearly needed.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that Sargramostim does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with Sargramostim in clinical trials at doses ranging from 60–1,000 mcg/m2/day intravenously and 4–1,500 mcg/m2/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid Sargramostim or lyophilized Sargramostim reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates
### Geriatic Use
- In the clinical trials, experience in older patients (age ≥65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with Sargramostim in this randomized study, 22 patients were age 65–70 years and 30 patients were age 55–64 years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65–70 yrs) vs younger patients (55–64 yrs). Greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Sargramostim with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sargramostim with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sargramostim in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sargramostim in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sargramostim in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sargramostim in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Sargramostim Administration in the drug label.
### Monitoring
There is limited information regarding Sargramostim Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Sargramostim and IV administrations.
# Overdosage
- The maximum amount of Sargramostim that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of Sargramostim.
- In case of overdosage, Sargramostim therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms.
# Pharmacology
## Mechanism of Action
There is limited information regarding Sargramostim Mechanism of Action in the drug label.
## Structure
There is limited information regarding Sargramostim Structure in the drug label.
## Pharmacodynamics
### In vitro Studies of Sargramostim in Human Cells
- The biological activity of GM-CSF is species-specific. Consequently, in vitro studies have been performed on human cells to characterize the pharmacological activity of Sargramostim. In vitro exposure of human bone marrow cells to Sargramostim at concentrations ranging from 1–100 ng/mL results in the proliferation of hematopoietic progenitors and in the formation of pure granulocyte, pure macrophage and mixed granulocytemacrophage colonies. Chemotactic, anti-fungal and anti-parasitic activities of granulocytes and monocytes are increased by exposure to Sargramostim in vitro. Sargramostim increases the cytotoxicity of monocytes toward certain neoplastic cell lines and activates polymorphonuclear neutrophils to inhibit the growth of tumor cells.
## Pharmacokinetics
### General
- GM-CSF belongs to a group of growth factors termed colony stimulating factors which support survival, clonal expansion, and differentiation of hematopoietic progenitor cells. GM-CSF induces partially committed progenitor cells to divide and differentiate in the granulocyte-macrophage pathways which include neutrophils, monocytes/macrophages and myeloid-derived dendritic cells.
- GM-CSF is also capable of activating mature granulocytes and macrophages. GM-CSF is a multilineage factor and, in addition to dose-dependent effects on the myelomonocytic lineage, can promote the proliferation of megakaryocytic and erythroid progenitors. However, other factors are required to induce complete maturation in these two lineages. The various cellular responses (i.e., division, maturation, activation) are induced through GM-CSF binding to specific receptors expressed on the cell surface of target cells.2
### In vivo Primate Studies of Sargramostim
- Pharmacology/toxicology studies of Sargramostim were performed in cynomolgus monkeys. An acute toxicity study revealed an absence of treatment-related toxicity following a single IV bolus injection at a dose of 300 mcg/kg. Two subacute studies were performed using IV injection (maximum dose 200 mcg/kg/day × 14 days) and subcutaneous injection (SC) (maximum dose 200 mcg/kg/day × 28 days). No major visceral organ toxicity was documented. Notable histopathology findings included increased cellularity in hematologic organs and heart and lung tissues. A dose-dependent increase in leukocyte count, which consisted primarily of segmented neutrophils, occurred during the dosing period; increases in monocytes, basophils, eosinophils and lymphocytes were also noted. Leukocyte counts decreased to pretreatment values over a 1–2 week recovery period.
### Pharmacokinetics
- Pharmacokinetic profiles have been analyzed in controlled studies of 24 normal male volunteers. Liquid and lyophilized Sargramostim at the recommended dose of 250 mcg/m2, have been determined to be bioequivalent based on the statistical evaluation of AUC.5
- When Sargramostim (either liquid or lyophilized) was administered IV over two hours to normal volunteers, the mean beta half-life was approximately 60 minutes. Peak concentrations of GM-CSF were observed in blood samples obtained during or immediately after completion of Sargramostim infusion. For liquid Sargramostim the mean maximum concentration (Cmax) was 5.0 ng/mL, the mean clearance rate was approximately 420 mL/min/m2 and the mean AUC (0–inf) was 640 ng/mL•min. Corresponding results for lyophilized Sargramostim in the same subjects were mean Cmax of 5.4 ng/mL, mean clearance rate of 431 mL/min/m2, and mean AUC (0–inf) of 677 ng/mL•min. GM-CSF was last detected in blood samples obtained at three or six hours.
- When Sargramostim (either liquid or lyophilized) was administered SC to normal volunteers, GM-CSF was detected in the serum at 15 minutes, the first sample point. The mean beta half-life was approximately 162 minutes. Peak levels occurred at one to three hours post injection, and Sargramostim remained detectable for up to six hours after injection. The mean Cmax was 1.5 ng/mL. For liquid Sargramostim the mean clearance was 549 mL/min/m2 and the mean AUC (0–inf) was 549 ng/mL•min. For lyophilized Sargramostim, the mean clearance was 529 mL/min/m2 and the mean AUC (0–inf) was 501 ng/mL•min
## Nonclinical Toxicology
There is limited information regarding Sargramostim Nonclinical Toxicology in the drug label.
# Clinical Studies
### Acute Myelogenous Leukemia
- The safety and efficacy of Sargramostim in patients with AML who are younger than 55 years of age have not been determined. Based on Phase II data suggesting the best therapeutic effects could be achieved in patients at highest risk for severe infections and mortality while neutropenic, the Phase III clinical trial was conducted in older patients. The safety and efficacy of Sargramostim in the treatment of AML were evaluated in a multi-center, randomized, double-blind placebo-controlled trial of 99 newly diagnosed adult patients, 55–70 years of age, receiving induction with or without consolidation. A combination of standard doses of daunorubicin (days 1–3) and ara-C (days 1–7) was administered during induction and high dose ara-C was administered days 1–6 as a single course of consolidation, if given. Bone marrow evaluation was performed on day 10 following induction chemotherapy. If hypoplasia with <5% blasts was not achieved, patients immediately received a second cycle of induction chemotherapy. If the bone marrow was hypoplastic with <5% blasts on day 10 or four days following the second cycle of induction chemotherapy, Sargramostim (250 mcg/m2/day) or placebo was given IV over four hours each day, starting four days after the completion of chemotherapy. Study drug was continued until an ANC ≥1500/mm3 for three consecutive days was attained or a maximum of 42 days. Sargramostim or placebo was also administered after the single course of consolidation chemotherapy if delivered (ara-C 3–6 weeks after induction following neutrophil recovery). Study drug was discontinued immediately if leukemic regrowth occurred.
- Sargramostim significantly shortened the median duration of ANC <500/mm3 by 4 days and <1000/mm3 by 7 days following induction (see TABLE 1). 75% of patients receiving Sargramostim achieved ANC >500/mm3 by day 16, compared to day 25 for patients receiving placebo. The proportion of patients receiving one cycle (70%) or two cycles (30%) of induction was similar in both treatment groups; Sargramostim significantly shortened the median times to neutrophil recovery whether one cycle (12 versus 15 days) or two cycles (14 versus 23 days) of induction chemotherapy was administered. Median times to platelet (>20,000/mm3) and RBC transfusion independence were not significantly different between treatment groups.
- During the consolidation phase of treatment, Sargramostim did not shorten the median time to recovery of ANC to 500/mm3 (13 days) or 1000/mm3 (14.5 days) compared to placebo. There were no significant differences in time to platelet and RBC transfusion independence.
- The incidence of severe infections and deaths associated with infections was significantly reduced in patients who received Sargramostim During induction or consolidation, 27 of 52 patients receiving Sargramostim and 35 of 47 patients receiving placebo had at least one grade 3, 4 or 5 infection (p=0.02). Twenty-five patients receiving Sargramostim and 30 patients receiving placebo experienced severe and fatal infections during induction only. There were significantly fewer deaths from infectious causes in the Sargramostim arm (3 versus 11, p=0.02). The majority of deaths in the placebo group were associated with fungal infections with pneumonia as the primary infection.
- Disease outcomes were not adversely affected by the use of Sargramostim The proportion of patients achieving complete remission (CR) was higher in the Sargramostim group (69% as compared to 55% for the placebo group), but the difference was not significant (p=0.21). There was no significant difference in relapse rates; 12 of 36 patients who received Sargramostim and five of 26 patients who received placebo relapsed within 180 days of documented CR (p=0.26). The overall median survival was 378 days for patients receiving Sargramostim and 268 days for those on placebo (p=0.17). The study was not sized to assess the impact of Sargramostim treatment on response or survival.
### Mobilization and Engraftment of PBPC
- A retrospective review was conducted of data from patients with cancer undergoing collection of peripheral blood progenitor cells (PBPC) at a single transplant center. Mobilization of PBPC and myeloid reconstitution post-transplant were compared between four groups of patients (n=196) receiving Sargramostim for mobilization and a historical control group who did not receive any mobilization treatment (progenitor cells collected by leukapheresis without mobilization (n=100)). Sequential cohorts received Sargramostim The cohorts differed by dose (125 or 250 mcg/m2/day), route (IV over 24 hours or SC) and use of Sargramostim post-transplant. Leukaphereses were initiated for all mobilization groups after the WBC reached 10,000/mm3. Leukaphereses continued until both a minimum number of mononucleated cells (MNC) were collected (6.5 or 8.0 × 108/kg body weight) and a minimum number of phereses (5–8) were performed. Both minimum requirements varied by treatment cohort and planned conditioning regimen. If subjects failed to reach a WBC of 10,000 cells/mm3 by day five, another cytokine was substituted for Sargramostim; these subjects were all successfully leukapheresed and transplanted. The most marked mobilization and post-transplant effects were seen in patients administered the higher dose of Sargramostim (250 mcg/m2) either IV (n=63) or SC (n=41).
- PBPCs from patients treated at the 250 mcg/m2/day dose had significantly higher number of granulocyte-macrophage colony-forming units (CFU-GM) than those collected without mobilization. The mean value after thawing was 11.41 × 104 CFU-GM/kg for all Sargramostim-mobilized patients, compared to 0.96 × 104/kg for the non-mobilized group. A similar difference was observed in the mean number of erythrocyte burst-forming units (BFU-E) collected (23.96 × 104/kg for patients mobilized with 250 mcg/m2 doses of Sargramostim administered SC vs. 1.63 × 104/kg for non-mobilized patients).
- After transplantation, mobilized subjects had shorter times to myeloid engraftment and fewer days between transplantation and the last platelet transfusion compared to non-mobilized subjects. Neutrophil recovery (ANC >500/mm3) was more rapid in patients administered Sargramostim following PBPC transplantation with Sargramostim-mobilized cells (see TABLE 2). Mobilized patients also had fewer days to the last platelet transfusion and last RBC transfusion, and a shorter duration of hospitalization than did non-mobilized subjects.
- A second retrospective review of data from patients undergoing PBPC at another single transplant center was also conducted. Sargramostim was given SC at 250 mcg/m2/day once a day (n=10) or twice a day (n=21) until completion of the phereses. Phereses were begun on day 5 of Sargramostim administration and continued until the targeted MNC count of 9 × 108/kg or CD34+ cell count of 1 × 106/kg was reached. There was no difference in CD34+ cell count in patients receiving Sargramostim once or twice a day. The median time to ANC>500/mm3 was 12 days and to platelet recovery (>25,000/mm3) was 23 days.
- Survival studies comparing mobilized study patients to the nonmobilized patients and to an autologous historical bone marrow transplant group showed no differences in median survival time.
### Autologous Bone Marrow Transplantation
Following a dose-ranging Phase I/II trial in patients undergoing autologous BMT for lymphoid malignancies, three single center, randomized, placebo-controlled and double-blinded studies were conducted to evaluate the safety and efficacy of Sargramostim for promoting hematopoietic reconstitution following autologous BMT. A total of 128 patients (65 Sargramostim 63 placebo) were enrolled in these three studies. The majority of the patients had lymphoid malignancy (87 NHL, 17 ALL), 23 patients had Hodgkin's disease, and one patient had acute myeloblastic leukemia (AML). In 72 patients with NHL or ALL, the bone marrow harvest was purged prior to storage with one of several monoclonal antibodies. No chemical agent was used for in vitro treatment of the bone marrow. Preparative regimens in the three studies included cyclophosphamide (total dose 120–150 mg/kg) and total body irradiation (total dose 1,200–1,575 rads). Other regimens used in patients with Hodgkin's disease and NHL without radiotherapy consisted of three or more of the following in combination (expressed as total dose): cytosine arabinoside (400 mg/m2) and carmustine (300 mg/m2), cyclophosphamide (140–150 mg/kg), hydroxyurea (4.5 grams/m2) and etoposide (375–450 mg/m2).
- Compared to placebo, administration of Sargramostim in two studies (n=44 and 47) significantly improved the following hematologic and clinical endpoints: time to neutrophil engraftment, duration of hospitalization and infection experience or antibacterial usage. In the third study (n=37) there was a positive trend toward earlier myeloid engraftment in favor of Sargramostim This latter study differed from the other two in having enrolled a large number of patients with Hodgkin's disease who had also received extensive radiation and chemotherapy prior to harvest of autologous bone marrow. A subgroup analysis of the data from all three studies revealed that the median time to engraftment for patients with Hodgkin's disease, regardless of treatment, was six days longer when compared to patients with NHL and ALL, but that the overall beneficial Sargramostim treatment effect was the same. In the following combined analysis of the three studies, these two subgroups (NHL and ALL vs. Hodgkin's disease) are presented separately.
### Patients with Lymphoid Malignancy (Non-Hodgkin's Lymphoma and Acute Lymphoblastic Leukemia)
- Myeloid engraftment (absolute neutrophil count ANC≥500 cells/mm3) in 54 patients receiving Sargramostim was observed 6 days earlier than in 50 patients treated with placebo (see TABLE 3). Accelerated myeloid engraftment was associated with significant clinical benefits. The median duration of hospitalization was six days shorter for the Sargramostim group than for the placebo group. Median duration of infectious episodes (defined as fever and neutropenia; or two positive cultures of the same organism; or fever >38°C and one positive blood culture; or clinical evidence of infection) was three days less in the group treated with Sargramostim. The median duration of antibacterial administration in the post-transplantation period was four days shorter for the patients treated with Sargramostim than for placebo-treated patients. The study was unable to detect a significant difference between the treatment groups in rate of disease relapse 24 months post-transplantation. As a group, leukemic subjects receiving Sargramostim derived less benefit than NHL subjects. However, both the leukemic and NHL groups receiving Sargramostim engrafted earlier than controls.
### Patients with Hodgkin's Disease
- If patients with Hodgkin's disease are analyzed separately, a trend toward earlier myeloid engraftment is noted. Sargramostim-treated patients engrafted earlier (by five days) than the placebo-treated patients (p=0.189, Wilcoxon) but the number of patients was small (n=22).
### Allogeneic Bone Marrow Transplantation
- A multi-center, randomized, placebo-controlled, and double-blinded study was conducted to evaluate the safety and efficacy of Sargramostim for promoting hematopoietic reconstitution following allogeneic BMT. A total of 109 patients (53 Sargramostim, 56 placebo) were enrolled in the study. Twenty-three patients (11 Sargramostim, 12 placebo) were 18 years old or younger. Sixty-seven patients had myeloid malignancies (33 AML, 34 CML), 17 had lymphoid malignancies (12 ALL, 5 NHL), three patients had Hodgkin's disease, six had multiple myeloma, nine had myelodysplastic disease, and seven patients had aplastic anemia. In 22 patients at one of the seven study sites, bone marrow harvests were depleted of T cells. Preparative regimens included cyclophosphamide, busulfan, cytosine arabinoside, etoposide, methotrexate, corticosteroids, and asparaginase. Some patients also received total body, splenic, or testicular irradiation. Primary graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and a corticosteroid.
- Accelerated myeloid engraftment was associated with significant laboratory and clinical benefits. Compared to placebo, administration of Sargramostim significantly improved the following: time to neutrophil engraftment, duration of hospitalization, number of patients with bacteremia and overall incidence of infection (see TABLE 4).
- Median time to myeloid engraftment (ANC ≥ 500 cells/mm3) in 53 patients receiving Sargramostim was 4 four days less than in 56 patients treated with placebo (see TABLE 4). The number of patients with bacteremia and infection was significantly lower in the Sargramostim group compared to the placebo group (9/53 versus 19/56 and 30/53 versus 42/56, respectively). There were a number of secondary laboratory and clinical endpoints. Of these, only the incidence of severe (grade 3/4) mucositis was significantly improved in the Sargramostim group (4/53) compared to the placebo group (16/56) at p<0.05. Sargramostim-treated patients also had a shorter median duration of post-transplant IV antibiotic infusions, and shorter median number of days to last platelet and RBC transfusions compared to placebo patients, but none of these differences reached statistical significance.
### Bone Marrow Transplantation Failure or Engraftment Delay
- A historically-controlled study was conducted in patients experiencing graft failure following allogeneic or autologous BMT to determine whether Sargramostim improved survival after BMT failure.
- Three categories of patients were eligible for this study:
patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 28 post-transplantation);
patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 21 post-transplantation) and who had evidence of an active infection; and
patients who lost their marrow graft after a transient engraftment (manifested by an average of ANC ≥ 500 cells/mm3 for at least one week followed by loss of engraftment with ANC < 500 cells/mm3 for at least one week beyond day 21 post-transplantation).
- patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 28 post-transplantation);
- patients displaying a delay in engraftment (ANC ≤ 100 cells/mm3 by day 21 post-transplantation) and who had evidence of an active infection; and
- patients who lost their marrow graft after a transient engraftment (manifested by an average of ANC ≥ 500 cells/mm3 for at least one week followed by loss of engraftment with ANC < 500 cells/mm3 for at least one week beyond day 21 post-transplantation).
- A total of 140 eligible patients from 35 institutions were treated with Sargramostim and evaluated in comparison to 103 historical control patients from a single institution. One hundred sixty-three patients had lymphoid leukemia or myeloid leukemia, 24 patients had non-Hodgkin's lymphoma, 19 patients had Hodgkin's disease and 37 patients had other diseases, such as aplastic anemia, myelodysplasia or non-hematologic malignancy. The majority of patients (223 out of 243) had received prior chemotherapy with or without radiotherapy and/or immunotherapy prior to preparation for transplantation.
- One hundred day survival was improved in favor of the patients treated with Sargramostim after graft failure following either autologous or allogeneic BMT. In addition, the median survival was improved by greater than two-fold. The median survival of patients treated with Sargramostim after autologous failure was 474 days versus 161 days for the historical patients. Similarly, after allogeneic failure, the median survival was 97 days with Sargramostim treatment and 35 days for the historical controls. Improvement in survival was better in patients with fewer impaired organs.
- The MOF score is a simple clinical and laboratory assessment of seven major organ systems: cardiovascular, respiratory, gastrointestinal, hematologic, renal, hepatic and neurologic.10 Assessment of the MOF score is recommended as an additional method of determining the need to initiate treatment with Sargramostim in patients with graft failure or delay in engraftment following autologous or allogeneic BMT (see TABLE 5).
### Factors that Contribute to Survival
- The probability of survival was relatively greater for patients with any one of the following characteristics: autologous BMT failure or delay in engraftment, exclusion of total body irradiation from the preparative regimen, a non-leukemic malignancy or MOF score ≤ two (zero, one or two dysfunctional organ systems). Leukemic subjects derived less benefit than other subjects.
# How Supplied
Liquid Sargramostim is available in vials containing 500 mcg/mL (2.8 × 106 IU/mL) sargramostim. Lyophilized Sargramostim is available in vials containing 250 mcg (1.4 × 106 IU/vial) sargramostim.
- Each dosage form is supplied as follows:
Lyophilized Sargramostim: Carton of five vials of lyophilized Sargramostim 250 mcg (NDC 0024-5843-05)
Liquid Sargramostim: Carton of one multiple-use vial; each vial contains 1 mL of preserved 500 mcg/mL liquid Sargramostim (NDC 0024-5844-01)
- Lyophilized Sargramostim: Carton of five vials of lyophilized Sargramostim 250 mcg (NDC 0024-5843-05)
- Liquid Sargramostim: Carton of one multiple-use vial; each vial contains 1 mL of preserved 500 mcg/mL liquid Sargramostim (NDC 0024-5844-01)
- Carton of five multiple-use vials; each vial contains 1 mL of preserved 500 mcg/mL liquid Sargramostim (NDC 0024-5844-05)
## Storage
- Sargramostim should be refrigerated at 2–8°C (36–46°F). Do not freeze or shake. Do not use beyond the expiration date printed on the vial.
# Images
## Drug Images
## Package and Label Display Panel
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# Patient Counseling Information
There is limited information regarding Sargramostim Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Sargramostim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Leukine
# Look-Alike Drug Names
There is limited information regarding Sargramostim Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Leukine | |
4825e3afccc4dbcb7309a88021825592001fdeec | wikidoc | Leukopoiesis | Leukopoiesis
Leukopoiesis is a form of haematopoiesis in which white blood cells (WBC, or leukocytes) are formed in the bone marrow. WBCs arise from the maturation of hemocytoblasts, which are the general stem cell for all blood cells and platelets, into various pluripotential stem cells which can then further differentiate into the different classes of WBCs.
# Myeloid Stem Cell Productions
This stem cell will differentiate into either a proerythroblast (and eventually a red blood cell) or a progenitor cell. The progenitor cell will differentiate into a megakaryocyte (and then a platelet), or a myeloblast or monoblast.
## Myeloblast Productions
These differentiate into 3 different types of myelocytes, which become band cells. These 3 types of band cells eventually mature into Basophils, Eosinophils, and Neutrophils.
## Monoblast Productions
monoblasts differentriate into promonocytes, which mature into monocytes. Monocytes eventually enter the tissues and become Macrophages.
# Lymphoid Stem Cell Productions
Lymphoid stem cells mature into lymphoblasts, and then prolymphocytes, and finally mature lymphocytes, either a B or T cell. | Leukopoiesis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Leukopoiesis is a form of haematopoiesis in which white blood cells (WBC, or leukocytes) are formed in the bone marrow. WBCs arise from the maturation of hemocytoblasts, which are the general stem cell for all blood cells and platelets, into various pluripotential stem cells which can then further differentiate into the different classes of WBCs.
# Myeloid Stem Cell Productions
This stem cell will differentiate into either a proerythroblast (and eventually a red blood cell) or a progenitor cell. The progenitor cell will differentiate into a megakaryocyte (and then a platelet), or a myeloblast or monoblast.
## Myeloblast Productions
These differentiate into 3 different types of myelocytes, which become band cells. These 3 types of band cells eventually mature into Basophils, Eosinophils, and Neutrophils.
## Monoblast Productions
monoblasts differentriate into promonocytes, which mature into monocytes. Monocytes eventually enter the tissues and become Macrophages.
# Lymphoid Stem Cell Productions
Lymphoid stem cells mature into lymphoblasts, and then prolymphocytes, and finally mature lymphocytes, either a B or T cell.
# External links
- Template:EMedicineDictionary
- Leukopoiesis at the US National Library of Medicine Medical Subject Headings (MeSH)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Leukopoiesis | |
fde871370bfcff839c5271d614f5b45be5c627d6 | wikidoc | Levalbuterol | Levalbuterol
# 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
Levalbuterol is a beta2-adrenergic agonist that is FDA approved for the {{{indicationType}}} of asthma. Common adverse reactions include palpitations, chest pain, tachycardia, headache, dizziness, tremor and nervousness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dosage of XOPENEX Inhalation Solution for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: Global Initiative for Chronic Obstructive Lung Disease (GOLD)
- Class of Recommendation: Class IIb
- Strength of Evidence: Category B
- Dosing Information
- Levalbuterol 6 to 8 hr NEB.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Levalbuterol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Children 6-11 years old: The recommended dosage of XOPENEX Inhalation Solution for patients 6-11 years old is 0.31 mg administered three times a day, by nebulization. Routine dosing should not exceed 0.63 mg three times a day.
- Adolescents ≥12 years old: The recommended starting dosage of XOPENEX Inhalation Solution for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Levalbuterol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Levalbuterol in pediatric patients.
# Contraindications
- XOPENEX Inhalation Solution is contraindicated in patients with a history of hypersensitivity to levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.
# Warnings
### Precautions
- Paradoxical Bronchospasm
- XOPENEX Inhalation Solution can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, XOPENEX Inhalation Solution should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new vial.
- Deterioration of Asthma
- Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of XOPENEX Inhalation Solution than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
- Use of Anti-Inflammatory Agents
- XOPENEX Inhalation Solution is not a substitute for corticosteroids. The use of beta-adrenergic agonist alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.
- Cardiovascular Effects
- XOPENEX Inhalation Solution, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and symptoms. Although such effects are uncommon after administration of XOPENEX Inhalation Solution at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the t-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
- Do Not Exceed Recommended Dose
- Do not exceed the recommended dose. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.
- Immediate Hypersensitivity Reactions
- Immediate hypersensitivity reactions may occur after administration of levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving XOPENEX Inhalation Solution.
- Coexisting Conditions
- XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator.
- Changes in blood glucose may occur. Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
- Hypokalemia
- As with other beta-adrenergic agonist medications, XOPENEX Inhalation Solution may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of the drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reaction information concerning XOPENEX Inhalation Solution in adults and adolescents is derived from one 4-week, multicenter, randomized, double-blind, active-, and placebo-controlled trial in 362 patients with asthma 12 years of age and older. Adverse reactions reported in ≥2% of patients receiving XOPENEX Inhalation Solution or racemic albuterol and more frequently than in patients receiving placebo are listed in Table 1.
- The incidence of certain systemic beta-adrenergic adverse reactions (e.g., tremor, nervousness) was slightly less in the XOPENEX Inhalation Solution 0.63 mg group compared with the other active treatment groups. The clinical significance of these small differences is unknown.
- Changes in heart rate 15 minutes after drug administration and in plasma glucose and potassium 1 hour after drug administration on day 1 and day 29 were clinically comparable in the XOPENEX Inhalation Solution 1.25 mg and racemic albuterol 2.5 mg groups (see Table 2). Changes in heart rate and plasma glucose were slightly less in the XOPENEX Inhalation Solution 0.63 mg group compared with the other active treatment groups (see Table 2). The clinical significance of these small differences is unknown. After 4 weeks, effects on heart rate, plasma glucose, and plasma potassium were generally diminished compared with day 1 in all active treatment groups.
- No other clinically relevant laboratory abnormalities related to administration of XOPENEX Inhalation Solution were observed in this study.
- In the clinical trials, a slightly greater number of serious adverse events, discontinuations due to adverse events, and clinically significant ECG changes were reported in patients who received XOPENEX 1.25 mg compared with the other active treatment groups.
- The following adverse reactions, considered potentially related to XOPENEX, occurred in less than 2% of the 292 subjects who received XOPENEX and more frequently than in patients who received placebo in any clinical trial:
Chills, pain, chest pain
ECG abnormal, ECG change, hypertension, hypotension, syncope
Diarrhea, dry mouth, dry throat, dyspepsia, gastroenteritis, nausea
Lymphadenopathy
Leg cramps, myalgia
Anxiety, hyperesthesia of the hand, insomnia, paresthesia, tremor
Eye itch
- The following reactions, considered potentially related to XOPENEX, occurred in less than 2% of the treated subjects but at a frequency less than in patients who received placebo: asthma exacerbation, cough increased, wheezing, sweating, and vomiting.
- Adverse reaction information concerning XOPENEX Inhalation Solution in pediatric patients is derived from one 3-week, multicenter, randomized, double-blind, active-, and placebo-controlled trial in 316 pediatric patients 6 to 11 years of age. Adverse reactions reported in ≥2% of patients in any treatment group and more frequently than in patients receiving placebo are listed in Table 3.
- Changes in heart rate, plasma glucose, and serum potassium are shown in Table 4. The clinical significance of these small differences is unknown.
## Postmarketing Experience
- In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been observed in postapproval use of XOPENEX Inhalation Solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to their seriousness, their frequency of reporting, or their likely beta-mediated mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), asthma, chest pain, cough increased, dysphonia, dyspnea, gastrooesophageal reflux disease (GERD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, urticaria.
- In addition, XOPENEX Inhalation Solution, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, headache, and drying or irritation of the oropharynx.
# Drug Interactions
- Short-Acting Bronchodilators
- Avoid concomitant use of other short-acting sympathomimetic bronchodilators or epinephrine in patients being treated with XOPENEX Inhalation Solution. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.
- Beta-blockers
- Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists such as XOPENEX Inhalation Solution, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.
- Diuretics
- The ECG changes or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop and thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium-sparing diuretics. Consider monitoring potassium levels.
- Digoxin
- Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving XOPENEX Inhalation Solution and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and XOPENEX Inhalation Solution.
- Monoamine Oxidase Inhibitors or Tricyclic Antidepressants
- XOPENEX Inhalation Solution should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of levalbuterol on the vascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of XOPENEX Inhalation Solution in pregnant women. Because animal reproduction studies are not always predictive of human response, XOPENEX Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in newborns of women treated with racemic albuterol which contains the levalbuterol isomer (active drug substance of XOPENEX Inhalation Solution). However, since multiple medications were taken during some of the pregnancies and there was no consistent pattern of anomalies, it was not possible to establish a relationship between racemic albuterol use and the occurrence of these congenital anomalies.
- In animal studies, oral administration of levalbuterol HCl to pregnant New Zealand White rabbits found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 108 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m2 basis).
- However, other studies demonstrated that racemic albuterol sulfate was teratogenic in mice and rabbits at doses comparable to the human therapeutic range. Pregnant mice administered racemic albuterol sulfate subcutaneously had a dose-related increased incidence of cleft palate in their fetuses (4.5% of fetuses at 0.25 mg/kg/day or greater, corresponding to approximately 0.3 times the MRDI dose, 9.3% of fetuses at 2.5 mg/kg/day, approximately 3 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg/day (approximately 0.03 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis). In addition, oral administration of racemic albuterol sulfate to pregnant rabbits resulted in an increased incidence of cranioschisis in fetuses (approximately 215 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis).
- Non-Teratogenic Effects: A study in which pregnant rats were dosed with radiolabeled racemic albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Levalbuterol in women who are pregnant.
### Labor and Delivery
- Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of XOPENEX Inhalation Solution for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
- XOPENEX Inhalation Solution has not been approved for the management of preterm labor. The benefit:risk ratio when levalbuterol HCl is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including racemic albuterol.
### Nursing Mothers
- Plasma concentrations of levalbuterol after inhalation of therapeutic doses are very low in humans. It is not known whether levalbuterol is excreted in human milk.
- Because of the potential for tumorigenicity shown for racemic albuterol in animal studies and the lack of experience with the use of XOPENEX Inhalation Solution by nursing mothers, 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. Caution should be exercised when XOPENEX Inhalation Solution is administered to a nursing woman.
### Pediatric Use
- The safety and efficacy of XOPENEX Inhalation Solution have been established in pediatric patients 6 years of age and older in an adequate and well-controlled clinical trial. Use of XOPENEX Inhalation Solution in children is also supported by evidence from adequate and well-controlled studies of XOPENEX Inhalation Solution in adults, considering that the pathophysiology, systemic exposure of the drug and clinical profile in pediatric and adult patients are substantially similar. Safety and effectiveness of XOPENEX Inhalation Solution in pediatric patients below the age of 6 years have not been established.
### Geriatic Use
- Clinical studies of XOPENEX Inhalation Solution did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Only 5 patients 65 years of age and older were treated with XOPENEX Inhalation Solution in a 4-week clinical study (n=2 for 0.63 mg and n=3 for 1.25 mg). In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment. In general, patients 65 years of age and older should be started at a dose of 0.63 mg of XOPENEX Inhalation Solution. If clinically warranted due to insufficient bronchodilator response, the dose of XOPENEX Inhalation Solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose.
### Gender
There is no FDA guidance on the use of Levalbuterol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Levalbuterol with respect to specific racial populations.
### Renal Impairment
- Albuterol is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Hepatic Impairment
There is no FDA guidance on the use of Levalbuterol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Levalbuterol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Levalbuterol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Inhalational
### Monitoring
There is limited information regarding Monitoring of Levalbuterol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Levalbuterol in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of the symptoms listed under Adverse Reactions (6), e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia also may occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of XOPENEX Inhalation Solution.
### Management
- Treatment consists of discontinuation of XOPENEX Inhalation Solution together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of XOPENEX Inhalation Solution.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Levalbuterol in the drug label.
# Pharmacology
## Mechanism of Action
- Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cyclic-3´, 5´-adenosine monophosphate (cyclic AMP). The increase in cyclic AMP is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are beta2-adrenergic receptors. The precise function of these receptors has not been established. However, all beta-adrenergic agonist drugs can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.
## Structure
- XOPENEX Inhalation Solution is a sterile, clear, colorless, preservative-free solution of the hydrochloride salt of levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol. Levalbuterol HCl is a relatively selective beta2-adrenergic receptor agonist. The chemical name for levalbuterol HCl is (R)-α1-methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and its established chemical structure is as follows:
- The molecular weight of levalbuterol HCl is 275.8, and its empirical formula is C13H21NO3HCl. It is a white to off-white, crystalline solid, with a melting point of approximately 187°C and solubility of approximately 180 mg/mL in water.
- Levalbuterol HCl is the USAN modified name for (R)-albuterol HCl in the United States.
- XOPENEX Inhalation Solution is supplied in unit-dose vials and requires no dilution before administration by nebulization. Each 3 mL unit-dose vial contains 0.31 mg of levalbuterol (as 0.36 mg of levalbuterol HCl) or 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCl) or 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust tonicity, and sulfuric acid to adjust the pH to 4.0 (3.3 to 4.5).
## Pharmacodynamics
- In a randomized, double-blind, placebo-controlled, cross-over study, 20 adults with mild-to-moderate asthma received single doses of XOPENEX Inhalation Solution (0.31 mg, 0.63 mg, and 1.25 mg) and racemic albuterol sulfate inhalation solution (2.5 mg). All doses of active treatment produced a significantly greater degree of bronchodilation (as measured by percent change from pre-dose mean FEV1) than placebo, and there were no significant differences between any of the active treatment arms. The bronchodilator responses to 1.25 mg of XOPENEX Inhalation Solution and 2.5 mg of racemic albuterol sulfate inhalation solution were clinically comparable over the 6-hour evaluation period, except for a slightly longer duration of action (>15% increase in FEV1 from baseline) after administration of 1.25 mg of XOPENEX Inhalation Solution. Systemic beta-adrenergic adverse effects were observed with all active doses and were generally dose-related for (R)-albuterol. XOPENEX Inhalation Solution at a dose of 1.25 mg produced a slightly higher rate of systemic beta-adrenergic adverse effects than the 2.5 mg dose of racemic albuterol sulfate inhalation solution.
- In a randomized, double-blind, placebo-controlled, cross-over study, 12 adults with mild-to-moderate asthma were challenged with inhaled methacholine chloride 20 and 180 minutes following administration of a single dose of 2.5 mg of racemic albuterol sulfate, 1.25 mg of XOPENEX, 1.25 mg of (S)-albuterol, or placebo using a Pari LC Jet™ nebulizer. Racemic albuterol sulfate, XOPENEX, and (S)-albuterol had a protective effect against methacholine-induced bronchoconstriction 20 minutes after administration, although the effect of (S)-albuterol was minimal. At 180 minutes after administration, the bronchoprotective effect of 1.25 mg of XOPENEX was comparable to that of 2.5 mg of racemic albuterol sulfate. At 180 minutes after administration, 1.25 mg of (S)-albuterol had no bronchoprotective effect.
- In a clinical study in adults with mild-to-moderate asthma, comparable efficacy (as measured by change from baseline FEV1) and safety (as measured by heart rate, blood pressure, ECG, serum potassium, and tremor) were demonstrated after a cumulative dose of 5 mg of XOPENEX Inhalation Solution (four consecutive doses of 1.25 mg administered every 30 minutes) and 10 mg of racemic albuterol sulfate inhalation solution (four consecutive doses of 2.5 mg administered every 30 minutes).
## Pharmacokinetics
- The inhalation pharmacokinetics of XOPENEX Inhalation Solution were investigated in a randomized cross-over study in 30 healthy adults following administration of a single dose of 1.25 mg and a cumulative dose of 5 mg of XOPENEX Inhalation Solution and a single dose of 2.5 mg and a cumulative dose of 10 mg of racemic albuterol sulfate inhalation solution by nebulization using a PARI LC Jet™ nebulizer with a Dura-Neb® 2000 compressor.
- Following administration of a single 1.25 mg dose of XOPENEX Inhalation Solution, exposure to (R)-albuterol (AUC of 3.3 nghr/mL) was approximately 2-fold higher than following administration of a single 2.5 mg dose of racemic albuterol inhalation solution (AUC of 1.7 nghr/mL) (see Table 5). Following administration of a cumulative 5 mg dose of XOPENEX Inhalation Solution (1.25 mg given every 30 minutes for a total of four doses) or a cumulative 10 mg dose of racemic albuterol inhalation solution (2.5 mg given every 30 minutes for a total of four doses), Cmax and AUC of (R)-albuterol were comparable (see Table 5).
- The pharmacokinetic parameters of (R)- and (S)-albuterol in children with asthma were obtained using population pharmacokinetic analysis. These data are presented in Table 6. For comparison, adult data obtained by conventional pharmacokinetic analysis from a different study also are presented in Table 6.
- In children, AUC and Cmax of (R)-albuterol following administration of 0.63 mg XOPENEX Inhalation Solution were comparable to those following administration of 1.25 mg racemic albuterol sulfate inhalation solution.
- When the same dose of 0.63 mg of XOPENEX Inhalation Solution was given to children and adults, the predicted Cmax of (R)-albuterol in children was similar to that in adults (0.52 vs. 0.56 ng/mL), while predicted AUC in children (2.55 nghr/mL) was about 1.5-fold higher than that in adults (1.65 nghr/mL). These data support lower doses for children 6-11 years old compared with the adult doses.
- Metabolism and Elimination
- Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol enantiomers in humans is SULT1A3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3.
- The primary route of elimination of albuterol enantiomers is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine.
- Special Populations
- Hepatic Impairment
- The effect of hepatic impairment on the pharmacokinetics of XOPENEX Inhalation Solution has not been evaluated.
- Renal Impairment
- The effect of renal impairment on the pharmacokinetics of racemic albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in racemic albuterol clearance. Caution should be used when administering high doses of XOPENEX Inhalation Solution to patients with renal impairment.
## Nonclinical Toxicology
- Although there have been no carcinogenesis studies with levalbuterol HCl, racemic albuterol sulfate has been evaluated for its carcinogenic potential.
- In a 2-year study in Sprague-Dawley rats, dietary administration of racemic albuterol sulfate resulted in a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at doses of 2 mg/kg/day and greater (approximately 4 times the MRDI dose of levalbuterol HCl for adults and approximately 5 times the MRDI dose of levalbuterol HCl for children on a mg/m2 basis). In an 18-month study in CD-1 mice and a 22-month study in the golden hamster, dietary administration of racemic albuterol sulfate showed no evidence of tumorigenicity. Dietary doses in CD-1 mice were up to 500 mg/kg/day (approximately 540 times the MRDI dose of levalbuterol HCl for adults and approximately 630 times the MRDI dose of levalbuterol HCl for children on a mg/m2 basis) and doses in the golden hamster study were up to 50 mg/kg/day (approximately 90 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis and approximately 105 times the MRDI dose of levalbuterol HCl for children on a mg/m2 basis).
- Levalbuterol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Levalbuterol HCl was not clastogenic in the in vivo micronucleus test in mouse bone marrow. Racemic albuterol sulfate was not clastogenic in an in vitro chromosomal aberration assay in CHO cell cultures.
- No fertility studies have been conducted with levalbuterol hydrochloride. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg/day (approximately 108 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m2 basis).
# Clinical Studies
- The safety and efficacy of XOPENEX Inhalation Solution were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV1 60% of predicted). Approximately half of the patients were also receiving inhaled corticosteroids. Patients were randomized to receive XOPENEX 0.63 mg, XOPENEX 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb® portable compressor. Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered-dose inhaler (MDI) was used on an as-needed basis as the rescue medication.
- Efficacy, as measured by the mean percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 29. On both day 1 (see Figure 1) and day 29 (see Figure 2), 1.25 mg of XOPENEX demonstrated the largest mean percent change from baseline FEV1 compared with the other active treatments. A dose of 0.63 mg of XOPENEX and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean percent change from baseline FEV1 on both day 1 and day 29.
- The mean time to onset of a 15% increase in FEV1 over baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment. The mean duration of effect, as measured by a >15% increase from baseline FEV1, was approximately 5 hours after administration of 0.63 mg of levalbuterol and approximately 6 hours after administration of 1.25 mg of levalbuterol after 4 weeks of treatment. In some patients, the duration of effect was as long as 8 hours.
- A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV1 73% of predicted) (n=316). Following a 1-week placebo run-in, subjects were randomized to XOPENEX (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), or placebo, which were delivered three times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb® 3000 compressor.
- Efficacy, as measured by mean peak percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 21. Time profile FEV1 curves for day 1 and day 21 are shown in Figure 3 and Figure 4, respectively. The onset of effect (time to a 15% increase in FEV1 over test-day baseline) and duration of effect (maintenance of a >15% increase in FEV1 over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.
# How Supplied
- XOPENEX Inhalation Solution is supplied in 3 mL unit-dose, low-density polyethylene (LDPE) vials as a clear, colorless, sterile, preservative-free, aqueous solution, in three different strengths of levalbuterol (0.31 mg, 0.63 mg, 1.25 mg). Each strength of XOPENEX Inhalation Solution is available in a shelf-carton containing one or more foil pouches, each containing 12 unit-dose LDPE vials.
- XOPENEX (levalbuterol HCl) Inhalation Solution, 0.31 mg (foil pouch label color green) contains 0.31 mg of levalbuterol (as 0.36 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 63402-511-24).
- XOPENEX (levalbuterol HCl) Inhalation Solution, 0.63 mg (foil pouch label color yellow) contains 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 63402-512-24).
- XOPENEX (levalbuterol HCl) Inhalation Solution, 1.25 mg (foil pouch label color red) contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 63402-513-24).
- XOPENEX Inhalation Solution is also available as a concentrate in individually pouched 0.5 mL unit-dose vials containing 1.25 mg of levalbuterol (NDC 63402-515-30).
- Store XOPENEX Inhalation Solution in the protective foil pouch at 20-25°C (68-77°F). Protect from light and excessive heat. Keep unopened vials in the foil pouch. Once the foil pouch is opened, the vials should be used within 2 weeks. Vials removed from the pouch, if not used immediately, should be protected from light and used within 1 week. Discard any vial if the solution is not colorless.
## Storage
There is limited information regarding Levalbuterol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Hypersensitivity
- Query patients about previously experienced hypersensitivity to levalbuterol or racemic albuterol and counsel patients to report any hypersensitivity reactions to their physician.
- Frequency of Use
- Inform patients not to increase the dose or use XOPENEX Inhalation Solution more frequently than recommended without consulting their physician. If patients find that treatment with XOPENEX Inhalation Solution becomes less effective for symptomatic relief, symptoms become worse, or they need to use the product more frequently than usual, they should seek medical attention immediately.
- Paradoxical Bronchospasm
- Inform patients that XOPENEX Inhalation Solution can produce paradoxical bronchospasm. Instruct patients to discontinue XOPENEX Inhalation Solution if paradoxical bronchospasm occurs.
- Concomitant Drug Use
- Inform patients using XOPENEX Inhalation Solution, that other inhaled drugs and asthma medications should be taken only as directed by their physician.
- Common Adverse Reactions
- Advise patients of the common adverse reactions of treatment with XOPENEX Inhalation Solution including palpitations, chest pain, fast heart rate, headache, dizziness, tremor and nervousness.
- Pregnancy
- Advise patients who are pregnant or nursing to contact their physician about the use of XOPENEX Inhalation Solution.
- General Information on Use
- Advise patients to store XOPENEX Inhalation Solution in the foil pouch between 20°C and 25°C (68°F and 77°F) protected from light and excessive heat. Do not use after the expiration date stamped on the container. Unused vials should be stored in the protective foil pouch. Once the foil pouch is opened, the vials should be used within 2 weeks. Vials removed from the pouch, if not used immediately, should be protected from light and used within 1 week. Discard any vial if the solution is not colorless.
- Advise patients not to mix XOPENEX Inhalation Solution with other drugs in a nebulizer.
# Precautions with Alcohol
- Alcohol-Levalbuterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- XOPENEX®
# Look-Alike Drug Names
There is limited information regarding Levalbuterol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Levalbuterol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Levalbuterol is a beta2-adrenergic agonist that is FDA approved for the {{{indicationType}}} of asthma. Common adverse reactions include palpitations, chest pain, tachycardia, headache, dizziness, tremor and nervousness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dosage of XOPENEX Inhalation Solution for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: Global Initiative for Chronic Obstructive Lung Disease (GOLD)
- Class of Recommendation: Class IIb
- Strength of Evidence: Category B
- Dosing Information
- Levalbuterol 6 to 8 hr NEB.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Levalbuterol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Children 6-11 years old: The recommended dosage of XOPENEX Inhalation Solution for patients 6-11 years old is 0.31 mg administered three times a day, by nebulization. Routine dosing should not exceed 0.63 mg three times a day.
- Adolescents ≥12 years old: The recommended starting dosage of XOPENEX Inhalation Solution for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Levalbuterol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Levalbuterol in pediatric patients.
# Contraindications
- XOPENEX Inhalation Solution is contraindicated in patients with a history of hypersensitivity to levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.
# Warnings
### Precautions
- Paradoxical Bronchospasm
- XOPENEX Inhalation Solution can produce paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, XOPENEX Inhalation Solution should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new vial.
- Deterioration of Asthma
- Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of XOPENEX Inhalation Solution than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
- Use of Anti-Inflammatory Agents
- XOPENEX Inhalation Solution is not a substitute for corticosteroids. The use of beta-adrenergic agonist alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.
- Cardiovascular Effects
- XOPENEX Inhalation Solution, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and symptoms. Although such effects are uncommon after administration of XOPENEX Inhalation Solution at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the t-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
- Do Not Exceed Recommended Dose
- Do not exceed the recommended dose. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.
- Immediate Hypersensitivity Reactions
- Immediate hypersensitivity reactions may occur after administration of levalbuterol or racemic albuterol. Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving XOPENEX Inhalation Solution.
- Coexisting Conditions
- XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator.
- Changes in blood glucose may occur. Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
- Hypokalemia
- As with other beta-adrenergic agonist medications, XOPENEX Inhalation Solution may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of the drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reaction information concerning XOPENEX Inhalation Solution in adults and adolescents is derived from one 4-week, multicenter, randomized, double-blind, active-, and placebo-controlled trial in 362 patients with asthma 12 years of age and older. Adverse reactions reported in ≥2% of patients receiving XOPENEX Inhalation Solution or racemic albuterol and more frequently than in patients receiving placebo are listed in Table 1.
- The incidence of certain systemic beta-adrenergic adverse reactions (e.g., tremor, nervousness) was slightly less in the XOPENEX Inhalation Solution 0.63 mg group compared with the other active treatment groups. The clinical significance of these small differences is unknown.
- Changes in heart rate 15 minutes after drug administration and in plasma glucose and potassium 1 hour after drug administration on day 1 and day 29 were clinically comparable in the XOPENEX Inhalation Solution 1.25 mg and racemic albuterol 2.5 mg groups (see Table 2). Changes in heart rate and plasma glucose were slightly less in the XOPENEX Inhalation Solution 0.63 mg group compared with the other active treatment groups (see Table 2). The clinical significance of these small differences is unknown. After 4 weeks, effects on heart rate, plasma glucose, and plasma potassium were generally diminished compared with day 1 in all active treatment groups.
- No other clinically relevant laboratory abnormalities related to administration of XOPENEX Inhalation Solution were observed in this study.
- In the clinical trials, a slightly greater number of serious adverse events, discontinuations due to adverse events, and clinically significant ECG changes were reported in patients who received XOPENEX 1.25 mg compared with the other active treatment groups.
- The following adverse reactions, considered potentially related to XOPENEX, occurred in less than 2% of the 292 subjects who received XOPENEX and more frequently than in patients who received placebo in any clinical trial:
Chills, pain, chest pain
ECG abnormal, ECG change, hypertension, hypotension, syncope
Diarrhea, dry mouth, dry throat, dyspepsia, gastroenteritis, nausea
Lymphadenopathy
Leg cramps, myalgia
Anxiety, hyperesthesia of the hand, insomnia, paresthesia, tremor
Eye itch
- The following reactions, considered potentially related to XOPENEX, occurred in less than 2% of the treated subjects but at a frequency less than in patients who received placebo: asthma exacerbation, cough increased, wheezing, sweating, and vomiting.
- Adverse reaction information concerning XOPENEX Inhalation Solution in pediatric patients is derived from one 3-week, multicenter, randomized, double-blind, active-, and placebo-controlled trial in 316 pediatric patients 6 to 11 years of age. Adverse reactions reported in ≥2% of patients in any treatment group and more frequently than in patients receiving placebo are listed in Table 3.
- Changes in heart rate, plasma glucose, and serum potassium are shown in Table 4. The clinical significance of these small differences is unknown.
## Postmarketing Experience
- In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been observed in postapproval use of XOPENEX Inhalation Solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to their seriousness, their frequency of reporting, or their likely beta-mediated mechanism: angioedema, anaphylaxis, arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), asthma, chest pain, cough increased, dysphonia, dyspnea, gastrooesophageal reflux disease (GERD), metabolic acidosis, nausea, nervousness, rash, tachycardia, tremor, urticaria.
- In addition, XOPENEX Inhalation Solution, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, sleeplessness, headache, and drying or irritation of the oropharynx.
# Drug Interactions
- Short-Acting Bronchodilators
- Avoid concomitant use of other short-acting sympathomimetic bronchodilators or epinephrine in patients being treated with XOPENEX Inhalation Solution. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.
- Beta-blockers
- Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists such as XOPENEX Inhalation Solution, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.
- Diuretics
- The ECG changes or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop and thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium-sparing diuretics. Consider monitoring potassium levels.
- Digoxin
- Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving XOPENEX Inhalation Solution and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and XOPENEX Inhalation Solution.
- Monoamine Oxidase Inhibitors or Tricyclic Antidepressants
- XOPENEX Inhalation Solution should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of levalbuterol on the vascular system may be potentiated. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of XOPENEX Inhalation Solution in pregnant women. Because animal reproduction studies are not always predictive of human response, XOPENEX Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in newborns of women treated with racemic albuterol which contains the levalbuterol isomer (active drug substance of XOPENEX Inhalation Solution). However, since multiple medications were taken during some of the pregnancies and there was no consistent pattern of anomalies, it was not possible to establish a relationship between racemic albuterol use and the occurrence of these congenital anomalies.
- In animal studies, oral administration of levalbuterol HCl to pregnant New Zealand White rabbits found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 108 times the maximum recommended daily inhalation [MRDI] dose of levalbuterol HCl for adults on a mg/m2 basis).
- However, other studies demonstrated that racemic albuterol sulfate was teratogenic in mice and rabbits at doses comparable to the human therapeutic range. Pregnant mice administered racemic albuterol sulfate subcutaneously had a dose-related increased incidence of cleft palate in their fetuses (4.5% of fetuses at 0.25 mg/kg/day or greater, corresponding to approximately 0.3 times the MRDI dose, 9.3% of fetuses at 2.5 mg/kg/day, approximately 3 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg/day (approximately 0.03 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis). In addition, oral administration of racemic albuterol sulfate to pregnant rabbits resulted in an increased incidence of cranioschisis in fetuses (approximately 215 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis).
- Non-Teratogenic Effects: A study in which pregnant rats were dosed with radiolabeled racemic albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Levalbuterol in women who are pregnant.
### Labor and Delivery
- Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of XOPENEX Inhalation Solution for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
- XOPENEX Inhalation Solution has not been approved for the management of preterm labor. The benefit:risk ratio when levalbuterol HCl is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including racemic albuterol.
### Nursing Mothers
- Plasma concentrations of levalbuterol after inhalation of therapeutic doses are very low in humans. It is not known whether levalbuterol is excreted in human milk.
- Because of the potential for tumorigenicity shown for racemic albuterol in animal studies and the lack of experience with the use of XOPENEX Inhalation Solution by nursing mothers, 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. Caution should be exercised when XOPENEX Inhalation Solution is administered to a nursing woman.
### Pediatric Use
- The safety and efficacy of XOPENEX Inhalation Solution have been established in pediatric patients 6 years of age and older in an adequate and well-controlled clinical trial. Use of XOPENEX Inhalation Solution in children is also supported by evidence from adequate and well-controlled studies of XOPENEX Inhalation Solution in adults, considering that the pathophysiology, systemic exposure of the drug and clinical profile in pediatric and adult patients are substantially similar. Safety and effectiveness of XOPENEX Inhalation Solution in pediatric patients below the age of 6 years have not been established.
### Geriatic Use
- Clinical studies of XOPENEX Inhalation Solution did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Only 5 patients 65 years of age and older were treated with XOPENEX Inhalation Solution in a 4-week clinical study (n=2 for 0.63 mg and n=3 for 1.25 mg). In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment. In general, patients 65 years of age and older should be started at a dose of 0.63 mg of XOPENEX Inhalation Solution. If clinically warranted due to insufficient bronchodilator response, the dose of XOPENEX Inhalation Solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose.
### Gender
There is no FDA guidance on the use of Levalbuterol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Levalbuterol with respect to specific racial populations.
### Renal Impairment
- Albuterol is known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Hepatic Impairment
There is no FDA guidance on the use of Levalbuterol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Levalbuterol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Levalbuterol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Inhalational
### Monitoring
There is limited information regarding Monitoring of Levalbuterol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Levalbuterol in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of the symptoms listed under Adverse Reactions (6), e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia also may occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of XOPENEX Inhalation Solution.
### Management
- Treatment consists of discontinuation of XOPENEX Inhalation Solution together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of XOPENEX Inhalation Solution.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Levalbuterol in the drug label.
# Pharmacology
## Mechanism of Action
- Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cyclic-3´, 5´-adenosine monophosphate (cyclic AMP). The increase in cyclic AMP is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are beta2-adrenergic receptors. The precise function of these receptors has not been established. However, all beta-adrenergic agonist drugs can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.
## Structure
- XOPENEX Inhalation Solution is a sterile, clear, colorless, preservative-free solution of the hydrochloride salt of levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol. Levalbuterol HCl is a relatively selective beta2-adrenergic receptor agonist. The chemical name for levalbuterol HCl is (R)-α1-[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and its established chemical structure is as follows:
- The molecular weight of levalbuterol HCl is 275.8, and its empirical formula is C13H21NO3•HCl. It is a white to off-white, crystalline solid, with a melting point of approximately 187°C and solubility of approximately 180 mg/mL in water.
- Levalbuterol HCl is the USAN modified name for (R)-albuterol HCl in the United States.
- XOPENEX Inhalation Solution is supplied in unit-dose vials and requires no dilution before administration by nebulization. Each 3 mL unit-dose vial contains 0.31 mg of levalbuterol (as 0.36 mg of levalbuterol HCl) or 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCl) or 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust tonicity, and sulfuric acid to adjust the pH to 4.0 (3.3 to 4.5).
## Pharmacodynamics
- In a randomized, double-blind, placebo-controlled, cross-over study, 20 adults with mild-to-moderate asthma received single doses of XOPENEX Inhalation Solution (0.31 mg, 0.63 mg, and 1.25 mg) and racemic albuterol sulfate inhalation solution (2.5 mg). All doses of active treatment produced a significantly greater degree of bronchodilation (as measured by percent change from pre-dose mean FEV1) than placebo, and there were no significant differences between any of the active treatment arms. The bronchodilator responses to 1.25 mg of XOPENEX Inhalation Solution and 2.5 mg of racemic albuterol sulfate inhalation solution were clinically comparable over the 6-hour evaluation period, except for a slightly longer duration of action (>15% increase in FEV1 from baseline) after administration of 1.25 mg of XOPENEX Inhalation Solution. Systemic beta-adrenergic adverse effects were observed with all active doses and were generally dose-related for (R)-albuterol. XOPENEX Inhalation Solution at a dose of 1.25 mg produced a slightly higher rate of systemic beta-adrenergic adverse effects than the 2.5 mg dose of racemic albuterol sulfate inhalation solution.
- In a randomized, double-blind, placebo-controlled, cross-over study, 12 adults with mild-to-moderate asthma were challenged with inhaled methacholine chloride 20 and 180 minutes following administration of a single dose of 2.5 mg of racemic albuterol sulfate, 1.25 mg of XOPENEX, 1.25 mg of (S)-albuterol, or placebo using a Pari LC Jet™ nebulizer. Racemic albuterol sulfate, XOPENEX, and (S)-albuterol had a protective effect against methacholine-induced bronchoconstriction 20 minutes after administration, although the effect of (S)-albuterol was minimal. At 180 minutes after administration, the bronchoprotective effect of 1.25 mg of XOPENEX was comparable to that of 2.5 mg of racemic albuterol sulfate. At 180 minutes after administration, 1.25 mg of (S)-albuterol had no bronchoprotective effect.
- In a clinical study in adults with mild-to-moderate asthma, comparable efficacy (as measured by change from baseline FEV1) and safety (as measured by heart rate, blood pressure, ECG, serum potassium, and tremor) were demonstrated after a cumulative dose of 5 mg of XOPENEX Inhalation Solution (four consecutive doses of 1.25 mg administered every 30 minutes) and 10 mg of racemic albuterol sulfate inhalation solution (four consecutive doses of 2.5 mg administered every 30 minutes).
## Pharmacokinetics
- The inhalation pharmacokinetics of XOPENEX Inhalation Solution were investigated in a randomized cross-over study in 30 healthy adults following administration of a single dose of 1.25 mg and a cumulative dose of 5 mg of XOPENEX Inhalation Solution and a single dose of 2.5 mg and a cumulative dose of 10 mg of racemic albuterol sulfate inhalation solution by nebulization using a PARI LC Jet™ nebulizer with a Dura-Neb® 2000 compressor.
- Following administration of a single 1.25 mg dose of XOPENEX Inhalation Solution, exposure to (R)-albuterol (AUC of 3.3 ng•hr/mL) was approximately 2-fold higher than following administration of a single 2.5 mg dose of racemic albuterol inhalation solution (AUC of 1.7 ng•hr/mL) (see Table 5). Following administration of a cumulative 5 mg dose of XOPENEX Inhalation Solution (1.25 mg given every 30 minutes for a total of four doses) or a cumulative 10 mg dose of racemic albuterol inhalation solution (2.5 mg given every 30 minutes for a total of four doses), Cmax and AUC of (R)-albuterol were comparable (see Table 5).
- The pharmacokinetic parameters of (R)- and (S)-albuterol in children with asthma were obtained using population pharmacokinetic analysis. These data are presented in Table 6. For comparison, adult data obtained by conventional pharmacokinetic analysis from a different study also are presented in Table 6.
- In children, AUC and Cmax of (R)-albuterol following administration of 0.63 mg XOPENEX Inhalation Solution were comparable to those following administration of 1.25 mg racemic albuterol sulfate inhalation solution.
- When the same dose of 0.63 mg of XOPENEX Inhalation Solution was given to children and adults, the predicted Cmax of (R)-albuterol in children was similar to that in adults (0.52 vs. 0.56 ng/mL), while predicted AUC in children (2.55 ng•hr/mL) was about 1.5-fold higher than that in adults (1.65 ng•hr/mL). These data support lower doses for children 6-11 years old compared with the adult doses.
- Metabolism and Elimination
- Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol enantiomers in humans is SULT1A3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3.
- The primary route of elimination of albuterol enantiomers is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine.
- Special Populations
- Hepatic Impairment
- The effect of hepatic impairment on the pharmacokinetics of XOPENEX Inhalation Solution has not been evaluated.
- Renal Impairment
- The effect of renal impairment on the pharmacokinetics of racemic albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in racemic albuterol clearance. Caution should be used when administering high doses of XOPENEX Inhalation Solution to patients with renal impairment.
## Nonclinical Toxicology
- Although there have been no carcinogenesis studies with levalbuterol HCl, racemic albuterol sulfate has been evaluated for its carcinogenic potential.
- In a 2-year study in Sprague-Dawley rats, dietary administration of racemic albuterol sulfate resulted in a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at doses of 2 mg/kg/day and greater (approximately 4 times the MRDI dose of levalbuterol HCl for adults and approximately 5 times the MRDI dose of levalbuterol HCl for children on a mg/m2 basis). In an 18-month study in CD-1 mice and a 22-month study in the golden hamster, dietary administration of racemic albuterol sulfate showed no evidence of tumorigenicity. Dietary doses in CD-1 mice were up to 500 mg/kg/day (approximately 540 times the MRDI dose of levalbuterol HCl for adults and approximately 630 times the MRDI dose of levalbuterol HCl for children on a mg/m2 basis) and doses in the golden hamster study were up to 50 mg/kg/day (approximately 90 times the MRDI dose of levalbuterol HCl for adults on a mg/m2 basis and approximately 105 times the MRDI dose of levalbuterol HCl for children on a mg/m2 basis).
- Levalbuterol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Levalbuterol HCl was not clastogenic in the in vivo micronucleus test in mouse bone marrow. Racemic albuterol sulfate was not clastogenic in an in vitro chromosomal aberration assay in CHO cell cultures.
- No fertility studies have been conducted with levalbuterol hydrochloride. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg/day (approximately 108 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m2 basis).
# Clinical Studies
- The safety and efficacy of XOPENEX Inhalation Solution were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV1 60% of predicted). Approximately half of the patients were also receiving inhaled corticosteroids. Patients were randomized to receive XOPENEX 0.63 mg, XOPENEX 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb® portable compressor. Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered-dose inhaler (MDI) was used on an as-needed basis as the rescue medication.
- Efficacy, as measured by the mean percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 29. On both day 1 (see Figure 1) and day 29 (see Figure 2), 1.25 mg of XOPENEX demonstrated the largest mean percent change from baseline FEV1 compared with the other active treatments. A dose of 0.63 mg of XOPENEX and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean percent change from baseline FEV1 on both day 1 and day 29.
- The mean time to onset of a 15% increase in FEV1 over baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment. The mean duration of effect, as measured by a >15% increase from baseline FEV1, was approximately 5 hours after administration of 0.63 mg of levalbuterol and approximately 6 hours after administration of 1.25 mg of levalbuterol after 4 weeks of treatment. In some patients, the duration of effect was as long as 8 hours.
- A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV1 73% of predicted) (n=316). Following a 1-week placebo run-in, subjects were randomized to XOPENEX (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), or placebo, which were delivered three times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb® 3000 compressor.
- Efficacy, as measured by mean peak percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 21. Time profile FEV1 curves for day 1 and day 21 are shown in Figure 3 and Figure 4, respectively. The onset of effect (time to a 15% increase in FEV1 over test-day baseline) and duration of effect (maintenance of a >15% increase in FEV1 over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.
# How Supplied
- XOPENEX Inhalation Solution is supplied in 3 mL unit-dose, low-density polyethylene (LDPE) vials as a clear, colorless, sterile, preservative-free, aqueous solution, in three different strengths of levalbuterol (0.31 mg, 0.63 mg, 1.25 mg). Each strength of XOPENEX Inhalation Solution is available in a shelf-carton containing one or more foil pouches, each containing 12 unit-dose LDPE vials.
- XOPENEX (levalbuterol HCl) Inhalation Solution, 0.31 mg (foil pouch label color green) contains 0.31 mg of levalbuterol (as 0.36 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 63402-511-24).
- XOPENEX (levalbuterol HCl) Inhalation Solution, 0.63 mg (foil pouch label color yellow) contains 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 63402-512-24).
- XOPENEX (levalbuterol HCl) Inhalation Solution, 1.25 mg (foil pouch label color red) contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl) and is available in cartons of 24 unit-dose LDPE vials (NDC 63402-513-24).
- XOPENEX Inhalation Solution is also available as a concentrate in individually pouched 0.5 mL unit-dose vials containing 1.25 mg of levalbuterol (NDC 63402-515-30).
- Store XOPENEX Inhalation Solution in the protective foil pouch at 20-25°C (68-77°F). Protect from light and excessive heat. Keep unopened vials in the foil pouch. Once the foil pouch is opened, the vials should be used within 2 weeks. Vials removed from the pouch, if not used immediately, should be protected from light and used within 1 week. Discard any vial if the solution is not colorless.
## Storage
There is limited information regarding Levalbuterol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Hypersensitivity
- Query patients about previously experienced hypersensitivity to levalbuterol or racemic albuterol and counsel patients to report any hypersensitivity reactions to their physician.
- Frequency of Use
- Inform patients not to increase the dose or use XOPENEX Inhalation Solution more frequently than recommended without consulting their physician. If patients find that treatment with XOPENEX Inhalation Solution becomes less effective for symptomatic relief, symptoms become worse, or they need to use the product more frequently than usual, they should seek medical attention immediately.
- Paradoxical Bronchospasm
- Inform patients that XOPENEX Inhalation Solution can produce paradoxical bronchospasm. Instruct patients to discontinue XOPENEX Inhalation Solution if paradoxical bronchospasm occurs.
- Concomitant Drug Use
- Inform patients using XOPENEX Inhalation Solution, that other inhaled drugs and asthma medications should be taken only as directed by their physician.
- Common Adverse Reactions
- Advise patients of the common adverse reactions of treatment with XOPENEX Inhalation Solution including palpitations, chest pain, fast heart rate, headache, dizziness, tremor and nervousness.
- Pregnancy
- Advise patients who are pregnant or nursing to contact their physician about the use of XOPENEX Inhalation Solution.
- General Information on Use
- Advise patients to store XOPENEX Inhalation Solution in the foil pouch between 20°C and 25°C (68°F and 77°F) protected from light and excessive heat. Do not use after the expiration date stamped on the container. Unused vials should be stored in the protective foil pouch. Once the foil pouch is opened, the vials should be used within 2 weeks. Vials removed from the pouch, if not used immediately, should be protected from light and used within 1 week. Discard any vial if the solution is not colorless.
- Advise patients not to mix XOPENEX Inhalation Solution with other drugs in a nebulizer.
# Precautions with Alcohol
- Alcohol-Levalbuterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- XOPENEX®[1]
# Look-Alike Drug Names
There is limited information regarding Levalbuterol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Levalbuterol | |
adf15d8d0b75c3a8d599c818c2bd4ca17afef466 | wikidoc | Levomoramide | Levomoramide
# Overview
Levomoramide is the inactive isomer of the opioid analgesic dextromoramide, invented by the chemist Paul Janssen in 1956. Unlike dextromoramide, which is a potent analgesic with high abuse potential, levomoramide is virtually without activity.
"Resolution reveals that the analgetic activity in this case resides almost entirely in the (+) isomer."
"In the α-CH3 series, one of the optical isomers of each enantiomorphic pair is about twice as active as the racemic mixture; the other isomer is devoid of significant analgesic activity."
However despite being inactive, levomoramide is controlled internationally as a Schedule I drug. | Levomoramide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Levomoramide is the inactive isomer of the opioid analgesic dextromoramide, invented by the chemist Paul Janssen in 1956. Unlike dextromoramide, which is a potent analgesic with high abuse potential, levomoramide is virtually without activity.[1][2]
"Resolution reveals that the analgetic activity in this case resides almost entirely in the (+) isomer."[3]
"In the α-CH3 series, one of the optical isomers of each enantiomorphic pair is about twice as active as the racemic mixture; the other isomer is devoid of significant analgesic activity."[4]
However despite being inactive, levomoramide is controlled internationally as a Schedule I drug. | https://www.wikidoc.org/index.php/Levomoramide | |
b0257650711d22e2be732d79fc54830a8861d59d | wikidoc | Levosimendan | Levosimendan
# Overview
Levosimendan (INN) (Template:PronEng) is a calcium sensitiser used in the management of acutely decompensated congestive heart failure. It is marketed under the trade name Simdax (Abbott).
# Mode of action
Levosimendan is a calcium sensitiser – it increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. Levosimendan exerts its positive inotropic effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin C in a calcium-dependent manner. It also has a vasodilatory effect, by opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation. The combined inotropic and vasodilatory actions result in an increased force of contraction, decreased preload and decreased afterload. Moreover, by opening also the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect.
# Clinical use
## Indications
Levosimendan is indicated for inotropic support in acutely-decompensated severe congestive heart failure.
Some of the Phase-III studies in the extensive clinical program were the trials LIDO (200 patients), RUSSLAN (500), CASINO (250), REVIVE-I (100), REVIVE-II (600) and finally SURVIVE (1350)
, a head-to-head trial between levosimendan and dobutamine in acute decompensated heart failure. In total, the clinical data base includes more than 3500 patients in Phase IIb and III double-blind studies, which is the highest number ever in testing a drug for acute decompensated heart failure.
The drug has a marketing authorization in 48 countries (Aug 9, 2007).
## Contraindications
The use of levosimendan is contraindicated in patients with: moderate-to-severe renal impairment, severe hepatic impairment, severe ventricular filling or outflow obstruction, severe hypotension and tachycardia, and/or history of torsades de pointes.
## Adverse effects
Common adverse drug reactions (≥1% of patients) associated with levosimendan therapy include: headache, hypotension, arrhythmias (atrial fibrillation, extrasystoles, atrial tachycardia, ventricular tachycardia), myocardial ischaemia, hypokalaemia and/or nausea (Rossi, 2006).
## Formulations
Levosimendan is marketed as a 2.5 mg/mL concentrated solution for IV infusion. The concentrate is diluted with glucose 5% solution before infusion. | Levosimendan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Levosimendan (INN) (Template:PronEng) is a calcium sensitiser used in the management of acutely decompensated congestive heart failure. It is marketed under the trade name Simdax (Abbott).
# Mode of action
Levosimendan is a calcium sensitiser – it increases the sensitivity of the heart to calcium, thus increasing cardiac contractility without a rise in intracellular calcium. Levosimendan exerts its positive inotropic effect by increasing calcium sensitivity of myocytes by binding to cardiac troponin C in a calcium-dependent manner. It also has a vasodilatory effect, by opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle to cause smooth muscle relaxation. The combined inotropic and vasodilatory actions result in an increased force of contraction, decreased preload and decreased afterload. Moreover, by opening also the mitochondrial (ATP)-sensitive potassium channels in cardiomyocytes, the drug exerts a cardioprotective effect.
# Clinical use
## Indications
Levosimendan is indicated for inotropic support in acutely-decompensated severe congestive heart failure.
Some of the Phase-III studies in the extensive clinical program were the trials LIDO (200 patients), RUSSLAN (500), CASINO (250), REVIVE-I (100), REVIVE-II (600) and finally SURVIVE (1350)[1]
, a head-to-head trial between levosimendan and dobutamine in acute decompensated heart failure. In total, the clinical data base includes more than 3500 patients in Phase IIb and III double-blind studies, which is the highest number ever in testing a drug for acute decompensated heart failure.
The drug has a marketing authorization in 48 countries (Aug 9, 2007).
## Contraindications
The use of levosimendan is contraindicated in patients with: moderate-to-severe renal impairment, severe hepatic impairment, severe ventricular filling or outflow obstruction, severe hypotension and tachycardia, and/or history of torsades de pointes.[2]
## Adverse effects
Common adverse drug reactions (≥1% of patients) associated with levosimendan therapy include: headache, hypotension, arrhythmias (atrial fibrillation, extrasystoles, atrial tachycardia, ventricular tachycardia), myocardial ischaemia, hypokalaemia and/or nausea (Rossi, 2006).
## Formulations
Levosimendan is marketed as a 2.5 mg/mL concentrated solution for IV infusion. The concentrate is diluted with glucose 5% solution before infusion. | https://www.wikidoc.org/index.php/Levosimendan | |
b0ced44d0df184f4fe396de7f328778fbe720b10 | wikidoc | Splenic vein | Splenic vein
# Overview
In anatomy, the splenic vein (in the past called the lienal vein) is the blood vessel that drains blood from the spleen.
It joins with the superior mesenteric vein, to form the hepatic portal vein and follows a course superior to the pancreas, along side of the similarly named artery, the splenic artery.
It collects branches from the stomach and pancreas and most notably from the large intestine, which is drained by the inferior mesenteric vein and joins with splenic vein shortly before it forms the portal vein.
# Additional images
- The pancreas and duodenum from behind. | Splenic vein
Template:Infobox Vein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In anatomy, the splenic vein (in the past called the lienal vein) is the blood vessel that drains blood from the spleen.
It joins with the superior mesenteric vein, to form the hepatic portal vein and follows a course superior to the pancreas, along side of the similarly named artery, the splenic artery.
It collects branches from the stomach and pancreas and most notably from the large intestine, which is drained by the inferior mesenteric vein and joins with splenic vein shortly before it forms the portal vein.
# Additional images
- The pancreas and duodenum from behind.
# External links
- Template:GraySubject - "The Spleen"
- Template:GPnotebook - "Splenic vein thrombosis"
- Template:SUNYAnatomyLabs - "Intestines and Pancreas: Structures Posterior to the Pancreas:
- Template:SUNYAnatomyImage
- Template:NormanAnatomy (Template:NormanAnatomyFig)
- Splenic vein - medterms.com
Template:Veins
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Lienal_vein | |
f92934a092bdbb9db7275b9ce0ceaeed8b92c436 | wikidoc | Life support | Life support
Life support, in the medical field, refers to a set of therapies for preserving a patient's life when essential body systems are not functioning sufficiently to sustain life unaided. Life support therapies utilize some combination of several techniques: feeding tubes, intravenous drips, total parenteral nutrition, mechanical respiration, heart/lung bypass, urinary catheterization and dialysis. The same techniques are also used for intensive care or in some cases during surgery, though life support is employed to stabilize a patient and is typically not sufficient to allow full recovery from their condition.
# Ethics
It has been proposed that the practice of artificially prolonging the life of an individual who will not recover to be unethical.
Roman Catholic moral teachings, pronounced in 1993, suggest that the employment of artificial means is not necessary to fulfill the duty to respect life; however the term "artificial means" may vary in meaning between different schools of thought within and outside Catholicism. Most Catholic theologians however, divide the issue into "ordinary" and "extraordinary" means, and believe that it is an ethical imperative to continue the ordinary means, but ethically neutral to withhold the extraordinary means. They define ordinary means as things like feeding, and extraordinary means as things like artificial breathing. Also you could say that it is illegal in some states.
by:college professors | Life support
Life support, in the medical field, refers to a set of therapies for preserving a patient's life when essential body systems are not functioning sufficiently to sustain life unaided. Life support therapies utilize some combination of several techniques: feeding tubes, intravenous drips, total parenteral nutrition, mechanical respiration, heart/lung bypass, urinary catheterization and dialysis. The same techniques are also used for intensive care or in some cases during surgery, though life support is employed to stabilize a patient and is typically not sufficient to allow full recovery from their condition.
# Ethics
It has been proposed that the practice of artificially prolonging the life of an individual who will not recover to be unethical.
Roman Catholic moral teachings, pronounced in 1993, suggest that the employment of artificial means is not necessary to fulfill the duty to respect life; however the term "artificial means" may vary in meaning between different schools of thought within and outside Catholicism. Most Catholic theologians however, divide the issue into "ordinary" and "extraordinary" means, and believe that it is an ethical imperative to continue the ordinary means, but ethically neutral to withhold the extraordinary means. They define ordinary means as things like feeding, and extraordinary means as things like artificial breathing. Also you could say that it is illegal in some states.
by:college professors | https://www.wikidoc.org/index.php/Life-support |
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