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333ef105c0c0826444933824762f3f02dfd1a49d | wikidoc | Ingestion | Ingestion
# Overview
Ingestion is the consumption of a substance by an organism. In animals, it is accomplished by taking the substance in through the mouth into the gastrointestinal tract, such as through eating or drinking. In single-celled organisms, ingestion can take place through taking the substance through the cell wall.
Besides nutritional items, other substances which may be ingested include medications, recreational drugs, and substances considered inedible such as foreign bodies or excrement. Ingestion is a common route taken by pathogenic organisms and poisons entering the body.
Ingestion can also refer to a mechanism picking up something and making it enter an internal hollow of that mechanism.
# Pathogens
Some pathogens are transmitted via ingestion, including viruses, bacteria, and parasites. Most commonly, this takes place via the fecal-oral route. This commonly takes place via an intermediate step, such as drinking water contaminated by feces or food prepared by workers who fail to practice adequate hand-washing, and is more common in regions where untreated sewage is common. Diseases transmitted via the fecal-oral route include hepatitis A, polio, and cholera.
Some pathogenic organisms are typically ingested by other routes.
- Larvae of the parasite Trichinella encyst within muscles and are transmitted when the new hosts eat the infected flesh.
- The parasite Dracunculus is ingested in drinking water, which is contaminated with larvae released as the parasite emerges from the host's body.
- The bacterium Salmonella most commonly infects humans via consumption of undercooked eggs.
# Toxins
# Foreign objects
Disk batteries, or button cells, are often mistakenly ingested, particularly by children and the elderly. They may be mistaken for pills because of their size and shape, or they may be swallowed after being held in the mouth while the battery is being changed. Battery ingestion can cause medical problems including blocked airway, vomiting, irritability, persistent drooling, and rash (due to nickel metal allergy).
Pica is an abnormal appetite for non-nutritive items or for food items in a form not normally eaten, such as flour. Coprophagia is the consumption of feces, a behavior common in some animals. | Ingestion
# Overview
Ingestion is the consumption of a substance by an organism. In animals, it is accomplished by taking the substance in through the mouth into the gastrointestinal tract, such as through eating or drinking. In single-celled organisms, ingestion can take place through taking the substance through the cell wall.
Besides nutritional items, other substances which may be ingested include medications, recreational drugs, and substances considered inedible such as foreign bodies or excrement. Ingestion is a common route taken by pathogenic organisms and poisons entering the body.
Ingestion can also refer to a mechanism picking up something and making it enter an internal hollow of that mechanism.
# Pathogens
Some pathogens are transmitted via ingestion, including viruses, bacteria, and parasites. Most commonly, this takes place via the fecal-oral route. This commonly takes place via an intermediate step, such as drinking water contaminated by feces or food prepared by workers who fail to practice adequate hand-washing, and is more common in regions where untreated sewage is common. Diseases transmitted via the fecal-oral route include hepatitis A, polio, and cholera.
Some pathogenic organisms are typically ingested by other routes.
- Larvae of the parasite Trichinella encyst within muscles and are transmitted when the new hosts eat the infected flesh.[1]
- The parasite Dracunculus is ingested in drinking water, which is contaminated with larvae released as the parasite emerges from the host's body.[2]
- The bacterium Salmonella most commonly infects humans via consumption of undercooked eggs.[3]
# Toxins
# Foreign objects
Disk batteries, or button cells, are often mistakenly ingested, particularly by children and the elderly. They may be mistaken for pills because of their size and shape, or they may be swallowed after being held in the mouth while the battery is being changed. Battery ingestion can cause medical problems including blocked airway, vomiting, irritability, persistent drooling, and rash (due to nickel metal allergy).[4]
Pica is an abnormal appetite for non-nutritive items or for food items in a form not normally eaten, such as flour. Coprophagia is the consumption of feces, a behavior common in some animals. | https://www.wikidoc.org/index.php/Ingest | |
7d97878aeeeb9663a553dcea4855ebf00ef74c31 | wikidoc | Insightec | Insightec
InSightec Ltd., founded in 1999, is a privately held company owned by Elbit Medical Imaging (EMI), General Electric, private investors and employees. InSightec was founded specifically to develop MR (magnetic resonance) guided Focused Ultrasound technology. Headquartered in Tirat Hacarmel near Haifa, Israel, with US headquarters in Dallas Texas, the company has over 100 employees.
InSightec developed ExAblate® 2000 – a surgical system that combines Magnetic resonance imaging and Focused Ultrasound to non-invasively treat tumors inside the body without the need for incisions. During this outpatient procedure, the patient lies inside an MRI scanner, which provides three-dimensional images of the diseased tissue and surrounding area, enabling precise guidance of the ultrasound waves. High intensity focused ultrasound waves are then directed into the body at specific tissue, raising the temperature of the targeted tissue to 65 to 85 degrees Celsius, destroying it. The imaging capabilities of the MRI scanner provide real-time feedback on all aspects of the procedure which gives the physician a high degree of control over its therapeutic outcome.
ExAblate® 2000 has been approved to treat uterine fibroids, and is currently in use in the US, Israel, Europe and Asia. Clinical trials are being conducted to evaluate ExAblate® 2000 for treatment of other diseases such as breast, liver, bone and brain cancers. | Insightec
InSightec Ltd., founded in 1999, is a privately held company owned by Elbit Medical Imaging (EMI), General Electric, private investors and employees. InSightec was founded specifically to develop MR (magnetic resonance) guided Focused Ultrasound technology. Headquartered in Tirat Hacarmel near Haifa, Israel, with US headquarters in Dallas Texas, the company has over 100 employees.
InSightec developed ExAblate® 2000 – a surgical system that combines Magnetic resonance imaging and Focused Ultrasound to non-invasively treat tumors inside the body without the need for incisions. During this outpatient procedure, the patient lies inside an MRI scanner, which provides three-dimensional images of the diseased tissue and surrounding area, enabling precise guidance of the ultrasound waves. High intensity focused ultrasound waves are then directed into the body at specific tissue, raising the temperature of the targeted tissue to 65 to 85 degrees Celsius, destroying it. The imaging capabilities of the MRI scanner provide real-time feedback on all aspects of the procedure which gives the physician a high degree of control over its therapeutic outcome.
ExAblate® 2000 has been approved to treat uterine fibroids, and is currently in use in the US, Israel, Europe and Asia. Clinical trials are being conducted to evaluate ExAblate® 2000 for treatment of other diseases such as breast, liver, bone and brain cancers. | https://www.wikidoc.org/index.php/Insightec | |
dba5167e04a25161971ea7993ae2b7c2c10569f5 | wikidoc | Insulator | Insulator
An insulator is a genetic boundary element that plays two distinct roles in gene expression, either as an enhancer-blocking element, or more rarely as a barrier against condensed chromatin proteins spreading onto active chromatin. The need for them arises where two adjacent genes on a chromosome have very different transcription patterns, and it is critical that the inducing or repressing mechanisms of one do not interfere with the neighbouring gene.
# As an enhancer-blocking element
An insulator is a genetic boundary element that plays two distinct roles in gene expression, either as an enhancer-blocking element, or more rarely as a barrier against condensed chromatin proteins spreading onto active chromatin. The need for them arises where two adjacent genes on a chromosome have very different transcription patterns, and it is critical that the inducing or repressing mechanisms of one do not interfere with the neighbouring gene.
# Reference
Burgess-Beusse, B; et al. (2002). "The insulation of genes from external enhancers and silencing chromatin". Proc. Natl Acad. Sci. USA. 9 (Suppl 4): 16433–16437. doi:10.1073/pnas.162342499. Unknown parameter |month= ignored (help)CS1 maint: Explicit use of et al. (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
de:Isolator (Genetik) | Insulator
An insulator is a genetic boundary element that plays two distinct roles in gene expression, either as an enhancer-blocking element, or more rarely as a barrier against condensed chromatin proteins spreading onto active chromatin. The need for them arises where two adjacent genes on a chromosome have very different transcription patterns, and it is critical that the inducing or repressing mechanisms of one do not interfere with the neighbouring gene.[1]
# As an enhancer-blocking element
An insulator is a genetic boundary element that plays two distinct roles in gene expression, either as an enhancer-blocking element, or more rarely as a barrier against condensed chromatin proteins spreading onto active chromatin. The need for them arises where two adjacent genes on a chromosome have very different transcription patterns, and it is critical that the inducing or repressing mechanisms of one do not interfere with the neighbouring gene.[1]
# Reference
- ↑
Burgess-Beusse, B; et al. (2002). "The insulation of genes from external enhancers and silencing chromatin". Proc. Natl Acad. Sci. USA. 9 (Suppl 4): 16433–16437. doi:10.1073/pnas.162342499. Unknown parameter |month= ignored (help)CS1 maint: Explicit use of et al. (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
de:Isolator (Genetik)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Insulator | |
9fd284d63ab6f8f36eef947af67f07235c37b9bb | wikidoc | Iodixanol | Iodixanol
# 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
Iodixanol is a radiological contrast media that is FDA approved for the procedure of digital subtraction angiography, angiocardiography, peripheral arteriography, visceral arteriography, and cerebral arteriography. Common adverse reactions include chest pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Iodixanol 270 mgI/mL is indicated for intra-arterial digital subtraction angiography.
- Iodixanol 320 mgI/mL is indicated for angiocardiography (left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography.
- Iodixanol (270 mgI/mL) is indicated for CECT imaging of the head and body, excretory urography, and peripheral venography.
- Iodixanol (320 mgI/mL) is indicated for CECT imaging of the head and body, and excretory urography.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iodixanol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iodixanol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The recommended dose in children over 1 year of age for the evaluation of:
- Intra-arterial Administration for Cerebral, Cardiac chambers and related major arteries, and Visceral Studies
- iodixanol 320 mgI/mL as 1 to 2 mL/kg. The recommended total dose of iodixanol should not exceed 4 mL/kg.
- Intravenous Administration for Contrast Enhanced Computerized Tomography or Excretory Urography
- iodixanol 270 mgI/mL as 1 to 2 mL/kg. The recommended total dose of iodixanol should not exceed 2 mL/kg.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iodixanol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iodixanol in pediatric patients.
# Contraindications
- Iodixanol is not indicated for intrathecal use.
- In the pediatric population prolonged fasting and the administration of a laxative before iodixanol injection are contraindicated.
# Warnings
Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not administered intrathecally.
Nonionic, iodinated contrast media inhibit blood coagulation in vitro less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing nonionic contrast media. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiocardiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and concomitant medications, may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended, including close attention to guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions, and minimizing the length of the procedure.
Serious or rare fatal reactions have been associated with the administration of iodine-containing radiopaque media. It is of utmost importance to be completely prepared to treat any reaction associated with the use of any contrast agent.
Caution must be exercised in patients with severely impaired renal function, combined renal and hepatic disease, combined renal and cardiac disease, severe thyrotoxicosis, myelomatosis, or anuria, particularly when large doses are administered.
Intravascularly administered iodine-containing radiopaque media are potentially hazardous in patients with multiple myeloma or other paraproteinaceous diseases, who are prone to disease induced renal insufficiency and/or renal failure. Although neither the contrast agent nor dehydration has been proven to be the cause of renal insufficiency (or worsening renal insufficiency) in myelomatous patients, it has been speculated that the combination of both may be causative. Special precautions, including maintenance of normal hydration and close monitoring, are required. Partial dehydration in the preparation of these patients is not recommended since it may predispose the patient to precipitation of the myeloma protein.
Reports of thyroid storm following the intravascular use of iodinated radiopaque contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in such patients before use of any contrast agent.
Administration of radiopaque materials to patients known to have, or suspected of having, pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure, and measures for the treatment of hypertensive crisis should be readily available. These patients should be monitored very closely during contrast-enhanced procedures.
Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when the agents are administered intravascularly.
Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, congestive heart disease, diabetic patients, and other patients such as those on medications which alter renal function and the elderly with age-related renal impairment. Patients should be adequately hydrated prior to and following intravascular administration of iodinated contrast agent. Dose adjustments in renal impairment have not been studied.
Iodinated contrast agents may cross the blood-brain barrier. In patients where the blood-brain barrier is known or suspected to be disrupted, or in patients with normal blood-brain barrier and associated renal impairment, CAUTION MUST BE EXERCISED IN THE USE OF AN IODINATED CONTRAST AGENT.
Patients with congestive heart failure receiving concurrent diuretic therapy may have relative intravascular volume depletion, which may affect the renal response to the contrast agent osmotic load. These patients should be observed following the procedure to detect delayed hemodynamic renal function disturbances.
The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered. Increased risk is associated with a history of a previous reaction to contrast agent, a known sensitivity to iodine and known allergies (i.e., bronchial asthma, drug, or food allergies), other hypersensitivities, and underlying immune disorders, autoimmunity or immunodeficiencies that predispose to specific or nonspecific mediator release. If during administration there is evidence of an allergy-like reaction, the injection should be discontinued and appropriate treatment initiated.
Skin testing cannot be relied upon to predict severe reactions and may itself be hazardous to the patient. A thorough medical history with emphasis on allergy and hypersensitivity, immune, autoimmune and immunodeficiency disorders, and prior receipt of and response to the injection of any contrast agent may be more accurate than pretesting in predicting potential adverse reactions.
Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions does not prevent serious life-threatening reactions, but may reduce both their incidence and severity. Extreme caution should be exercised in considering the use of iodinated contrast agents in patients with these histories or disorders. Patients with a history of allergy or drug reaction should be observed for several hours after drug administration.
General anesthesia may be indicated in the performance of some procedures in selected patients; however, a higher incidence of adverse reactions have been reported in these patients. It is not clear if this is due to the inability of the patient to identify untoward symptoms or to the hypotensive effect of anesthesia, which can prolong the circulation time and increase the duration of exposure to a contrast agent.
In angiographic procedures, the possibility of dislodging plaques, or damaging or perforating the vessel wall with resultant pseudoaneurysms, hemorrhage at puncture site, dissection of coronary artery, etc., should be considered during catheter manipulations and contrast agent injection. Angiography may be associated with local and distal organ damage, ischemia, thrombosis and organ failure (e.g., brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepatorenal function abnormalities, etc.). Test injections to ensure proper catheter placement are suggested. During these procedures, increased thrombosis and activation of the complement system has also occurred.
Angiocardiography should be avoided whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism.
In an uncontrolled study of 204 patients who received iodixanol Injection and who had cardiovascular disease associated with either Class II-IV congestive failure, angina, recent myocardial infarction, left ventricular ejection fraction of < 35% or valvular disease, the patients were evaluated for the types of interventions needed for treatment of adverse events. The reported type and frequency of adverse events were comparable to those in all clinical intra-arteriographic studies. Of 204 patients, 63 (31%) of patients had 99 adverse events. Of the 99 events, 68 (68%) required medical intervention of some type. Patients with 17 (17%) of these adverse events required treatment with cardioversion, multiple medications, prolonged hospitalization or intensive care. These interventions were not compared to a control group of similar patients who did not have coronary arteriography.
Selective coronary arteriography should be performed only in patients for whom the expected benefits outweigh the procedural risk. Also, the inherent risks of angiocardiography in patients with chronic pulmonary emphysema must be weighed against the necessity for performing this procedure.
In addition to the general precautions previously described, special care is required when venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection, venous thrombosis or a totally obstructed venous system.
Extreme caution during injection of a contrast agent is necessary to avoid extravasation. This is especially important in patients with severe arterial or venous disease.
# Adverse Reactions
## Clinical Trials Experience
Iodixanol was administered to 1244 patients. The comparators administered to 861 patients included low osmolar nonionic, and high and low osmolar ionic contrast media.
Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast media, including iodixanol Injection. In clinical trials, 3/1244 patients given iodixanol Injection and 1/861 patients given a comparator died within 5 days or later after drug administration. Also, 7/1244 patients given iodixanol Injection and 8/861 given a comparator had serious adverse events. Rare reports of anaphylaxis have been documented during postmarket surveillance.
As with other contrast agents, iodixanol is often associated with sensations of discomfort, warmth or pain. In a subgroup of 1259 patients, for whom data are available; similar percentages of patients (30%) who received iodixanol or a comparator had application site discomfort, pain, warmth or cold. iodixanol had a trend toward fewer patient reports of moderate or severe pain or warmth; however, whether or not this related to the dose, rate of administration, site of injection or concentration has not been determined.
The following table of incidence of events is based upon blinded, controlled clinical trials with iodixanol Injection in controlled clinical studies in which iodixanol (1244 patients) was compared with low osmolar nonionic (iohexol, iopromide), a low osmolar ionic (ioxaglate), and a high osmolar ionic (diatrizoate) contrast agents. This listing includes all reported adverse events regardless of attribution. Adverse events (AEs) are listed by body system and in decreasing order of occurrence greater than 0.5% in the iodixanol group.
As the table shows, one or more adverse events were recorded in 248 of 1244 (20%) patients during the clinical trials, with the administration of iodixanol Injection or within the defined duration of the study follow-up period (24 to 72 hours). In intravenous and intra-arterial procedures, the incidence and type adverse reaction was similar to those of the studied nonionic comparators (iohexol). In a 757 patient subgroup for which data are available, women reported more adverse events 83/299 (27.8%) than men 77/458 (16.2%). Women reported more chest pain (9/299 or 3%) than men (4/458 or 0.8%).
The following selected adverse events were reported in ≤0.5% of the 1244 patients in controlled clinical trials who received iodixanol Injection.
- Body as a Whole—General Disorders: back pain, fatigue, malaise.
- Cardiovascular Disorders: arrhythmias, cardiac failure, conduction abnormalities, hypotension, myocardial infarction.
- Nervous System: cerebral vascular disorder, convulsions, hypoesthesia, stupor, confusion
- Gastrointestinal System Disorders: dyspepsia.
- Hypersensitivity Disorders: pharyngeal edema.
- Respiratory System Disorders: asthma, bronchitis, dyspnea, pulmonary edema, rhinitis.
- Renal System Disorders: abnormal renal function, acute renal failure, hematuria.
- Peripheral Vascular Disorders: flushing, peripheral ischemia.
- Skin and Appendage Disorders: hematoma, increased sweating.
- Special Senses, Other Disorders: tinnitus.
- Vision Disorders: abnormal vision.
## Postmarketing Experience
Additional adverse events reported in other clinical studies and in foreign postmarketing surveillance and foreign clinical trials with the use of iodixanol Injection are: anaphylactic reactions, anaphylactoid reactions, hypoglycemia, amnesia, cardiac arrest, hypertension, dyskinesia, hemorrhage not otherwise specified, polymyalgia rheumatica, pulmonary embolism, respiratory depression, and cortical blindness.
The overall character, quality, and severity of adverse reactions in pediatric patients is similar to that reported in adult populations from domestic and foreign postmarketing surveillance and other information. Selected commonly reported adverse events in pediatrics include: vomiting, nausea, fever, rash, and pruritus. Less frequently reported events are apnea, disseminated intravascular coagulation, atrioventricular block and bundle branch block, arrhythmia, cardiac failure, renal failure and dysgeusia.
# Drug Interactions
Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be postponed in patients who have recently received an oral cholecystographic contrast agent.
Other drugs should not be mixed with iodixanol Injection.
The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for at least 16 days following administration of iodinated contrast agents. However, thyroid function tests which do not depend on iodine estimations (e.g., T3 resin uptake and total or free thyroxine T4 assays) are not affected.
As reported with other contrast agents, iodixanol may produce a false-positive result for protein in the urine using Multistix®. However, the Coomassie blue method has been shown to give accurate results for the measurement of urine protein in the presence of iodixanol. In addition, care should be used in interpreting the results of urine specific gravity measurements in the presence of high levels of iodixanol and other contrast agents in the urine. Refractometry or urine osmolality may be substituted.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproduction studies performed in rats and rabbits at doses up to 2.0 gI/kg have not revealed evidence of impaired fertility or harm to the fetus due to iodixanol. Adequate and well-controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Iodixanol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Iodixanol during labor and delivery.
### Nursing Mothers
It is not known whether iodixanol Injection is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast agents are administered to nursing women because of the potential for adverse reactions, and consideration should be given to temporarily discontinue nursing.
### Pediatric Use
The safety and efficacy of iodixanol has been established in the pediatric population over 1 year of age for arterial studies and for intravenous procedures. Use of iodixanol in these age groups is supported by evidence from adequate and well controlled studies of iodixanol in adults and additional safety data obtained in pediatric studies. Although iodixanol has been administered to pediatric patients less than 1 year of age, the relative safety of the volumes injected, the optimal concentrations, and the potential need for dose adjustment because of prolonged elimination half-lives have not been systematically studied.
Iodixanol was administered to 459 pediatric patients. There were 26 patients administered iodixanol Injection in the birth to <29 day age range, 148 from 29 days to 2 years, 263 from 2 to <12 years, and 22 from 12 to 18 years. The mean age was 4.4 years (range <1 day to 17.4 years). Of the 459 patients, 252 (55%) were male and 207 (45%) were female. The racial distribution was: Caucasian-81%, Black-14%, Oriental-2%, and other or unknown-4%. The demographic information for the pool of patients who received a comparison contrast agent was similar.
In pediatric patients who received intravenous injection for computerized tomography or excretory urography, a concentration of 270 mgI/mL was used in 144 patients, and a concentration of 320 mgI/mL in 154 patients. All patients received one intravenous injection of 1-2 mL/kg.
In pediatric patients who received intra-arterial and intracardiac studies, a concentration of 320 mgI/mL was used in 161 patients. Of the 161 patients in the intra-arterial studies, the mean age was 2.6 years. Twenty-two patients were < 29 days of age; 78 were 29 days to 2 years of age; and 61 were over 2 years. Most of these pediatric patients received initial volumes of 1-2 mL/kg and most patients had a maximum of 3 injections.
Optimal volumes, concentrations or injection rates of iodixanol have not been established because different injection volumes, concentrations, and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target vascular bed has not been established. The potential need for dose adjustment to maximize efficacy of computerized tomography, or to minimize the toxicity to other immature body tissues, has not been studied in neonates or infants with immature renal function.
In the above patients, adverse events were associated with decreasing age and intra-arterial procedures. In general the type of adverse events reported are similar to those of adults. Although the frequency of events appears to be comparable, the percentages cannot be confirmed because of the different ability of pediatric and adult patients to report adverse events.
### Geriatic Use
Of the total number of patients in clinical studies of iodixanol in the U.S., 254/757 (34%) were 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Iodixanol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Iodixanol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Iodixanol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Iodixanol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Iodixanol did not impair the fertility of male or female rats when administered at doses up to 2.0 gI/kg (1.3 times the maximum recommended dose for a 50 kg human, or approximately 0.2 times the maximum recommended dose for a 50 kg human following normalization of the data to body surface area estimates).
### Immunocompromised Patients
There is no FDA guidance one the use of Iodixanol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Iodixanol Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Iodixanol and IV administrations.
# Overdosage
The adverse effects of overdosage of any contrast agent may be life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdosage is directed toward the support of all vital functions and prompt institution of symptomatic therapy. iodixanol Injection does not bind to plasma or serum protein and can be dialyzed.
# Pharmacology
There is limited information regarding Iodixanol Pharmacology in the drug label.
## Mechanism of Action
Intravascular injection of iodixanol opacifies those vessels in the path of flow of the contrast agent, permitting radiographic visualization of the internal structures until significant dilution and elimination occurs.
## Structure
Iodixanol has the following chemical structure:
## Pharmacodynamics
As with other iodinated contrast agents, following administration of iodixanol Injection, the degree of enhancement is directly related to the iodine content in an administered dose; peak iodine plasma levels occur immediately following rapid intravascular injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments.
Contrast enhancement with iodinated contrast agents appears to be greatest immediately after bolus injections (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (i.e., dynamic computed tomographic imaging).
Iodinated contrast agents may be visualized in the renal parenchyma within 30-60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1-3 minutes, with optimum contrast occurring within 5-15 minutes.
AS WITH OTHER IODINATED CONTRAST AGENTS, THE USE OF iodixanol INJECTION CONTRAST ENHANCEMENT MAY OBSCURE SOME LESIONS WHICH WERE SEEN ON PREVIOUSLY UNENHANCED CT SCANS.
In CECT some performance characteristics are different in the brain and body. In CECT of the body, iodinated contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to relative differences in extravascular diffusion between adjacent tissues.
In normal brain with an intact blood-brain barrier, contrast enhancement is generally due to the presence of iodinated contrast agent within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations and aneurysms, depends on the iodine content of the circulating blood pool.
In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial spaces of the brain. The time to maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to one hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine-containing medium within the lesion and outside the blood pool. The mechanism by which this occurs is not clear.
IN PATIENTS WITH NORMAL BLOOD-BRAIN BARRIERS and RENAL FAILURE, iodinated contrast agents have been associated with blood-brain barrier DISRUPTION and ACCUMULATION OF CONTRAST IN THE BRAIN.
The usefulness of contrast enhancement for the investigation of the retrobulbar space and of low grade or infiltrative glioma has not been demonstrated. Calcified lesions are less likely to enhance. The enhancement of tumors after therapy may decrease. The opacification of the inferior vermis following contrast agent administration has resulted in false-positive diagnosis. Cerebral infarctions of recent onset may be better visualized with contrast enhancement. Older infarctions may be obscured by the contrast agent.
## Pharmacokinetics
In an in vitro human plasma study, iodixanol did not bind to protein. The volume of distribution was 0.26 L/kg body weight, consistent with distribution to extracellular space.
Iodixanol metabolites have not been demonstrated.
Plasma and urine levels suggest that body clearance of iodixanol is primarily due to renal clearance. In adults, approximately 97% of the injected dose of iodixanol is excreted unchanged in urine within 24 hours, with less than 2% excreted in feces within five days post-injection. In 40 healthy, young male volunteers receiving a single intravenous administration of iodixanol Injection in doses of 0.3 to 1.2 gI/kg body weight, the elimination half-life was 2.1 hr (± 0.1); and renal clearance was 110 mL/min (±14), equivalent to glomerular filtration (108 mL/min). These values were independent of the dose administered.
## Nonclinical Toxicology
Long-term animal studies have not been performed with iodixanol to evaluate carcinogenic potential. Iodixanol was not genotoxic in a series of studies including the Ames test, the CHO/HGPRT assay, a chromosome aberration assay in CHO cells, and a mouse micronucleus assay.
# Clinical Studies
Iodixanol was administered to 1244 adult patients. The comparators administered to 861 adult patients included low osmolar nonionic, and high and low osmolar ionic contrast media. Approximately one-half (590) of the iodixanol patients were 60 years of age or older; the mean age was 56 years (range 18-90). Of the 1244 patients, 806 (65%) were male and 438 (35%) were female. The racial distribution was: Caucasian-85%, Black-12%, Oriental <1%, and other or unknown-3%. The demographic information for the pool of patients who received a comparison contrast agent was similar.
There were 1235 patients given iodixanol and 855 patients given other contrast agents were evaluated for efficacy. Efficacy assessment was based on quality of the radiographic diagnostic visualization (i.e., either excellent, good, poor, or none) and on the ability to make a diagnosis (i.e., either confirmed a previous diagnosis, found normal, or diagnosed new findings). Results were compared to those of active controls (ioxaglate, iohexol, iopromide, and meglumine-sodium diatrizoate) at concentrations which were similar to those of iodixanol Injection.
Angiocardiography, cerebral arteriography, peripheral arteriography, and visceral arteriography were studied with either one or both concentrations of iodixanol Injection (270 mgI/mL or 320 mgI/mL). In these intra-arterial studies, diagnostic visualization ratings were good or excellent in 100% of the patients and a radiologic diagnosis was made in all (100%) of the patients given iodixanol Injection. In additional intra-arterial studies, overall quality of diagnostic visualization was rated optimal in the majority of patients and a radiologic diagnosis was made in all (100%) of the patients administered iodixanol Injection. Results were compared to those of active controls (ioxaglate, iohexol, iopromide). The number of patients studied in each indication is provided below.
Angiocardiography was evaluated in two randomized, double-blind clinical trials in 101 adult patients given iodixanol Injection 320 mgI/mL and 97 given iohexol 350 mgI/mL. Seven additional angiocardiography studies were performed in 217 adult patients given iodixanol Injection 320 mgI/mL, 37 given iohexol 350 mgI/mL, 40 given meglumine-sodium diatrizoate 370 mgI/mL, and 96 given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Cerebral arteriography was evaluated in two randomized, double-blind clinical trials in 51 adult patients given iodixanol Injection 320 mgI/mL and 48 given iohexol 300 mgI/mL. Two additional cerebral arteriography studies were performed in 15 adult patients given iodixanol Injection 270 mgI/mL, 40 patients given iodixanol Injection 320 mgI/mL, and 40 patients given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Peripheral arteriography was evaluated in two randomized, double-blind clinical trials in 49 adult patients given iodixanol Injection 320 mgI/mL, 25 given iohexol 350 mgI/mL, and 25 given ioxaglate 320 mgI/mL. Four additional peripheral arteriography studies were performed in 41 adult patients given iodixanol Injection 270 mgI/mL, 85 patients given iodixanol Injection 320 mgI/mL, 37 given iohexol 300 mgI/mL, and 47 given iopromide 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Visceral arteriography was evaluated in two randomized, double-blind clinical trials in 55 adult patients given iodixanol Injection 320 mgI/mL, 26 given iohexol 350 mgI/mL, and 25 given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to iohexol. Confirmation of the radiologic findings by other diagnostic methods was not obtained. The risk added to renal arteriography by giving iodixanol could not be analyzed.
Similar studies with digital subtraction angiography (DSA) were completed with comparable findings noted in cerebral arteriography, peripheral arteriography, and visceral arteriography. Studies have not been conducted to determine the lowest effective concentration.
Excretory urography, contrast-enhanced computed tomography (CECT) of the head, CECT of the body, and peripheral venography were studied with either one or both iodixanol Injection concentrations (270 mgI/mL or 320 mgI/mL). In these intravenous studies, diagnostic visualization ratings were good or excellent in 96-100% of the patients and a radiologic diagnosis was made in all (100%) of the patients given iodixanol Injection. Results were compared to those of the active control. The number of patients studied in each indication is provided below.
Excretory urography was evaluated in one uncontrolled, unblinded clinical trial in 40 patients, 20 given iodixanol Injection 270 mgI/mL and 20 given iodixanol Injection 320 mgI/mL, and in two randomized, double-blind clinical trials in 50 adult patients given iodixanol Injection 270 mgI/mL, 50 patients given iodixanol Injection 320 mgI/mL, and 50 patients given iohexol 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active control. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
CECT of the head was evaluated in two randomized, double-blind clinical trials in 49 adult patients given iodixanol Injection 270 mgI/mL, in 50 patients given iodixanol Injection 320 mgI/mL, and in 49 patients given iohexol 300 mgI/mL. CECT of the body was evaluated in three randomized, double-blind clinical trials in 104 adult patients given iodixanol Injection 270 mgI/mL, in 109 patients given iodixanol Injection 320 mgI/mL, and in 101 patients given iohexol 300 mgI/mL. In both CECT of the head and body, visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Peripheral venography was evaluated in two randomized, double-blind clinical trials in 46 adult patients given iodixanol Injection 270 mgI/mL and in 50 patients given iohexol 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active control. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
# How Supplied
- Iodixanol Injection 270 mgI/mL
- Iodixanol Injection 320 mgI/mL
## Storage
Stored between 20°C-25°C (68°F-77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients receiving an iodinated intravascular contrast agent should be instructed to:
- Inform your physician if you are pregnant.
- Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder.
- Inform your physician if you are allergic to any drugs or food, or if you have immune, autoimmune or immune deficiency disorders. Also inform your physician if you had any reactions to previous injections of dyes used for x-ray procedures.
- Inform your physician about all medications you are currently taking, including nonprescription (over-the-counter) drugs, before you have this procedure.
# Precautions with Alcohol
Alcohol-Iodixanol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Visipaque
# Look-Alike Drug Names
There is limited information regarding Iodixanol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Iodixanol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
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# Overview
Iodixanol is a radiological contrast media that is FDA approved for the procedure of digital subtraction angiography, angiocardiography, peripheral arteriography, visceral arteriography, and cerebral arteriography. Common adverse reactions include chest pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Iodixanol 270 mgI/mL is indicated for intra-arterial digital subtraction angiography.
- Iodixanol 320 mgI/mL is indicated for angiocardiography (left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography.
- Iodixanol (270 mgI/mL) is indicated for CECT imaging of the head and body, excretory urography, and peripheral venography.
- Iodixanol (320 mgI/mL) is indicated for CECT imaging of the head and body, and excretory urography.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iodixanol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iodixanol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The recommended dose in children over 1 year of age for the evaluation of:
- Intra-arterial Administration for Cerebral, Cardiac chambers and related major arteries, and Visceral Studies
- iodixanol 320 mgI/mL as 1 to 2 mL/kg. The recommended total dose of iodixanol should not exceed 4 mL/kg.
- Intravenous Administration for Contrast Enhanced Computerized Tomography or Excretory Urography
- iodixanol 270 mgI/mL as 1 to 2 mL/kg. The recommended total dose of iodixanol should not exceed 2 mL/kg.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iodixanol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iodixanol in pediatric patients.
# Contraindications
- Iodixanol is not indicated for intrathecal use.
- In the pediatric population prolonged fasting and the administration of a laxative before iodixanol injection are contraindicated.
# Warnings
Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. Special attention must be given to insure that this drug product is not administered intrathecally.
Nonionic, iodinated contrast media inhibit blood coagulation in vitro less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing nonionic contrast media. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiocardiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and concomitant medications, may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended, including close attention to guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions, and minimizing the length of the procedure.
Serious or rare fatal reactions have been associated with the administration of iodine-containing radiopaque media. It is of utmost importance to be completely prepared to treat any reaction associated with the use of any contrast agent.
Caution must be exercised in patients with severely impaired renal function, combined renal and hepatic disease, combined renal and cardiac disease, severe thyrotoxicosis, myelomatosis, or anuria, particularly when large doses are administered.
Intravascularly administered iodine-containing radiopaque media are potentially hazardous in patients with multiple myeloma or other paraproteinaceous diseases, who are prone to disease induced renal insufficiency and/or renal failure. Although neither the contrast agent nor dehydration has been proven to be the cause of renal insufficiency (or worsening renal insufficiency) in myelomatous patients, it has been speculated that the combination of both may be causative. Special precautions, including maintenance of normal hydration and close monitoring, are required. Partial dehydration in the preparation of these patients is not recommended since it may predispose the patient to precipitation of the myeloma protein.
Reports of thyroid storm following the intravascular use of iodinated radiopaque contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in such patients before use of any contrast agent.
Administration of radiopaque materials to patients known to have, or suspected of having, pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure, and measures for the treatment of hypertensive crisis should be readily available. These patients should be monitored very closely during contrast-enhanced procedures.
Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when the agents are administered intravascularly.
Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, congestive heart disease, diabetic patients, and other patients such as those on medications which alter renal function and the elderly with age-related renal impairment. Patients should be adequately hydrated prior to and following intravascular administration of iodinated contrast agent. Dose adjustments in renal impairment have not been studied.
Iodinated contrast agents may cross the blood-brain barrier. In patients where the blood-brain barrier is known or suspected to be disrupted, or in patients with normal blood-brain barrier and associated renal impairment, CAUTION MUST BE EXERCISED IN THE USE OF AN IODINATED CONTRAST AGENT.
Patients with congestive heart failure receiving concurrent diuretic therapy may have relative intravascular volume depletion, which may affect the renal response to the contrast agent osmotic load. These patients should be observed following the procedure to detect delayed hemodynamic renal function disturbances.
The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered. Increased risk is associated with a history of a previous reaction to contrast agent, a known sensitivity to iodine and known allergies (i.e., bronchial asthma, drug, or food allergies), other hypersensitivities, and underlying immune disorders, autoimmunity or immunodeficiencies that predispose to specific or nonspecific mediator release. If during administration there is evidence of an allergy-like reaction, the injection should be discontinued and appropriate treatment initiated.
Skin testing cannot be relied upon to predict severe reactions and may itself be hazardous to the patient. A thorough medical history with emphasis on allergy and hypersensitivity, immune, autoimmune and immunodeficiency disorders, and prior receipt of and response to the injection of any contrast agent may be more accurate than pretesting in predicting potential adverse reactions.
Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions does not prevent serious life-threatening reactions, but may reduce both their incidence and severity. Extreme caution should be exercised in considering the use of iodinated contrast agents in patients with these histories or disorders. Patients with a history of allergy or drug reaction should be observed for several hours after drug administration.
General anesthesia may be indicated in the performance of some procedures in selected patients; however, a higher incidence of adverse reactions have been reported in these patients. It is not clear if this is due to the inability of the patient to identify untoward symptoms or to the hypotensive effect of anesthesia, which can prolong the circulation time and increase the duration of exposure to a contrast agent.
In angiographic procedures, the possibility of dislodging plaques, or damaging or perforating the vessel wall with resultant pseudoaneurysms, hemorrhage at puncture site, dissection of coronary artery, etc., should be considered during catheter manipulations and contrast agent injection. Angiography may be associated with local and distal organ damage, ischemia, thrombosis and organ failure (e.g., brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepatorenal function abnormalities, etc.). Test injections to ensure proper catheter placement are suggested. During these procedures, increased thrombosis and activation of the complement system has also occurred.
Angiocardiography should be avoided whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism.
In an uncontrolled study of 204 patients who received iodixanol Injection and who had cardiovascular disease associated with either Class II-IV congestive failure, angina, recent myocardial infarction, left ventricular ejection fraction of < 35% or valvular disease, the patients were evaluated for the types of interventions needed for treatment of adverse events. The reported type and frequency of adverse events were comparable to those in all clinical intra-arteriographic studies. Of 204 patients, 63 (31%) of patients had 99 adverse events. Of the 99 events, 68 (68%) required medical intervention of some type. Patients with 17 (17%) of these adverse events required treatment with cardioversion, multiple medications, prolonged hospitalization or intensive care. These interventions were not compared to a control group of similar patients who did not have coronary arteriography.
Selective coronary arteriography should be performed only in patients for whom the expected benefits outweigh the procedural risk. Also, the inherent risks of angiocardiography in patients with chronic pulmonary emphysema must be weighed against the necessity for performing this procedure.
In addition to the general precautions previously described, special care is required when venography is performed in patients with suspected thrombosis, phlebitis, severe ischemic disease, local infection, venous thrombosis or a totally obstructed venous system.
Extreme caution during injection of a contrast agent is necessary to avoid extravasation. This is especially important in patients with severe arterial or venous disease.
# Adverse Reactions
## Clinical Trials Experience
Iodixanol was administered to 1244 patients. The comparators administered to 861 patients included low osmolar nonionic, and high and low osmolar ionic contrast media.
Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast media, including iodixanol Injection. In clinical trials, 3/1244 patients given iodixanol Injection and 1/861 patients given a comparator died within 5 days or later after drug administration. Also, 7/1244 patients given iodixanol Injection and 8/861 given a comparator had serious adverse events. Rare reports of anaphylaxis have been documented during postmarket surveillance.
As with other contrast agents, iodixanol is often associated with sensations of discomfort, warmth or pain. In a subgroup of 1259 patients, for whom data are available; similar percentages of patients (30%) who received iodixanol or a comparator had application site discomfort, pain, warmth or cold. iodixanol had a trend toward fewer patient reports of moderate or severe pain or warmth; however, whether or not this related to the dose, rate of administration, site of injection or concentration has not been determined.
The following table of incidence of events is based upon blinded, controlled clinical trials with iodixanol Injection in controlled clinical studies in which iodixanol (1244 patients) was compared with low osmolar nonionic (iohexol, iopromide), a low osmolar ionic (ioxaglate), and a high osmolar ionic (diatrizoate) contrast agents. This listing includes all reported adverse events regardless of attribution. Adverse events (AEs) are listed by body system and in decreasing order of occurrence greater than 0.5% in the iodixanol group.
As the table shows, one or more adverse events were recorded in 248 of 1244 (20%) patients during the clinical trials, with the administration of iodixanol Injection or within the defined duration of the study follow-up period (24 to 72 hours). In intravenous and intra-arterial procedures, the incidence and type adverse reaction was similar to those of the studied nonionic comparators (iohexol). In a 757 patient subgroup for which data are available, women reported more adverse events 83/299 (27.8%) than men 77/458 (16.2%). Women reported more chest pain (9/299 or 3%) than men (4/458 or 0.8%).
The following selected adverse events were reported in ≤0.5% of the 1244 patients in controlled clinical trials who received iodixanol Injection.
- Body as a Whole—General Disorders: back pain, fatigue, malaise.
- Cardiovascular Disorders: arrhythmias, cardiac failure, conduction abnormalities, hypotension, myocardial infarction.
- Nervous System: cerebral vascular disorder, convulsions, hypoesthesia, stupor, confusion
- Gastrointestinal System Disorders: dyspepsia.
- Hypersensitivity Disorders: pharyngeal edema.
- Respiratory System Disorders: asthma, bronchitis, dyspnea, pulmonary edema, rhinitis.
- Renal System Disorders: abnormal renal function, acute renal failure, hematuria.
- Peripheral Vascular Disorders: flushing, peripheral ischemia.
- Skin and Appendage Disorders: hematoma, increased sweating.
- Special Senses, Other Disorders: tinnitus.
- Vision Disorders: abnormal vision.
## Postmarketing Experience
Additional adverse events reported in other clinical studies and in foreign postmarketing surveillance and foreign clinical trials with the use of iodixanol Injection are: anaphylactic reactions, anaphylactoid reactions, hypoglycemia, amnesia, cardiac arrest, hypertension, dyskinesia, hemorrhage not otherwise specified, polymyalgia rheumatica, pulmonary embolism, respiratory depression, and cortical blindness.
The overall character, quality, and severity of adverse reactions in pediatric patients is similar to that reported in adult populations from domestic and foreign postmarketing surveillance and other information. Selected commonly reported adverse events in pediatrics include: vomiting, nausea, fever, rash, and pruritus. Less frequently reported events are apnea, disseminated intravascular coagulation, atrioventricular block and bundle branch block, arrhythmia, cardiac failure, renal failure and dysgeusia.
# Drug Interactions
Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be postponed in patients who have recently received an oral cholecystographic contrast agent.
Other drugs should not be mixed with iodixanol Injection.
The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for at least 16 days following administration of iodinated contrast agents. However, thyroid function tests which do not depend on iodine estimations (e.g., T3 resin uptake and total or free thyroxine T4 assays) are not affected.
As reported with other contrast agents, iodixanol may produce a false-positive result for protein in the urine using Multistix®. However, the Coomassie blue method has been shown to give accurate results for the measurement of urine protein in the presence of iodixanol. In addition, care should be used in interpreting the results of urine specific gravity measurements in the presence of high levels of iodixanol and other contrast agents in the urine. Refractometry or urine osmolality may be substituted.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Reproduction studies performed in rats and rabbits at doses up to 2.0 gI/kg [1.3 times the maximum recommended dose for a 50 kg human, or approximately 0.2 (rat) and 0.4 (rabbit) times the maximum recommended dose for a 50 kg human following normalization of the data to body surface estimates] have not revealed evidence of impaired fertility or harm to the fetus due to iodixanol. Adequate and well-controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Iodixanol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Iodixanol during labor and delivery.
### Nursing Mothers
It is not known whether iodixanol Injection is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast agents are administered to nursing women because of the potential for adverse reactions, and consideration should be given to temporarily discontinue nursing.
### Pediatric Use
The safety and efficacy of iodixanol has been established in the pediatric population over 1 year of age for arterial studies and for intravenous procedures. Use of iodixanol in these age groups is supported by evidence from adequate and well controlled studies of iodixanol in adults and additional safety data obtained in pediatric studies. Although iodixanol has been administered to pediatric patients less than 1 year of age, the relative safety of the volumes injected, the optimal concentrations, and the potential need for dose adjustment because of prolonged elimination half-lives have not been systematically studied.
Iodixanol was administered to 459 pediatric patients. There were 26 patients administered iodixanol Injection in the birth to <29 day age range, 148 from 29 days to 2 years, 263 from 2 to <12 years, and 22 from 12 to 18 years. The mean age was 4.4 years (range <1 day to 17.4 years). Of the 459 patients, 252 (55%) were male and 207 (45%) were female. The racial distribution was: Caucasian-81%, Black-14%, Oriental-2%, and other or unknown-4%. The demographic information for the pool of patients who received a comparison contrast agent was similar.
In pediatric patients who received intravenous injection for computerized tomography or excretory urography, a concentration of 270 mgI/mL was used in 144 patients, and a concentration of 320 mgI/mL in 154 patients. All patients received one intravenous injection of 1-2 mL/kg.
In pediatric patients who received intra-arterial and intracardiac studies, a concentration of 320 mgI/mL was used in 161 patients. Of the 161 patients in the intra-arterial studies, the mean age was 2.6 years. Twenty-two patients were < 29 days of age; 78 were 29 days to 2 years of age; and 61 were over 2 years. Most of these pediatric patients received initial volumes of 1-2 mL/kg and most patients had a maximum of 3 injections.
Optimal volumes, concentrations or injection rates of iodixanol have not been established because different injection volumes, concentrations, and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target vascular bed has not been established. The potential need for dose adjustment to maximize efficacy of computerized tomography, or to minimize the toxicity to other immature body tissues, has not been studied in neonates or infants with immature renal function.
In the above patients, adverse events were associated with decreasing age and intra-arterial procedures. In general the type of adverse events reported are similar to those of adults. Although the frequency of events appears to be comparable, the percentages cannot be confirmed because of the different ability of pediatric and adult patients to report adverse events.
### Geriatic Use
Of the total number of patients in clinical studies of iodixanol in the U.S., 254/757 (34%) were 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Iodixanol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Iodixanol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Iodixanol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Iodixanol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Iodixanol did not impair the fertility of male or female rats when administered at doses up to 2.0 gI/kg (1.3 times the maximum recommended dose for a 50 kg human, or approximately 0.2 times the maximum recommended dose for a 50 kg human following normalization of the data to body surface area estimates).
### Immunocompromised Patients
There is no FDA guidance one the use of Iodixanol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Iodixanol Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Iodixanol and IV administrations.
# Overdosage
The adverse effects of overdosage of any contrast agent may be life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdosage is directed toward the support of all vital functions and prompt institution of symptomatic therapy. iodixanol Injection does not bind to plasma or serum protein and can be dialyzed.
# Pharmacology
There is limited information regarding Iodixanol Pharmacology in the drug label.
## Mechanism of Action
Intravascular injection of iodixanol opacifies those vessels in the path of flow of the contrast agent, permitting radiographic visualization of the internal structures until significant dilution and elimination occurs.
## Structure
Iodixanol has the following chemical structure:
## Pharmacodynamics
As with other iodinated contrast agents, following administration of iodixanol Injection, the degree of enhancement is directly related to the iodine content in an administered dose; peak iodine plasma levels occur immediately following rapid intravascular injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments.
Contrast enhancement with iodinated contrast agents appears to be greatest immediately after bolus injections (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (i.e., dynamic computed tomographic imaging).
Iodinated contrast agents may be visualized in the renal parenchyma within 30-60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1-3 minutes, with optimum contrast occurring within 5-15 minutes.
AS WITH OTHER IODINATED CONTRAST AGENTS, THE USE OF iodixanol INJECTION CONTRAST ENHANCEMENT MAY OBSCURE SOME LESIONS WHICH WERE SEEN ON PREVIOUSLY UNENHANCED CT SCANS.
In CECT some performance characteristics are different in the brain and body. In CECT of the body, iodinated contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to relative differences in extravascular diffusion between adjacent tissues.
In normal brain with an intact blood-brain barrier, contrast enhancement is generally due to the presence of iodinated contrast agent within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations and aneurysms, depends on the iodine content of the circulating blood pool.
In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial spaces of the brain. The time to maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to one hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine-containing medium within the lesion and outside the blood pool. The mechanism by which this occurs is not clear.
IN PATIENTS WITH NORMAL BLOOD-BRAIN BARRIERS and RENAL FAILURE, iodinated contrast agents have been associated with blood-brain barrier DISRUPTION and ACCUMULATION OF CONTRAST IN THE BRAIN.
The usefulness of contrast enhancement for the investigation of the retrobulbar space and of low grade or infiltrative glioma has not been demonstrated. Calcified lesions are less likely to enhance. The enhancement of tumors after therapy may decrease. The opacification of the inferior vermis following contrast agent administration has resulted in false-positive diagnosis. Cerebral infarctions of recent onset may be better visualized with contrast enhancement. Older infarctions may be obscured by the contrast agent.
## Pharmacokinetics
In an in vitro human plasma study, iodixanol did not bind to protein. The volume of distribution was 0.26 L/kg body weight, consistent with distribution to extracellular space.
Iodixanol metabolites have not been demonstrated.
Plasma and urine levels suggest that body clearance of iodixanol is primarily due to renal clearance. In adults, approximately 97% of the injected dose of iodixanol is excreted unchanged in urine within 24 hours, with less than 2% excreted in feces within five days post-injection. In 40 healthy, young male volunteers receiving a single intravenous administration of iodixanol Injection in doses of 0.3 to 1.2 gI/kg body weight, the elimination half-life was 2.1 hr (± 0.1); and renal clearance was 110 mL/min (±14), equivalent to glomerular filtration (108 mL/min). These values were independent of the dose administered.
## Nonclinical Toxicology
Long-term animal studies have not been performed with iodixanol to evaluate carcinogenic potential. Iodixanol was not genotoxic in a series of studies including the Ames test, the CHO/HGPRT assay, a chromosome aberration assay in CHO cells, and a mouse micronucleus assay.
# Clinical Studies
Iodixanol was administered to 1244 adult patients. The comparators administered to 861 adult patients included low osmolar nonionic, and high and low osmolar ionic contrast media. Approximately one-half (590) of the iodixanol patients were 60 years of age or older; the mean age was 56 years (range 18-90). Of the 1244 patients, 806 (65%) were male and 438 (35%) were female. The racial distribution was: Caucasian-85%, Black-12%, Oriental <1%, and other or unknown-3%. The demographic information for the pool of patients who received a comparison contrast agent was similar.
There were 1235 patients given iodixanol and 855 patients given other contrast agents were evaluated for efficacy. Efficacy assessment was based on quality of the radiographic diagnostic visualization (i.e., either excellent, good, poor, or none) and on the ability to make a diagnosis (i.e., either confirmed a previous diagnosis, found normal, or diagnosed new findings). Results were compared to those of active controls (ioxaglate, iohexol, iopromide, and meglumine-sodium diatrizoate) at concentrations which were similar to those of iodixanol Injection.
Angiocardiography, cerebral arteriography, peripheral arteriography, and visceral arteriography were studied with either one or both concentrations of iodixanol Injection (270 mgI/mL or 320 mgI/mL). In these intra-arterial studies, diagnostic visualization ratings were good or excellent in 100% of the patients and a radiologic diagnosis was made in all (100%) of the patients given iodixanol Injection. In additional intra-arterial studies, overall quality of diagnostic visualization was rated optimal in the majority of patients and a radiologic diagnosis was made in all (100%) of the patients administered iodixanol Injection. Results were compared to those of active controls (ioxaglate, iohexol, iopromide). The number of patients studied in each indication is provided below.
Angiocardiography was evaluated in two randomized, double-blind clinical trials in 101 adult patients given iodixanol Injection 320 mgI/mL and 97 given iohexol 350 mgI/mL. Seven additional angiocardiography studies were performed in 217 adult patients given iodixanol Injection 320 mgI/mL, 37 given iohexol 350 mgI/mL, 40 given meglumine-sodium diatrizoate 370 mgI/mL, and 96 given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Cerebral arteriography was evaluated in two randomized, double-blind clinical trials in 51 adult patients given iodixanol Injection 320 mgI/mL and 48 given iohexol 300 mgI/mL. Two additional cerebral arteriography studies were performed in 15 adult patients given iodixanol Injection 270 mgI/mL, 40 patients given iodixanol Injection 320 mgI/mL, and 40 patients given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Peripheral arteriography was evaluated in two randomized, double-blind clinical trials in 49 adult patients given iodixanol Injection 320 mgI/mL, 25 given iohexol 350 mgI/mL, and 25 given ioxaglate 320 mgI/mL. Four additional peripheral arteriography studies were performed in 41 adult patients given iodixanol Injection 270 mgI/mL, 85 patients given iodixanol Injection 320 mgI/mL, 37 given iohexol 300 mgI/mL, and 47 given iopromide 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Visceral arteriography was evaluated in two randomized, double-blind clinical trials in 55 adult patients given iodixanol Injection 320 mgI/mL, 26 given iohexol 350 mgI/mL, and 25 given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to iohexol. Confirmation of the radiologic findings by other diagnostic methods was not obtained. The risk added to renal arteriography by giving iodixanol could not be analyzed.
Similar studies with digital subtraction angiography (DSA) were completed with comparable findings noted in cerebral arteriography, peripheral arteriography, and visceral arteriography. Studies have not been conducted to determine the lowest effective concentration.
Excretory urography, contrast-enhanced computed tomography (CECT) of the head, CECT of the body, and peripheral venography were studied with either one or both iodixanol Injection concentrations (270 mgI/mL or 320 mgI/mL). In these intravenous studies, diagnostic visualization ratings were good or excellent in 96-100% of the patients and a radiologic diagnosis was made in all (100%) of the patients given iodixanol Injection. Results were compared to those of the active control. The number of patients studied in each indication is provided below.
Excretory urography was evaluated in one uncontrolled, unblinded clinical trial in 40 patients, 20 given iodixanol Injection 270 mgI/mL and 20 given iodixanol Injection 320 mgI/mL, and in two randomized, double-blind clinical trials in 50 adult patients given iodixanol Injection 270 mgI/mL, 50 patients given iodixanol Injection 320 mgI/mL, and 50 patients given iohexol 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active control. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
CECT of the head was evaluated in two randomized, double-blind clinical trials in 49 adult patients given iodixanol Injection 270 mgI/mL, in 50 patients given iodixanol Injection 320 mgI/mL, and in 49 patients given iohexol 300 mgI/mL. CECT of the body was evaluated in three randomized, double-blind clinical trials in 104 adult patients given iodixanol Injection 270 mgI/mL, in 109 patients given iodixanol Injection 320 mgI/mL, and in 101 patients given iohexol 300 mgI/mL. In both CECT of the head and body, visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
Peripheral venography was evaluated in two randomized, double-blind clinical trials in 46 adult patients given iodixanol Injection 270 mgI/mL and in 50 patients given iohexol 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active control. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
# How Supplied
- Iodixanol Injection 270 mgI/mL
- Iodixanol Injection 320 mgI/mL
## Storage
Stored between 20°C-25°C (68°F-77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients receiving an iodinated intravascular contrast agent should be instructed to:
- Inform your physician if you are pregnant.
- Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder.
- Inform your physician if you are allergic to any drugs or food, or if you have immune, autoimmune or immune deficiency disorders. Also inform your physician if you had any reactions to previous injections of dyes used for x-ray procedures.
- Inform your physician about all medications you are currently taking, including nonprescription (over-the-counter) drugs, before you have this procedure.
# Precautions with Alcohol
Alcohol-Iodixanol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Visipaque [1]
# Look-Alike Drug Names
There is limited information regarding Iodixanol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Iodixanol | |
647c62edcd2b5a6b902bd67667c06cf46edb8956 | wikidoc | Iodometry | Iodometry
Iodometry is a method of volumetric chemical analysis, a titration where the appearance or disappearance of elementary iodine indicates the end point.
Usual reagents are sodium thiosulfate as titrant, starch as an indicator (it forms blue complex with iodine molecules - though polyvinyl alcohol has started to be used recently as well), and an iodine compound (iodide or iodate, depending on the desired reaction with the sample).
The principial reaction is the reduction of iodine to iodide by thiosulfate:
A common and illustrative use of iodometry is the measurement of concentration of chlorine in water. Chlorine in pH under 8 oxidizes iodide to iodine. An overabundance of potassium iodide is added to the known amount of sample in acidic environment (pH < 4, the reaction is not complete in more alkaline pH). Starch is added, forming blue clathrate complex with the liberated iodine. The blue solution is then titrated with thiosulfate until the blue color vanishes.
Two possible sources of error can influence the outcome of the iodometric titration. One is the air oxidation of acid-iodide solution and the other is the volatility of I2. The first one can be eliminated by adding an excess of sodium carbonate in the reaction vessel. This removes oxygen in the vessel by forming carbon dioxide(which is heavier than air). The other error can be reduced by using an excess of iodide solution which captures liberated iodine to form triiodide ions, I3−.
de:Iodometrie
uk:Йодометрія | Iodometry
Iodometry is a method of volumetric chemical analysis, a titration where the appearance or disappearance of elementary iodine indicates the end point.
Usual reagents are sodium thiosulfate as titrant, starch as an indicator (it forms blue complex with iodine molecules - though polyvinyl alcohol has started to be used recently as well), and an iodine compound (iodide or iodate, depending on the desired reaction with the sample).
The principial reaction is the reduction of iodine to iodide by thiosulfate:
A common and illustrative use of iodometry is the measurement of concentration of chlorine in water. Chlorine in pH under 8 oxidizes iodide to iodine. An overabundance of potassium iodide is added to the known amount of sample in acidic environment (pH < 4, the reaction is not complete in more alkaline pH). Starch is added, forming blue clathrate complex with the liberated iodine. The blue solution is then titrated with thiosulfate until the blue color vanishes.
Two possible sources of error can influence the outcome of the iodometric titration. One is the air oxidation of acid-iodide solution and the other is the volatility of I2. The first one can be eliminated by adding an excess of sodium carbonate in the reaction vessel. This removes oxygen in the vessel by forming carbon dioxide(which is heavier than air). The other error can be reduced by using an excess of iodide solution which captures liberated iodine to form triiodide ions, I3−.
[1]
Template:Chem-stub
de:Iodometrie
uk:Йодометрія
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Iodometry | |
baef6bdc0484e43c199e050031f7151a3bde095c | wikidoc | Ionophore | Ionophore
An ionophore is a lipid-soluble molecule usually synthesized by microorganisms to transport ions across the lipid bilayer of the cell membrane. There are two broad classifications of ionophores.
- Small molecules (mobile ion carriers) that bind to a particular ion, shielding its charge from the surrounding environment, and thus facilitating its crossing of the hydrophobic interior of the lipid membrane.
- Channel formers that introduce a hydrophilic pore into the membrane, allowing ions to pass through while avoiding contact with the membrane's hydrophobic interior.
Ionophores disrupt transmembrane ion concentration gradients, required for the proper functioning and survival of microorganisms, and thus have antibiotic properties. They are produced naturally by certain microbes and act as a defense against competing microbes.
In laboratory research, ionophores are used to increase the permeability of biological membranes to certain ions. Additionally, some ionophores are used as antibiotics. The U.S. Department of Agriculture sent a letter to Tyson Foods to remove labels for chickens that said "raised without antibiotics" because of the use of ionophores in their feed.
Representative ionophores (with the ion(s) they act upon):
- Monensin (Na+)
- Ionomycin (Ca++)
- Beauvericin (Ca++, Ba++)
- Nonactin (Ammonium ionophore I)
- Nigericin (K+, H+, Pb++)
- CCCP
- 2,4-Dinitrophenol (H+)
- Valinomycin (K+)
- Crown ether
- Chlorogenic acid
- Calixarene
- Calcimycine (A23187)
- FCCP (H+)
- Gramicidin A (H+, Na+, K+)
- Proton ionophore II (4-Nonadecylpyridine)
- Proton ionophore III (N,N-Dioctadecylmethylamine) | Ionophore
An ionophore is a lipid-soluble molecule usually synthesized by microorganisms to transport ions across the lipid bilayer of the cell membrane. There are two broad classifications of ionophores.
- Small molecules (mobile ion carriers) that bind to a particular ion, shielding its charge from the surrounding environment, and thus facilitating its crossing of the hydrophobic interior of the lipid membrane.
- Channel formers that introduce a hydrophilic pore into the membrane, allowing ions to pass through while avoiding contact with the membrane's hydrophobic interior.
Ionophores disrupt transmembrane ion concentration gradients, required for the proper functioning and survival of microorganisms, and thus have antibiotic properties. They are produced naturally by certain microbes and act as a defense against competing microbes.
In laboratory research, ionophores are used to increase the permeability of biological membranes to certain ions. Additionally, some ionophores are used as antibiotics. The U.S. Department of Agriculture sent a letter to Tyson Foods to remove labels for chickens that said "raised without antibiotics" because of the use of ionophores in their feed.[1]
Representative ionophores (with the ion(s) they act upon):
- Monensin (Na+)
- Ionomycin (Ca++)
- Beauvericin (Ca++, Ba++)
- Nonactin (Ammonium ionophore I)
- Nigericin (K+, H+, Pb++)
- CCCP
- 2,4-Dinitrophenol (H+)
- Valinomycin (K+)
- Crown ether
- Chlorogenic acid
- Calixarene
- Calcimycine (A23187)
- FCCP (H+)
- Gramicidin A (H+, Na+, K+)
- Proton ionophore II (4-Nonadecylpyridine)
- Proton ionophore III (N,N-Dioctadecylmethylamine) | https://www.wikidoc.org/index.php/Ion_carrier | |
d184a34d2fb687a494462d3bfb14ee74b5065d3c | wikidoc | Iopamidol | Iopamidol
# 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
Iopamidol is a radiological non-ionic contrast media that is FDA approved for the procedure of intrathecal administration in adult neuroradiology including myelography (lumbar, thoracic, cervical, total columnar), contrast enhancement of computed tomographic (CECT) cisternography and ventriculography and thoraco-lumbar myelography in children over the age of two years. Common adverse reactions include burning sensation, flushing, hot flashes, injection site pain, nausea, vomiting, backache, neck pain, and sensation of hot and cold.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ISOVUE-M (lopamidol Injection) is indicated for intrathecal administration in adult neuroradiology including myelography (lumbar, thoracic, cervical, total columnar), and for contrast enhancement of computed tomographic (CECT) cisternography and ventriculography.
- In adults a solution that is approximately isotonic (ISOVUE-M 200) is recommended for examination of the lumbar region. For movement of the contrast medium to distant target areas the more concentrated ISOVUE-M 300 preparation should be used to compensate for dilution of ISOVUE-M (lopamidol Injection) with cerebrospinal fluid.
- The usual recommended adult dose range for iopamidol is 2000-3000 mg iodine. Iopamidol formulated to contain more than 300 mgl/mL should not be used intrathecally in adults. The minimum dose needed to perform a procedure should always be used.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iopamidol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iopamidol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- ISOVUE-M (lopamidol Injection) is indicated for thoraco-lumbar myelography in children over the age of two years.
- In pediatric patients, a solution that is approximately isotonic (ISOVUE-M 200) is recommended for all intrathecal procedures. In children, loss of contrast due to mixing on movement of the medium is less apt to occur because of their shorter spinal cord.
- The usual recommended pediatric dose range for iopamidol is 1400-2400 mg iodine. Iopamidol formulated to contain more than 200 mgl/mL should not be used intrathecally in children. The minimum dose needed to perform a procedure should always be used. See pediatric dosage table for recommended dosage.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iopamidol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iopamidol in pediatric patients.
# Contraindications
- Intrathecal administration of corticosteroids with iopamidol is contraindicated. Because of overdosage considerations, immediate repeat myelography in the event of technical failure is contraindicated. Myelography should not be performed in the presence of significant local or systemic infection where bacteremia is likely.
# Warnings
- The need for myelographic examination should be carefully evaluated. Iopamidol should be administered with caution in patients with increased intracranial pressure or suspicion of intracranial tumor, abscess or hematoma, those with a history of convulsive disorder, severe cardiovascular disease, chronic alcoholism, or multiple sclerosis, and elderly patients.
- Particular attention must be given to state of hydration, concentration of medium, dose, and technique used in these patients.
- Contrast media may promote sickling in individuals who are homozygous for sickle cell disease when injected intravenously or intra-arterially. Although ISOVUE-M is not injected intravascularly, measurable plasma levels are attained after intrathecal administration of iopamidol.
- If frankly bloody cerebrospinal fluid is observed, the possible benefits of a myelographic examination should be considered in terms of risk to the patient.
- Patients on anticonvulsant medication should be maintained on this therapy.
- Direct intracisternal or ventricular administration for standard radiography (without computerized tomographic enhancement) is not recommended. Inadvertent intracranial entry of a large or concentrated bolus of the contrast medium, which increases the risk of neurotoxicity, can be prevented by careful patient management. Also, effort should be directed to avoid rapid dispersion of the medium causing inadvertent rise to intracranial levels (e.g., by active patient movement). If such intracranial entry of the medium occurs, prophylactic anticonvulsant treatment with diazepam or barbiturates orally for 24 to 48 hours should be considered.
- Use of medications that may lower the seizure threshold (phenothiazine derivatives, including those used for their antihistaminic properties; tricyclic antidepressants; MAO inhibitors; CNS stimulants; analeptics; antipsychotic agents) should be carefully evaluated. While the contributory role of such medications has not been established, some physicians have discontinued these agents at least 48 hours before and for at least 24 hours following intrathecal use.
- Focal and generalized motor seizures have been reported after intrathecal use of water-soluble contrast agents including iopamidol. In several of those cases reported with iopamidol, higher than recommended doses were employed. Therefore avoid:
- Deviations from recommended neuroradiologic procedure or patient management.
- Use in patients with a history of epilepsy unless medically justified.
- Overdosage.
- Intracranial entry of a bolus or premature diffusion of a high concentration of the medium.
- Failure to maintain elevation of the head during the procedure, on the stretcher, and in bed.
- Excessive and particularly active patient movement or straining.
### Precautions
- Diagnostic procedures which involve the use of any radiopaque agent should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of severe reaction to the contrast agent itself. After parenteral administration of a radiopaque agent, competent personnel and emergency facilities should be available for at least 30 to 60 minutes since severe delayed reactions may occur.
- Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with preexisting renal disease). Patients should be well hydrated prior to and following iopamidol administration.
- The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered. Patients at increased risk include those with a history of a previous reaction to a contrast medium, patients with a known sensitivity to iodine per se, and patients with a known clinical hypersensitivity (bronchial asthma, hay fever, and food allergies). The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and hypersensitivity, prior to the injection of any contrast medium, may be more accurate than pretesting in predicting potential adverse reactions. A positive history of allergies or hypersensitivity does not arbitrarily contraindicate the use of a contrast agent where a diagnostic procedure is thought essential, but caution should be exercised. Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions in such patients should be considered.
- Reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.
- The possibility of inducing bacterial meningitis in patients during intrathecal procedures should always be considered. To avoid bacterial contamination during spinal puncture, a sterile field should be maintained at all times.
- If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.
# Adverse Reactions
## Clinical Trials Experience
- The most frequently reported adverse reactions following intrathecal administration of iopamidol are headache, nausea, vomiting, and musculoskeletal pain. These reactions usually occur 1 to 10 hours after injection, almost all occurring within 24 hours. They are usually mild to moderate in degree, lasting for a few hours and usually disappearing within 24 hours. Rarely, headaches may be severe or persist for days. Headache is often accompanied by nausea and vomiting, and tends to be more frequent and persistent in patients not optimally hydrated. Backache, neck stiffness, numbness and paresthesias, leg or sciatic-type pain occurred less frequently, often in the form of a transient exacerbation of preexisting symptomatology. Transient alterations in vital signs may occur and their significance must be assessed on an individual basis.
- The following table of incidence of reactions is based on clinical studies with ISOVUE-M (lopamidol Injection) in about 686 patients.
- Other adverse effects reported in clinical literature for iopamidol include facial neuralgia, tinnitus, and sweating.
- Major motor seizures have been reported in the clinical literature and since market introduction in the United States. Early onset of seizures (less than two hours) is indicative of early substantial intracranial entry. Transitory EEG changes occur and usually take the form of slow wave activity.
- While not observed in controlled clinical studies with ISOVUE-M (lopamidol Injection), the following adverse reactions may occur because they have been reported with ISOVUE-M and other nonionic water soluble contrast agents: cardiovascular (arrhythmias); pulmonary (apnea); bacterial meningitis, and aseptic meningitis syndrome; allergy or idiosyncrasy (chills, pruritus, nasal congestion, Guillain-Barre syndrome); CNS irritation (psycho-organic syndrome: mild and transitory perceptual aberrations such as depersonalization, anxiety, depression, hyperesthesia, disturbances in speech, sight, or hearing, and disorientation; in addition, hyperreflexia or areflexia, hypertonia or flaccidity, restlessness, tremor, echoacousia, echolalia, asterixis or dysphasia have occurred). Profound mental disturbances have rarely been reported (various forms and degrees of aphasia, mental confusion or disorientation); the onset is usually at 8 to 10 hours and lasts for about 24 hours without aftereffects. However, occasionally they have been manifest as apprehension, agitation or progressive withdrawal to the point of stupor or coma. In a few cases, these have been accompanied by transitory hearing loss or other auditory symptoms and visual disturbances (believed subjective or delusional). Persistent cortical loss of vision in association with convulsions, and ventricular block have been reported. Rarely, persistent though transitory weakness in the leg or ocular muscles has been reported. Peripheral neuropathies have been rare and transitory. They include sensory and/or motor or nerve root disturbances, myelitis, persistent leg muscle pain or weakness, or sixth nerve palsy, or cauda equina syndrome. Muscle cramps, fasciculation or myoclonia, spinal convulsion, paralysis, or spasticity are unusual.
- Reactions known to occur with parenteral administration of iodinated ionic contrast agents (see the listing below) are possible with any nonionic agent. Approximately 95 percent of adverse reactions accompanying the use of other water-soluble intravascularly administered contrast agents are mild to moderate in degree. However, life-threatening reactions and fatalities, mostly of cardiovascular origin, have occurred. Reported incidences of death from the administration of other iodinated contrast media range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Most deaths occur during injection or 5 to 10 minutes later, the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. The incidence of shock is estimated to be 1 out of 20,000 (0.005 percent) patients.
- Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions. Chemotoxic reactions result from the physicochemical properties of the contrast medium, the dose, and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category. During intrathecal use, there is a lower incidence of electroencephalographic changes as well as neurotoxicity by virtue of the intrinsic properties of the iopamidol molecule.
- Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the amount of drug injected, the speed of injection, the mode of injection, and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory.
- The reported incidence of adverse reactions to contrast media in patients with a history of allergy is twice that for the general population. Patients with a history of previous reactions to a contrast medium are three times more susceptible than other patients. However, sensitivity to contrast media does not appear to increase with repeated examinations. Most adverse reactions to intravascular contrast agents appear within one to three minutes after the start of injection, but delayed reactions may occur.
- Because measurable plasma levels are attained following the intrathecal administration of iopamidol, adverse reactions reported with the use of intravascular contrast agents are theoretically possible. These include:
Vasodilation (feeling of warmth), cerebral hematomas, hemodynamic disturbances, sinus bradycardia, transient electrocardiographic abnormalities, ventricular fibrillation, petechiae.
Nausea, vomiting, severe unilateral or bilateral swelling of the parotid and submaxillary glands.
Paresthesia, dizziness, convulsions, paralysis, coma.
Increased cough, asthma, dyspnea, laryngeal edema, pulmonary edema, bronchospasm, rhinitis.
Injection site pain usually due to extravasation and/or erythematous swelling, skin necrosis, urticaria.
Osmotic nephrosis of proximal tubular cells, renal failure, pain.
Perversion of taste; bilateral ocular irritation; lacrimation; itching; conjunctival chemosis, infection, and conjunctivitis.
- The following reactions may also occur: neutropenia, thrombophlebitis, flushing, pallor, weakness, severe retching and choking, wheezing, cramps, tremors, and sneezing.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Iopamidol in the drug label.
# Drug Interactions
There is limited information regarding Iopamidol Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits at doses up to 2.7 and 1.4 times the maximum recommended human dose (1.48 gl/kg in a 50 kg individual), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to iopamidol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Iopamidol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Iopamidol 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 iopamidol is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Iopamidol with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Iopamidol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Iopamidol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Iopamidol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Iopamidol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Iopamidol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Iopamidol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Iopamidol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intrathecal
### Monitoring
There is limited information regarding Monitoring of Iopamidol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Iopamidol in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- A dose of 3000 mgl in adults and 2400 mgl in children is sufficient for most myelographic procedures. Doses above these levels may result in an increased frequency and severity of adverse reactions including seizures. However, in myelography, even use of a recommended dose can produce mental aberrations tantamount to overdosage, if incorrect management of the patient during or immediately following the procedure permits inadvertent early intracranial entry of a large portion of the medium.
### Management
- Treatment of an overdose of an injectable radiopaque contrast medium is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Iopamidol in the drug label.
# Pharmacology
## Mechanism of Action
- Organic iodine compounds block x-rays as they pass through the body, thereby allowing body structures containing iodine to be delineated in contrast to those structures that do not contain iodine. The degree of opacity produced by these compounds is directly proportional to the total amount (concentration and volume) of the iodinated contrast agent in the path of the x-rays. After intrathecal administration into the subarachnoid space, diffusion of iopamidol in the CSF allows the visualization of the subarachnoid spaces of the head and spinal canal. After intravascular administration, iopamidol makes opaque those vessels in its path of flow, allowing visualization of the internal structures until significant hemodilution occurs.
## Structure
- ISOVUE-M (lopamidol Injection) formulations are stable, aqueous, sterile, and nonpyrogenic solutions for intrathecal administration.
- Each mL of ISOVUE-M 200 (lopamidol Injection 41%) provides 408 mg iopamidol with 1 mg tromethamine and 0.26 mg edetate calcium disodium. The solution contains approximately 0.029 mg (0.001 mEq) sodium and 200 mg organically bound iodine per mL.
- Each mL of ISOVUE-M 300 (lopamidol Injection 61%) provides 612 mg iopamidol with 1 mg tromethamine and 0.39 mg edetate calcium disodium. The solution contains approximately 0.043 mg (0.002 mEq) sodium and 300 mg organically bound iodine per mL.
- The pH of ISOVUE-M contrast media has bean adjusted to 6.5-7.5 with hydrochloric acid and/or sodium hydroxide. Pertinent physicochemical data are noted below. ISOVUE-M (lopamidol Injection) is hypertonic as compared to plasma and cerebrospinal fluid (approximately 285 and 301 mOsm/kg water, respectively).
- Iopamidol is designated chemically as (S)-N,N’-bis- 2,4,6-triiodo-5-lactamidoisophthalamide. Structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Iopamidol in the drug label.
## Pharmacokinetics
- The pharmacokinetics of intravenously administered iopamidol in normal subjects conform to an open two-compartment model with first order elimination (a rapid alpha phase for drug distribution and a slow beta phase for drug elimination). The elimination serum or plasma half-life is approximately two hours; the half-life is not dose dependent. No significant metabolism, deiodination, or biotransformation occurs.
- Iopamidol is rapidly absorbed into the bloodstream from cerebrospinal fluid (CSF); following intrathecal administration, iopamidol appears in plasma within one hour and virtually all of the drug reaches the systemic circulation within 24 hours. Iopamidol is excreted mainly through the kidneys following intrathecal administration, and the drug is essentially undetectable in the plasma 48 hours later. In patients with impaired renal function, the elimination half-life is prolonged dependent upon the degree of impairment. In the absence of renal dysfunction, the cumulative urinary excretion for iopamidol, expressed as a percentage of administered intravenous dose is approximately 35 to 40 percent at 60 minutes, 80 to 90 percent at 8 hours, and 90 percent or more in the 72- to 96-hour period after administration. In normal subjects, approximately 1 percent or less of the administered dose appears in cumulative 72- to 96-hour fecal specimens.
- Iopamidol displays little tendency to bind to serum or plasma proteins.
- No evidence of in vivo complement activation has been found in normal subjects.
- Animal studies indicate that iopamidol does not cross the blood-brain barrier to any significant extent following intravascular administration.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate carcinogenic potential. No evidence of genetic toxicity was obtained in vitro tests.
# Clinical Studies
There is limited information regarding Clinical Studies of Iopamidol in the drug label.
# How Supplied
- ISOVUE-M 200 (lopamidol Injection 41%)
- Ten 10 mL single dose vials (NDC 0270-1411-11)
- Ten 20 mL single dose vials (NDC 0270-1411-25)
- ISOVUE-M 300 (lopamidol Injection 61%)
- Ten 15 mL single dose vials (NDC 0270-1412-15)
- Storage
- Store at 20-25° C (68-77° F). Protect from light.
## Storage
There is limited information regarding Iopamidol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients receiving injectable radiopaque diagnostic agents should be instructed to:
- Inform your physician if you are pregnant.
- Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder.
- Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous injections of substances used for x-ray procedures.
- Inform your physician about any other medications you are currently taking, including nonprescription drugs, before you have this procedure.
# Precautions with Alcohol
- Alcohol-Iopamidol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ISOVUE-M®
# Look-Alike Drug Names
There is limited information regarding Iopamidol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Iopamidol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Iopamidol is a radiological non-ionic contrast media that is FDA approved for the procedure of intrathecal administration in adult neuroradiology including myelography (lumbar, thoracic, cervical, total columnar), contrast enhancement of computed tomographic (CECT) cisternography and ventriculography and thoraco-lumbar myelography in children over the age of two years. Common adverse reactions include burning sensation, flushing, hot flashes, injection site pain, nausea, vomiting, backache, neck pain, and sensation of hot and cold.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ISOVUE-M (lopamidol Injection) is indicated for intrathecal administration in adult neuroradiology including myelography (lumbar, thoracic, cervical, total columnar), and for contrast enhancement of computed tomographic (CECT) cisternography and ventriculography.
- In adults a solution that is approximately isotonic (ISOVUE-M 200) is recommended for examination of the lumbar region. For movement of the contrast medium to distant target areas the more concentrated ISOVUE-M 300 preparation should be used to compensate for dilution of ISOVUE-M (lopamidol Injection) with cerebrospinal fluid.
- The usual recommended adult dose range for iopamidol is 2000-3000 mg iodine. Iopamidol formulated to contain more than 300 mgl/mL should not be used intrathecally in adults. The minimum dose needed to perform a procedure should always be used.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iopamidol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iopamidol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- ISOVUE-M (lopamidol Injection) is indicated for thoraco-lumbar myelography in children over the age of two years.
- In pediatric patients, a solution that is approximately isotonic (ISOVUE-M 200) is recommended for all intrathecal procedures. In children, loss of contrast due to mixing on movement of the medium is less apt to occur because of their shorter spinal cord.
- The usual recommended pediatric dose range for iopamidol is 1400-2400 mg iodine. Iopamidol formulated to contain more than 200 mgl/mL should not be used intrathecally in children. The minimum dose needed to perform a procedure should always be used. See pediatric dosage table for recommended dosage.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iopamidol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iopamidol in pediatric patients.
# Contraindications
- Intrathecal administration of corticosteroids with iopamidol is contraindicated. Because of overdosage considerations, immediate repeat myelography in the event of technical failure is contraindicated. Myelography should not be performed in the presence of significant local or systemic infection where bacteremia is likely.
# Warnings
- The need for myelographic examination should be carefully evaluated. Iopamidol should be administered with caution in patients with increased intracranial pressure or suspicion of intracranial tumor, abscess or hematoma, those with a history of convulsive disorder, severe cardiovascular disease, chronic alcoholism, or multiple sclerosis, and elderly patients.
- Particular attention must be given to state of hydration, concentration of medium, dose, and technique used in these patients.
- Contrast media may promote sickling in individuals who are homozygous for sickle cell disease when injected intravenously or intra-arterially. Although ISOVUE-M is not injected intravascularly, measurable plasma levels are attained after intrathecal administration of iopamidol.
- If frankly bloody cerebrospinal fluid is observed, the possible benefits of a myelographic examination should be considered in terms of risk to the patient.
- Patients on anticonvulsant medication should be maintained on this therapy.
- Direct intracisternal or ventricular administration for standard radiography (without computerized tomographic enhancement) is not recommended. Inadvertent intracranial entry of a large or concentrated bolus of the contrast medium, which increases the risk of neurotoxicity, can be prevented by careful patient management. Also, effort should be directed to avoid rapid dispersion of the medium causing inadvertent rise to intracranial levels (e.g., by active patient movement). If such intracranial entry of the medium occurs, prophylactic anticonvulsant treatment with diazepam or barbiturates orally for 24 to 48 hours should be considered.
- Use of medications that may lower the seizure threshold (phenothiazine derivatives, including those used for their antihistaminic properties; tricyclic antidepressants; MAO inhibitors; CNS stimulants; analeptics; antipsychotic agents) should be carefully evaluated. While the contributory role of such medications has not been established, some physicians have discontinued these agents at least 48 hours before and for at least 24 hours following intrathecal use.
- Focal and generalized motor seizures have been reported after intrathecal use of water-soluble contrast agents including iopamidol. In several of those cases reported with iopamidol, higher than recommended doses were employed. Therefore avoid:
- Deviations from recommended neuroradiologic procedure or patient management.
- Use in patients with a history of epilepsy unless medically justified.
- Overdosage.
- Intracranial entry of a bolus or premature diffusion of a high concentration of the medium.
- Failure to maintain elevation of the head during the procedure, on the stretcher, and in bed.
- Excessive and particularly active patient movement or straining.
### Precautions
- Diagnostic procedures which involve the use of any radiopaque agent should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of severe reaction to the contrast agent itself. After parenteral administration of a radiopaque agent, competent personnel and emergency facilities should be available for at least 30 to 60 minutes since severe delayed reactions may occur.
- Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetic patients, and in susceptible nondiabetic patients (often elderly with preexisting renal disease). Patients should be well hydrated prior to and following iopamidol administration.
- The possibility of a reaction, including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions, should always be considered. Patients at increased risk include those with a history of a previous reaction to a contrast medium, patients with a known sensitivity to iodine per se, and patients with a known clinical hypersensitivity (bronchial asthma, hay fever, and food allergies). The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be hazardous for the patient. It is suggested that a thorough medical history with emphasis on allergy and hypersensitivity, prior to the injection of any contrast medium, may be more accurate than pretesting in predicting potential adverse reactions. A positive history of allergies or hypersensitivity does not arbitrarily contraindicate the use of a contrast agent where a diagnostic procedure is thought essential, but caution should be exercised. Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions in such patients should be considered.
- Reports indicate that such pretreatment does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.
- The possibility of inducing bacterial meningitis in patients during intrathecal procedures should always be considered. To avoid bacterial contamination during spinal puncture, a sterile field should be maintained at all times.
- If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.
# Adverse Reactions
## Clinical Trials Experience
- The most frequently reported adverse reactions following intrathecal administration of iopamidol are headache, nausea, vomiting, and musculoskeletal pain. These reactions usually occur 1 to 10 hours after injection, almost all occurring within 24 hours. They are usually mild to moderate in degree, lasting for a few hours and usually disappearing within 24 hours. Rarely, headaches may be severe or persist for days. Headache is often accompanied by nausea and vomiting, and tends to be more frequent and persistent in patients not optimally hydrated. Backache, neck stiffness, numbness and paresthesias, leg or sciatic-type pain occurred less frequently, often in the form of a transient exacerbation of preexisting symptomatology. Transient alterations in vital signs may occur and their significance must be assessed on an individual basis.
- The following table of incidence of reactions is based on clinical studies with ISOVUE-M (lopamidol Injection) in about 686 patients.
- Other adverse effects reported in clinical literature for iopamidol include facial neuralgia, tinnitus, and sweating.
- Major motor seizures have been reported in the clinical literature and since market introduction in the United States. Early onset of seizures (less than two hours) is indicative of early substantial intracranial entry. Transitory EEG changes occur and usually take the form of slow wave activity.
- While not observed in controlled clinical studies with ISOVUE-M (lopamidol Injection), the following adverse reactions may occur because they have been reported with ISOVUE-M and other nonionic water soluble contrast agents: cardiovascular (arrhythmias); pulmonary (apnea); bacterial meningitis, and aseptic meningitis syndrome; allergy or idiosyncrasy (chills, pruritus, nasal congestion, Guillain-Barre syndrome); CNS irritation (psycho-organic syndrome: mild and transitory perceptual aberrations such as depersonalization, anxiety, depression, hyperesthesia, disturbances in speech, sight, or hearing, and disorientation; in addition, hyperreflexia or areflexia, hypertonia or flaccidity, restlessness, tremor, echoacousia, echolalia, asterixis or dysphasia have occurred). Profound mental disturbances have rarely been reported (various forms and degrees of aphasia, mental confusion or disorientation); the onset is usually at 8 to 10 hours and lasts for about 24 hours without aftereffects. However, occasionally they have been manifest as apprehension, agitation or progressive withdrawal to the point of stupor or coma. In a few cases, these have been accompanied by transitory hearing loss or other auditory symptoms and visual disturbances (believed subjective or delusional). Persistent cortical loss of vision in association with convulsions, and ventricular block have been reported. Rarely, persistent though transitory weakness in the leg or ocular muscles has been reported. Peripheral neuropathies have been rare and transitory. They include sensory and/or motor or nerve root disturbances, myelitis, persistent leg muscle pain or weakness, or sixth nerve palsy, or cauda equina syndrome. Muscle cramps, fasciculation or myoclonia, spinal convulsion, paralysis, or spasticity are unusual.
- Reactions known to occur with parenteral administration of iodinated ionic contrast agents (see the listing below) are possible with any nonionic agent. Approximately 95 percent of adverse reactions accompanying the use of other water-soluble intravascularly administered contrast agents are mild to moderate in degree. However, life-threatening reactions and fatalities, mostly of cardiovascular origin, have occurred. Reported incidences of death from the administration of other iodinated contrast media range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Most deaths occur during injection or 5 to 10 minutes later, the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. The incidence of shock is estimated to be 1 out of 20,000 (0.005 percent) patients.
- Adverse reactions to injectable contrast media fall into two categories: chemotoxic reactions and idiosyncratic reactions. Chemotoxic reactions result from the physicochemical properties of the contrast medium, the dose, and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast medium are included in this category. During intrathecal use, there is a lower incidence of electroencephalographic changes as well as neurotoxicity by virtue of the intrinsic properties of the iopamidol molecule.
- Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the amount of drug injected, the speed of injection, the mode of injection, and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening and treatment is urgent and mandatory.
- The reported incidence of adverse reactions to contrast media in patients with a history of allergy is twice that for the general population. Patients with a history of previous reactions to a contrast medium are three times more susceptible than other patients. However, sensitivity to contrast media does not appear to increase with repeated examinations. Most adverse reactions to intravascular contrast agents appear within one to three minutes after the start of injection, but delayed reactions may occur.
- Because measurable plasma levels are attained following the intrathecal administration of iopamidol, adverse reactions reported with the use of intravascular contrast agents are theoretically possible. These include:
Vasodilation (feeling of warmth), cerebral hematomas, hemodynamic disturbances, sinus bradycardia, transient electrocardiographic abnormalities, ventricular fibrillation, petechiae.
Nausea, vomiting, severe unilateral or bilateral swelling of the parotid and submaxillary glands.
Paresthesia, dizziness, convulsions, paralysis, coma.
Increased cough, asthma, dyspnea, laryngeal edema, pulmonary edema, bronchospasm, rhinitis.
Injection site pain usually due to extravasation and/or erythematous swelling, skin necrosis, urticaria.
Osmotic nephrosis of proximal tubular cells, renal failure, pain.
Perversion of taste; bilateral ocular irritation; lacrimation; itching; conjunctival chemosis, infection, and conjunctivitis.
- The following reactions may also occur: neutropenia, thrombophlebitis, flushing, pallor, weakness, severe retching and choking, wheezing, cramps, tremors, and sneezing.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Iopamidol in the drug label.
# Drug Interactions
There is limited information regarding Iopamidol Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits at doses up to 2.7 and 1.4 times the maximum recommended human dose (1.48 gl/kg in a 50 kg individual), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to iopamidol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Iopamidol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Iopamidol 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 iopamidol is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Iopamidol with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Iopamidol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Iopamidol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Iopamidol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Iopamidol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Iopamidol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Iopamidol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Iopamidol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intrathecal
### Monitoring
There is limited information regarding Monitoring of Iopamidol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Iopamidol in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- A dose of 3000 mgl in adults and 2400 mgl in children is sufficient for most myelographic procedures. Doses above these levels may result in an increased frequency and severity of adverse reactions including seizures. However, in myelography, even use of a recommended dose can produce mental aberrations tantamount to overdosage, if incorrect management of the patient during or immediately following the procedure permits inadvertent early intracranial entry of a large portion of the medium.
### Management
- Treatment of an overdose of an injectable radiopaque contrast medium is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Iopamidol in the drug label.
# Pharmacology
## Mechanism of Action
- Organic iodine compounds block x-rays as they pass through the body, thereby allowing body structures containing iodine to be delineated in contrast to those structures that do not contain iodine. The degree of opacity produced by these compounds is directly proportional to the total amount (concentration and volume) of the iodinated contrast agent in the path of the x-rays. After intrathecal administration into the subarachnoid space, diffusion of iopamidol in the CSF allows the visualization of the subarachnoid spaces of the head and spinal canal. After intravascular administration, iopamidol makes opaque those vessels in its path of flow, allowing visualization of the internal structures until significant hemodilution occurs.
## Structure
- ISOVUE-M (lopamidol Injection) formulations are stable, aqueous, sterile, and nonpyrogenic solutions for intrathecal administration.
- Each mL of ISOVUE-M 200 (lopamidol Injection 41%) provides 408 mg iopamidol with 1 mg tromethamine and 0.26 mg edetate calcium disodium. The solution contains approximately 0.029 mg (0.001 mEq) sodium and 200 mg organically bound iodine per mL.
- Each mL of ISOVUE-M 300 (lopamidol Injection 61%) provides 612 mg iopamidol with 1 mg tromethamine and 0.39 mg edetate calcium disodium. The solution contains approximately 0.043 mg (0.002 mEq) sodium and 300 mg organically bound iodine per mL.
- The pH of ISOVUE-M contrast media has bean adjusted to 6.5-7.5 with hydrochloric acid and/or sodium hydroxide. Pertinent physicochemical data are noted below. ISOVUE-M (lopamidol Injection) is hypertonic as compared to plasma and cerebrospinal fluid (approximately 285 and 301 mOsm/kg water, respectively).
- Iopamidol is designated chemically as (S)-N,N’-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]- 2,4,6-triiodo-5-lactamidoisophthalamide. Structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Iopamidol in the drug label.
## Pharmacokinetics
- The pharmacokinetics of intravenously administered iopamidol in normal subjects conform to an open two-compartment model with first order elimination (a rapid alpha phase for drug distribution and a slow beta phase for drug elimination). The elimination serum or plasma half-life is approximately two hours; the half-life is not dose dependent. No significant metabolism, deiodination, or biotransformation occurs.
- Iopamidol is rapidly absorbed into the bloodstream from cerebrospinal fluid (CSF); following intrathecal administration, iopamidol appears in plasma within one hour and virtually all of the drug reaches the systemic circulation within 24 hours. Iopamidol is excreted mainly through the kidneys following intrathecal administration, and the drug is essentially undetectable in the plasma 48 hours later. In patients with impaired renal function, the elimination half-life is prolonged dependent upon the degree of impairment. In the absence of renal dysfunction, the cumulative urinary excretion for iopamidol, expressed as a percentage of administered intravenous dose is approximately 35 to 40 percent at 60 minutes, 80 to 90 percent at 8 hours, and 90 percent or more in the 72- to 96-hour period after administration. In normal subjects, approximately 1 percent or less of the administered dose appears in cumulative 72- to 96-hour fecal specimens.
- Iopamidol displays little tendency to bind to serum or plasma proteins.
- No evidence of in vivo complement activation has been found in normal subjects.
- Animal studies indicate that iopamidol does not cross the blood-brain barrier to any significant extent following intravascular administration.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate carcinogenic potential. No evidence of genetic toxicity was obtained in vitro tests.
# Clinical Studies
There is limited information regarding Clinical Studies of Iopamidol in the drug label.
# How Supplied
- ISOVUE-M 200 (lopamidol Injection 41%)
- Ten 10 mL single dose vials (NDC 0270-1411-11)
- Ten 20 mL single dose vials (NDC 0270-1411-25)
- ISOVUE-M 300 (lopamidol Injection 61%)
- Ten 15 mL single dose vials (NDC 0270-1412-15)
- Storage
- Store at 20-25° C (68-77° F). Protect from light.
## Storage
There is limited information regarding Iopamidol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients receiving injectable radiopaque diagnostic agents should be instructed to:
- Inform your physician if you are pregnant.
- Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder.
- Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous injections of substances used for x-ray procedures.
- Inform your physician about any other medications you are currently taking, including nonprescription drugs, before you have this procedure.
# Precautions with Alcohol
- Alcohol-Iopamidol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ISOVUE-M®[1]
# Look-Alike Drug Names
There is limited information regarding Iopamidol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Iopamidol | |
9fdd4efe0957395c012b2a3b4a3b1b5e78b18d96 | wikidoc | Iopromide | Iopromide
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# Black Box Warning
# Overview
Iopromide is a radiographic contrast agent that is FDA approved for the procedure of cerebral arteriography and peripheral arteriography (300 mg i/ml), coronary arteriography and left ventriculography, visceral angiography and aortography (370 mg i/ml), peripheral venography (240 mg i/ml), contrast computed tomography (CT) imaging of head and body (300 mg i/ml and 370 mg i/ml), and excretory urography (300 mg i/ml). There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, dysguesia, abnormal vision, chest pain, vasodilatation, nausea, vomiting, back pain, urinary urgency, injection site and infusion site reactions, and pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The volume and rate of injection of the contrast agent will vary depending on the injection site and the area being examined. Inject contrast at rates approximately equal to the flow rate in the vessel being injected.
- Cerebral Arteriography (300 mg I/mL), Coronary Arteriography and Left Ventriculography (370 mg I/mL), Peripheral Arteriography (300 mg I/mL): see Table 1.
- Aortography and Visceral Angiography (370 mg I/mL):
- Use a volume and rate of contrast injection proportional to the blood flow and related to the vascular and pathological characteristics of the specific vessels being studied. Do not exceed 225 mL as total dose for the procedure.
- Peripheral Venography (240 mg I/mL):
- Inject the minimum volume necessary to visualize satisfactorily the structures under examination. Do not exceed 250 mL as total dose for the procedure.
- Contrast Computed Tomography (CT) (300 mg I/mL and 370 mg I/mL) and Excretory Urography (300 mg I/mL): see Table 2.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iopromide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iopromide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended dose in children over 2 years of age for the following evaluations is:
- Cardiac chambers and related arteries (370 mg I/mL):
- Inject 1 to 2 milliliters per kilogram (mL/kg). Do not exceed 4 mL/kg as total dose.
- Contrast Computerized Tomography or Excretory Urography (300 mg I/mL):
- Inject 1 to 2 mL/kg. Do not exceed 3 mL/kg as total dose.
- The safety and efficacy relationships of other doses, concentrations or procedures have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iopromide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iopromide in pediatric patients.
# Contraindications
- Do not administer ULTRAVIST Injection intrathecally. Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.
- Preparatory dehydration (for example, prolonged fasting and the administration of a laxative) before ULTRAVIST Injection is contraindicated in pediatric patients because of risk of acute renal failure.
# Warnings
### Precautions
- Anaphylactoid Reactions
- Life-threatening or fatal, anaphylactoid reactions, may occur during or after ULTRAVIST administration. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Increased risk is associated with a history of previous reaction to a contrast agent (3-fold), a known sensitivity to iodine and known allergic disorders (that is, bronchial asthma, hay fever and food allergies) or other hypersensitivities (2-fold). Exercise extreme caution when considering the use of iodinated contrast agents in patients with these histories or disorders.
- Emergency facilities and personnel trained in the treatment of anaphylactoid reactions should be available for at least 30 to 60 minutes after ULTRAVIST administration.
- Acute Renal Failure
- Acute renal insufficiency or failure may occur following ULTRAVIST administration, particularly in patients with advanced vascular disease, congestive heart disease, diabetes, multiple myeloma or other paraproteinacious diseases, patients on medications which alter renal function and the elderly with age-related renal impairment. ULTRAVIST is cleared by glomerular filtration; patients with renal insufficiency have increased systemic exposure to ULTRAVIST as compared to patients with normal renal function.
- Exercise caution and use the lowest necessary dose of ULTRAVIST in patients with renal insufficiency. Adequately hydrate patients prior to and following ULTRAVIST administration. Patients with congestive heart failure receiving concurrent diuretic therapy may have relative intravascular volume depletion, which may affect the renal response to the contrast agent osmotic load. Observe such patients for several hours following the procedure to detect delayed hemodynamic renal function disturbances.
- Cardiovascular Reactions
- The increase in the circulatory osmotic load may induce acute or delayed hemodynamic disturbances in patients with congestive heart failure, severely impaired renal function, combined renal and hepatic disease, combined renal and cardiac disease, particularly when repetitive and/or large doses are administered.
- Among patients who have had cardiovascular reactions, most deaths occurred from the start of injection to 10 minutes later; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Isolated reports of hypotensive collapse and shock have been published. Based upon published reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Observe patients with preexisting cardiovascular disease for several hours following ULTRAVIST administration.
- Thromboembolic Complications
- Angiography may be associated with local and distal organ damage, ischemia, thromboembolism and organ failure including stroke, brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepato-renal function abnormalities. For these reasons, meticulous angiographic techniques are recommended, including close attention to guide wire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions and minimizing the length of the procedure. In angiographic procedures, consider the possibility of dislodging plaques or damaging or perforating the vessel wall with resultant pseudoaneurysms, hemorrhage at puncture site, dissection of coronary artery during catheter manipulations and contrast agent injection. The physicochemical properties of the contrast agent, the dose and the speed of injection can influence the reactions. Test injections to ensure proper catheter placement are suggested. Increased thrombosis and activation of the complement system has also occurred. Specialized personnel, and adequate equipment and facilities for immediate resuscitation and cardioversion are necessary. Monitor electrocardiograms and vital signs throughout the procedure.
- Clotting may occur when blood remains in contact with syringes containing iodinated contrast agents.
- Avoid angiography whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism.
- Reactions in Patients with Hyperthyroidism, Pheochromocytoma, or Sickle Cell Disease
- Thyroid storm in patients with hyperthyroidism. Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of any iodinated contrast agent.
- Hypertensive crises in patients with pheochromocytoma. Administer iodinated contrast agents with extreme caution in patients with known or suspected of having pheochromocytoma. Inject the minimum amount of contrast necessary. Assess the blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.
- Sickle cell disease. Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when administered intravascularly.
- Extravasation
- Extravasation of ULTRAVIST Injection may cause tissue necrosis and/or compartment syndrome, particularly in patients with severe arterial or venous disease.
- Increased Radiation Exposure
- The decision to use contrast enhancement is associated with risk and increased radiation exposure. Use contrast after a careful evaluation of clinical, other radiologic data, and the results of non-contrast CT findings, taking into account the increased radiation dose and other risks.
- Interference with Image Interpretation
- As with other iodinated contrast agents, the use of ULTRAVIST Injection may obscure some lesions which were seen on non-contrast CT scans.
- Calcified lesions are less likely to enhance. The enhancement of tumors after therapy may decrease. The opacification of the inferior vermis following contrast agent administration has resulted in false-positive diagnosis. Cerebral infarctions of recent onset may be better visualized with contrast enhancement. However, older infarctions may be obscured by the contrast agent.
- In patients with normal blood-brain barriers and renal failure, iodinated contrast agents have been associated with blood-brain barrier disruption and accumulation of contrast in the brain. Accumulation of contrast in the brain also occurs in patients where the blood-brain barrier is known or suspected to be disrupted.
# 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 or predict the rates observed in practice.
- The following table of incidence of reactions is based upon controlled clinical trials in which ULTRAVIST Injection was administered to 1142 patients. This listing includes all reported adverse reactions regardless of attribution.
- Adverse reactions are listed by System Organ Class and in decreasing order of occurrence for rates greater than 1% in the ULTRAVIST group.
- One or more adverse reactions were recorded in 273 of 1142 (24%) patients during the clinical trials, coincident with the administration of ULTRAVIST Injection or within the defined duration of the study follow-up period (24–72 hours). ULTRAVIST Injection is often associated with sensations of warmth and/or pain.
- Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast media, including ULTRAVIST Injection. In clinical trials 7/1142 patients given ULTRAVIST Injection died 5 days or later after drug administration. Also, 10/1142 patients given ULTRAVIST Injection had serious adverse events.
- The following adverse reactions were observed in ≤1% of the subjects receiving ULTRAVIST Injection:
Atrio ventricular block (complete), bradycardia, ventricular extrasystole;
Abdominal discomfort, abdominal pain, abdominal pain upper, constipation, diarrhea, dry mouth, dyspepsia, gastrointestinal disorder, gastrointestinal pain, salivation increased, stomach discomfort, rectal tenesmus;
Asthenia, chest discomfort, chills, excessive thirst, extravasation, feeling hot, hyperhydrosis, malaise, edema peripheral, pyrexia;
Asthma, face edema;
Blood lactate dehydrogenase increased, blood urea increased, hemoglobin increased, white blood cell count increased;
Arthralgia, musculoskeletal pain, myasthenia, neck pain, pain in extremity;
Agitation, confusion, convulsion, dizziness, hypertonia, hypesthesia, incoordination, neuropathy, somnolence, speech disorder, tremor, paresthesia, visual field defect;
Anxiety;
Dysuria, renal pain, urinary retention;
Apnea, cough increased, dyspnea, hypoxia, pharyngeal edema, pharyngitis, pleural effusion, pulmonary hypertension, respiratory disorder, sore throat;
Erythema, pruritus, rash, urticaria;
Coronary artery thrombosis, flushing, hypertension, hypotension, peripheral vascular disorder, syncope, vascular anomaly.
- The overall character, quality, and severity of adverse reactions in pediatric patients are generally similar to those reported in adult patients. Additional adverse reactions reported in pediatric patients from foreign marketing surveillance or other information are: epistaxis, angioedema, migraine, joint disorder (effusion), muscle cramps, mucous membrane disorder (mucosal swelling), conjunctivitis, hypoxia, fixed eruptions, vertigo, diabetes insipidus, and brain edema.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of ULTRAVIST Injection. 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.
- Adverse reactions reported in foreign postmarketing surveillance and other trials with the use of ULTRAVIST Injection include:
Cardiac arrest, ventricular fibrillation, atrial fibrillation, tachycardia, palpitations, congestive heart failure, myocardial infarction, angina pectoris;
Vertigo, tinnitus;
Hyperthyroidism, thyrotoxic crisis, hypothyroidism;
Mydriasis, lacrimation disorder;
Dysphagia, swelling of salivary glands;
Anaphylactoid reaction (including fatal cases), respiratory arrest, anaphylactoid shock, angioedema, laryngeal edema, laryngospasm, bronchospasm, hypersensitivity;
Cerebral ischemia/infarction, paralysis, paresis, transient cortical blindness, aphasia, coma, unconsciousness, amnesia, hypotonia;
Renal failure, hematuria;
Pulmonary edema, acute respiratory distress syndrome, asthma;
Stevens-Johnson Syndrome, skin discoloration;
Vasospasm.
# Drug Interactions
- In patients taking biguanides (for example, metformin), acute alterations in renal function after iodinated contrast agents may precipitate lactic acidosis. Stop biguanides 48 hours before the contrast medium examination and withhold until 48 hours after the procedure.
- Patients on beta-blockers may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Because of the risk of hypersensitivity reactions, use caution when administering iodinated contrast agents to patients taking beta-blockers.
- Interleukins are associated with an increased prevalence of delayed hypersensitivity reactions after iodinated contrast agent administration. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria.
- Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be postponed in patients who have recently received a cholecystographic contrast agent.
- Do not mix other drugs with ULTRAVIST Injection.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies performed with iopromide in rats and rabbits at doses up to 3.7 g I/kg (2.2 times the maximum recommended dose for a 50 kg human, or approximately 0.7 times the human dose following normalization of the data to body surface area estimates) have revealed no evidence of direct harm to the fetus. Embryolethality was observed in rabbits that received 3.7 g I/kg, but this was considered to have been secondary to maternal toxicity. Adequate and well-controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Iopromide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Iopromide during labor and delivery.
### Nursing Mothers
- It is not known whether ULTRAVIST Injection is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast agents are administered to nursing women because of potential adverse reaction, and consideration should be given to temporarily discontinuing nursing.
### Pediatric Use
- The safety and efficacy of ULTRAVIST Injection have been established in the pediatric population over 2 years of age. Use of ULTRAVIST Injection in these age groups is supported by evidence from adequate and well controlled studies of ULTRAVIST Injection in adults and additional safety data obtained in literature and other reports in a total of 274 pediatric patients. Of these, there were 131 children (2–12 years), 57 adolescents, and 86 children of unreported or other ages. There were 148 females, 94 males and 32 in whom gender was not reported. The racial distribution was: Caucasian 93 (33.9%), Black 1 (0.4%), Asian 6 (2.2%), and unknown 174 (63.5%). These patients were evaluated in intra-arterial coronary angiographic (n=60), intravenous contrast computerized tomography (CT) (n=87), excretory urography (n=99) and 28 other procedures.
- In these pediatric patients, a concentration of 300 mg I/mL was employed for intravenous contrast CT or excretory urography. A concentration of 370 mg I/mL was employed for intra-arterial and intracardiac administration in the radiographic evaluation of the heart cavities and major arteries. Most pediatric patients received initial volumes of 1–2 mL/kg.
- Optimal doses of ULTRAVIST Injection have not been established because different injection volumes, concentrations and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target vascular bed has not been established. The potential need for dose adjustment on the basis of immature renal function has not been established. In the pediatric population, the pharmacokinetic parameters have not been established.
- Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent include those with asthma, a sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or a serum creatinine greater than 1.5 mg/dL. The injection rates in small vascular beds, and the relationship of the dose by volume or concentration in small pediatric patients have not been established. Exercise caution in selecting the dose.
- Safety and effectiveness in pediatric patients below the age of two have not been established.
### Geriatic Use
- Middle-aged and elderly patients, without significantly impaired renal function, who received ULTRAVIST Injection in doses corresponding to 9–30 g iodine, had mean steady-state volumes of distribution that ranged between 30–40 L. Mean total and renal clearances were between 81–125 mL/min and 70–115 mL/min respectively in these patients, and were similar to the values found in the young volunteers. The distribution phase half-life in this patient population was 0.1 hour, the main elimination phase half-life was 2.3 hours, and the terminal elimination phase half-life was 40 hours. The urinary excretion (97% of the dose) and fecal excretion (2%) was comparable to that observed in young healthy volunteers, suggesting that, compared to the renal route, biliary and/or gastrointestinal excretion is not significant for iopromide.
### Gender
There is no FDA guidance on the use of Iopromide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Iopromide with respect to specific racial populations.
### Renal Impairment
- In patients with renal impairment, opacification of the calyces and pelves by iopromide may be delayed due to slower renal excretion of iopromide.
- A pharmacokinetic study in patients with mild (n=2), moderate (n=6), and severe (n=3) renal impairment was conducted. The total clearance of iopromide was decreased proportionately to the baseline decrease in creatinine clearance. The plasma AUC increased about 2-fold in patients with moderate renal impairment and 6-fold in patients with severe renal impairment compared to subjects with normal renal function. The terminal half-life increased from 2.2 hrs for subjects with normal renal function to 11.6 hrs in patients with severe renal impairment. The peak plasma concentration of iopromide was not influenced by the extent of renal impairment. Exercise caution and use the lowest necessary dose of ULTRAVIST in patients with renal dysfunction.
### Hepatic Impairment
There is no FDA guidance on the use of Iopromide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Iopromide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Iopromide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Iopromide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Iopromide in the drug label.
# Overdosage
## Acute Overdose
- The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.
- ULTRAVIST Injection binds negligibly to plasma or serum protein and can, therefore, be dialyzed.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Iopromide in the drug label.
# Pharmacology
## Mechanism of Action
- Iopromide is a nonionic, water soluble, tri-iodinated x-ray contrast agent for intravascular administration.
- Intravascular injection of iopromide opacifies those vessels in the path of flow of the contrast agent, permitting radiographic visualization of the internal structures until significant hemodilution occurs.
## Structure
- ULTRAVIST (iopromide) Injection is a nonionic, water soluble x-ray contrast agent for intravascular administration. Each bottle is to be used as a Pharmacy Bulk Package for dispensing multiple single dose preparations utilizing a suitable transfer device. The chemical name for iopromide is N,N'-Bis(2,3-dihydroxypropyl) –2,4,6–triiodo–5– –N-methyl–1,3-benzenedicarboxamide. Iopromide has a molecular weight of 791.12 (iodine content 48.12%).
- Iopromide has the following structural formula:
- ULTRAVIST Injection is a nonionic, sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
- ULTRAVIST Injection is available in three strengths:
- 240 mg I/mL provides 498.72 mg/mL iopromide,
- 300 mg I/mL provides 623.4 mg/mL iopromide,
- 370 mg I/mL provides 768.86 mg/mL iopromide.
- During the manufacture of ULTRAVIST Injection, sodium hydroxide or hydrochloric acid may be added for pH adjustment. ULTRAVIST Injection has a pH of 7.4 (6.5–8) at 25± 2°C, is sterilized by autoclaving and contains no preservatives.
- The iodine concentrations (mg I/mL) available have the following physicochemical properties:
- Solutions of ULTRAVIST Injection 240 mg I/mL, 300 mg I/mL and 370 mg I/mL have osmolalities from approximately 1.1 to 2.7 times that of plasma (285 mOsmol/kg water).
## Pharmacodynamics
- Following ULTRAVIST administration, the degree of contrast enhancement is directly related to the iodine content in the administered dose; peak iodine plasma levels occur immediately following rapid intravenous injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments.
- Intravascular Contrast: Contrast enhancement appears to be greatest immediately after bolus injections (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (that is, dynamic computed tomographic imaging).
- ULTRAVIST Injection may be visualized in the renal parenchyma within 30–60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1–3 minutes, with optimum contrast occurring within 5–15 minutes.
- In contrast CT, some performance characteristics are different in the brain and body. In contrast CT of the body, iodinated contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to any relative differences in extravascular diffusion between adjacent tissues.
- In the normal brain with an intact blood-brain barrier, contrast is generally due to the presence of iodinated contrast agent within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations and aneurysms, depends on the iodine content of the circulating blood pool.
- In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial brain tissue. The time to maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to 1 hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing medium within the lesion and outside the blood pool. The mechanism by which this occurs is not clear.
## Pharmacokinetics
- Distribution
- After intravenous administration to healthy young volunteers, plasma iopromide concentration time profile shows an initial distribution phase with a half-life of 0.24 hour; a main elimination phase with a half-life of 2 hours; and a terminal elimination phase with a half-life of 6.2 hours. The total volume of distribution at steady state is about 16 L suggesting distribution in to extracellular space. Plasma protein binding of iopromide is 1%.
- Iodinated contrast agents may cross the blood-brain barrier.
- Elimination
- The amounts excreted unchanged in urine represent 97% of the dose in young healthy subjects. Only 2% of the dose is recovered in the feces. Similar recoveries in urine and feces are observed in middle-aged and elderly patients. This finding suggests that, compared to the renal route, biliary and/or gastrointestinal excretion is not important for iopromide. During the slower terminal phase only 3% of the dose is eliminated; 97% of the dose is disposed of during the earlier phases, the largest part of which occurs during the main elimination phase. The ratio of the renal clearance of iopromide to the creatinine clearance is 0.82 suggesting that iopromide is mainly excreted by glomerular filtration. Additional tubular reabsorption is possible. Pharmacokinetics of iopromide at intravenous doses up to 80 g iodine, are dose proportionate and first order.
- The mean total and renal clearances are 107 mL/min and 104 mL/min, respectively.
- Metabolism
- Iopromide is not metabolized.
- Specific Populations
- A pharmacokinetic study was conducted in 11 patients with renal impairment.
## Nonclinical Toxicology
- Long-term animal studies have not been performed with iopromide to evaluate carcinogenic potential or effects on fertility. Iopromide was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes analysis of chromosomal aberrations, an in vivo mouse micro-nucleus assay, and in an in vivo mouse dominant lethal assay.
# Clinical Studies
ULTRAVIST Injection was administered to 708 patients; 1 patient was less than 18 years of age, 347 patients were between 18 and 59 years of age, and 360 patients were equal to or greater than 60 years of age; the mean age was 56.6 years (range 17–88). Of the 708 patients, 446 (63%) were male and 262 (37%) were female. The racial distribution was: Caucasian 463 (65.4%), Black 95 (13.4%), Hispanic 36 (5.1%), Asian 11 (1.6 %), and other or unknown 103 (14.5%). Efficacy assessment was based on the global evaluation of the quality of the radiographs by rating visualization as either excellent, good, poor, or no image, and on the ability to make a diagnosis. Five (5) intra-arterial and three (3) intravenous procedures were studied with 1 of 4 concentrations (370 mg I/mL, 300 mg I/mL, 240 mg I/mL, and 150 mg I/mL). These procedures were: aortography/visceral angiography, coronary arteriography and left ventriculography, cerebral arteriography, peripheral arteriography, intra-arterial digital subtraction angiography (IA-DSA), contrast computed tomography (CT) of head and body, excretory urography, and peripheral venography.
- Cerebral arteriography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg I/mL in 80 patients with conditions such as altered cerebrovascular perfusion and/or permeability occurring in central nervous system diseases due to various CNS disorders. Visualization ratings were good or excellent in 99% of the patients with ULTRAVIST Injection; a radiologic diagnosis was made in the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
- Coronary arteriography/left ventriculography was evaluated in two randomized, double-blind clinical trials and one unblinded, unrandomized clinical trial of ULTRAVIST Injection 370 mg I/mL in 106 patients with conditions such as altered coronary artery perfusion due to metabolic causes and in patients with conditions such as altered ventricular function. Visualization ratings were good or excellent in 99% or more of the patients a radiologic diagnosis was made in the majority of the patients. A confirmation of the radiologic findings by other diagnostic methods was not obtained.
- Aortography/visceral angiography was evaluated in two randomized, double-blind clinical trials in 78 patients with conditions such as altered aortic blood flow and/or visceral vascular disorders. Visualization ratings were good or excellent in the majority of the patients; a radiologic diagnosis was made in 99% of the patients with ULTRAVIST Injection. A confirmation of radiologic findings by other diagnostic methods was not obtained. The risks of renal arteriography could not be analyzed.
- Contrast CT of head and body was evaluated in three randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg I/ml in 95 patients with vascular disorders. Visualization ratings were good or excellent in 99% of the patients; a radiologic diagnosis was made in the majority of the patients. A confirmation of contrast CT findings by other diagnostic methods was not obtained.
- ULTRAVIST Injection was evaluated in a blinded reader trial for CT of the head and body. Among the 382 patients who were evaluated with ULTRAVIST Injection 370 mg I/mL, visualization ratings were good or excellent in approximately 97% of patients.
- Peripheral venography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 240 mg I/mL in 63 patients with disorders affecting venous drainage of the limbs. Visualization ratings were good or excellent in 100% of the patients; a radiologic diagnosis was made in the majority of the patients. A confirmation of radiologic findings by other diagnostic methods was not obtained.
- Similar studies were completed with comparable findings noted in intra-arterial digital subtraction angiography, peripheral arteriography and excretory urography.
# How Supplied
- ULTRAVIST Injection is a sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution available in three strengths.
- ULTRAVIST Injection 240 mg I/mL Pharmacy Bulk Package
- 10 x 200 mL fill/250 mL bottles 50419-342-21
- ULTRAVIST Injection 300 mg I/mL Pharmacy Bulk Package
- 10 x 200 mL fill/250 mL bottles 50419-344-21
- 8 x 500 mL bottles 50419-344-58
- 8 x 500 mL bottles (RFID) 50419-344-48
- ULTRAVIST Injection 370 mg I/mL Pharmacy Bulk Package
- 10 x 250 mL bottles 50419-346-25
- 8 x 500 mL bottles 50419-346-58
- 8 x 500 mL bottles (RFID) 50419-346-48
- Inspect contrast agents visually prior to use. Do not use if discolored, if particulate matter (including crystals) is present, or if containers are defective. As ULTRAVIST Injection is a highly concentrated solution, crystallization (milky-cloudy appearance and/or sediment at bottom, or floating crystals) may occur.
- As with all contrast agents, because of the potential for chemical incompatibility, do not mix or inject ULTRAVIST Injection in intravenous administration lines containing other drugs, solutions or total nutritional admixtures.
- Use sterile technique in all vascular injections involving contrast agents.
- Inject intravascularly administered iodinated contrast agents at or close to body temperature.
- If nondisposable equipment is used, take scrupulous care to prevent residual contamination with traces of cleansing agents.
- Withdraw contrast agents from their containers under strict aseptic conditions using only sterile syringes and transfer devices. Use immediately contrast agents which have been transferred into other delivery systems.
- Store the preparation at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) and protected from light.
- Directions for Proper Use of ULTRAVIST Injection PHARMACY BULK PACKAGE
- Perform the transfer of ULTRAVIST Injection from the PHARMACY BULK PACKAGE in a suitable work area, such as a laminar flow hood, utilizing aseptic technique.
- Penetrate the container closure only one time, utilizing a suitable transfer device.
- After initial puncture use the contents of the PHARMACY BULK PACKAGE within 10 hours.
- Discard any unused ULTRAVIST Injection 10 hours after the initial puncture of the bulk package.
## Storage
There is limited information regarding Iopromide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients receiving ULTRAVIST Injection to inform their physician or healthcare provider of the following:
- If they are pregnant
- If they are diabetic or if they have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or thyroid disorder
- If they are allergic to any drugs or food, or if they have immune, autoimmune or immune deficiency disorders. Also, if they have had any reaction to previous injections of dyes used for x-ray procedures
- All medications they are currently taking, including non-prescription (over-the-counter) drugs.
# Precautions with Alcohol
- Alcohol-Iopromide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ULTRAVIST®
# Look-Alike Drug Names
There is limited information regarding Iopromide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Iopromide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Black Box Warning
# Overview
Iopromide is a radiographic contrast agent that is FDA approved for the procedure of cerebral arteriography and peripheral arteriography (300 mg i/ml), coronary arteriography and left ventriculography, visceral angiography and aortography (370 mg i/ml), peripheral venography (240 mg i/ml), contrast computed tomography (CT) imaging of head and body (300 mg i/ml and 370 mg i/ml), and excretory urography (300 mg i/ml). There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, dysguesia, abnormal vision, chest pain, vasodilatation, nausea, vomiting, back pain, urinary urgency, injection site and infusion site reactions, and pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The volume and rate of injection of the contrast agent will vary depending on the injection site and the area being examined. Inject contrast at rates approximately equal to the flow rate in the vessel being injected.
- Cerebral Arteriography (300 mg I/mL), Coronary Arteriography and Left Ventriculography (370 mg I/mL), Peripheral Arteriography (300 mg I/mL): see Table 1.
- Aortography and Visceral Angiography (370 mg I/mL):
- Use a volume and rate of contrast injection proportional to the blood flow and related to the vascular and pathological characteristics of the specific vessels being studied. Do not exceed 225 mL as total dose for the procedure.
- Peripheral Venography (240 mg I/mL):
- Inject the minimum volume necessary to visualize satisfactorily the structures under examination. Do not exceed 250 mL as total dose for the procedure.
- Contrast Computed Tomography (CT) (300 mg I/mL and 370 mg I/mL) and Excretory Urography (300 mg I/mL): see Table 2.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iopromide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iopromide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended dose in children over 2 years of age for the following evaluations is:
- Cardiac chambers and related arteries (370 mg I/mL):
- Inject 1 to 2 milliliters per kilogram (mL/kg). Do not exceed 4 mL/kg as total dose.
- Contrast Computerized Tomography or Excretory Urography (300 mg I/mL):
- Inject 1 to 2 mL/kg. Do not exceed 3 mL/kg as total dose.
- The safety and efficacy relationships of other doses, concentrations or procedures have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Iopromide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Iopromide in pediatric patients.
# Contraindications
- Do not administer ULTRAVIST Injection intrathecally. Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.
- Preparatory dehydration (for example, prolonged fasting and the administration of a laxative) before ULTRAVIST Injection is contraindicated in pediatric patients because of risk of acute renal failure.
# Warnings
### Precautions
- Anaphylactoid Reactions
- Life-threatening or fatal, anaphylactoid reactions, may occur during or after ULTRAVIST administration. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Increased risk is associated with a history of previous reaction to a contrast agent (3-fold), a known sensitivity to iodine and known allergic disorders (that is, bronchial asthma, hay fever and food allergies) or other hypersensitivities (2-fold). Exercise extreme caution when considering the use of iodinated contrast agents in patients with these histories or disorders.
- Emergency facilities and personnel trained in the treatment of anaphylactoid reactions should be available for at least 30 to 60 minutes after ULTRAVIST administration.
- Acute Renal Failure
- Acute renal insufficiency or failure may occur following ULTRAVIST administration, particularly in patients with advanced vascular disease, congestive heart disease, diabetes, multiple myeloma or other paraproteinacious diseases, patients on medications which alter renal function and the elderly with age-related renal impairment. ULTRAVIST is cleared by glomerular filtration; patients with renal insufficiency have increased systemic exposure to ULTRAVIST as compared to patients with normal renal function.
- Exercise caution and use the lowest necessary dose of ULTRAVIST in patients with renal insufficiency. Adequately hydrate patients prior to and following ULTRAVIST administration. Patients with congestive heart failure receiving concurrent diuretic therapy may have relative intravascular volume depletion, which may affect the renal response to the contrast agent osmotic load. Observe such patients for several hours following the procedure to detect delayed hemodynamic renal function disturbances.
- Cardiovascular Reactions
- The increase in the circulatory osmotic load may induce acute or delayed hemodynamic disturbances in patients with congestive heart failure, severely impaired renal function, combined renal and hepatic disease, combined renal and cardiac disease, particularly when repetitive and/or large doses are administered.
- Among patients who have had cardiovascular reactions, most deaths occurred from the start of injection to 10 minutes later; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Isolated reports of hypotensive collapse and shock have been published. Based upon published reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Observe patients with preexisting cardiovascular disease for several hours following ULTRAVIST administration.
- Thromboembolic Complications
- Angiography may be associated with local and distal organ damage, ischemia, thromboembolism and organ failure including stroke, brachial plexus palsy, chest pain, myocardial infarction, sinus arrest, hepato-renal function abnormalities. For these reasons, meticulous angiographic techniques are recommended, including close attention to guide wire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions and minimizing the length of the procedure. In angiographic procedures, consider the possibility of dislodging plaques or damaging or perforating the vessel wall with resultant pseudoaneurysms, hemorrhage at puncture site, dissection of coronary artery during catheter manipulations and contrast agent injection. The physicochemical properties of the contrast agent, the dose and the speed of injection can influence the reactions. Test injections to ensure proper catheter placement are suggested. Increased thrombosis and activation of the complement system has also occurred. Specialized personnel, and adequate equipment and facilities for immediate resuscitation and cardioversion are necessary. Monitor electrocardiograms and vital signs throughout the procedure.
- Clotting may occur when blood remains in contact with syringes containing iodinated contrast agents.
- Avoid angiography whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism.
- Reactions in Patients with Hyperthyroidism, Pheochromocytoma, or Sickle Cell Disease
- Thyroid storm in patients with hyperthyroidism. Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of any iodinated contrast agent.
- Hypertensive crises in patients with pheochromocytoma. Administer iodinated contrast agents with extreme caution in patients with known or suspected of having pheochromocytoma. Inject the minimum amount of contrast necessary. Assess the blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.
- Sickle cell disease. Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when administered intravascularly.
- Extravasation
- Extravasation of ULTRAVIST Injection may cause tissue necrosis and/or compartment syndrome, particularly in patients with severe arterial or venous disease.
- Increased Radiation Exposure
- The decision to use contrast enhancement is associated with risk and increased radiation exposure. Use contrast after a careful evaluation of clinical, other radiologic data, and the results of non-contrast CT findings, taking into account the increased radiation dose and other risks.
- Interference with Image Interpretation
- As with other iodinated contrast agents, the use of ULTRAVIST Injection may obscure some lesions which were seen on non-contrast CT scans.
- Calcified lesions are less likely to enhance. The enhancement of tumors after therapy may decrease. The opacification of the inferior vermis following contrast agent administration has resulted in false-positive diagnosis. Cerebral infarctions of recent onset may be better visualized with contrast enhancement. However, older infarctions may be obscured by the contrast agent.
- In patients with normal blood-brain barriers and renal failure, iodinated contrast agents have been associated with blood-brain barrier disruption and accumulation of contrast in the brain. Accumulation of contrast in the brain also occurs in patients where the blood-brain barrier is known or suspected to be disrupted.
# 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 or predict the rates observed in practice.
- The following table of incidence of reactions is based upon controlled clinical trials in which ULTRAVIST Injection was administered to 1142 patients. This listing includes all reported adverse reactions regardless of attribution.
- Adverse reactions are listed by System Organ Class and in decreasing order of occurrence for rates greater than 1% in the ULTRAVIST group.
- One or more adverse reactions were recorded in 273 of 1142 (24%) patients during the clinical trials, coincident with the administration of ULTRAVIST Injection or within the defined duration of the study follow-up period (24–72 hours). ULTRAVIST Injection is often associated with sensations of warmth and/or pain.
- Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast media, including ULTRAVIST Injection. In clinical trials 7/1142 patients given ULTRAVIST Injection died 5 days or later after drug administration. Also, 10/1142 patients given ULTRAVIST Injection had serious adverse events.
- The following adverse reactions were observed in ≤1% of the subjects receiving ULTRAVIST Injection:
Atrio ventricular block (complete), bradycardia, ventricular extrasystole;
Abdominal discomfort, abdominal pain, abdominal pain upper, constipation, diarrhea, dry mouth, dyspepsia, gastrointestinal disorder, gastrointestinal pain, salivation increased, stomach discomfort, rectal tenesmus;
Asthenia, chest discomfort, chills, excessive thirst, extravasation, feeling hot, hyperhydrosis, malaise, edema peripheral, pyrexia;
Asthma, face edema;
Blood lactate dehydrogenase increased, blood urea increased, hemoglobin increased, white blood cell count increased;
Arthralgia, musculoskeletal pain, myasthenia, neck pain, pain in extremity;
Agitation, confusion, convulsion, dizziness, hypertonia, hypesthesia, incoordination, neuropathy, somnolence, speech disorder, tremor, paresthesia, visual field defect;
Anxiety;
Dysuria, renal pain, urinary retention;
Apnea, cough increased, dyspnea, hypoxia, pharyngeal edema, pharyngitis, pleural effusion, pulmonary hypertension, respiratory disorder, sore throat;
Erythema, pruritus, rash, urticaria;
Coronary artery thrombosis, flushing, hypertension, hypotension, peripheral vascular disorder, syncope, vascular anomaly.
- The overall character, quality, and severity of adverse reactions in pediatric patients are generally similar to those reported in adult patients. Additional adverse reactions reported in pediatric patients from foreign marketing surveillance or other information are: epistaxis, angioedema, migraine, joint disorder (effusion), muscle cramps, mucous membrane disorder (mucosal swelling), conjunctivitis, hypoxia, fixed eruptions, vertigo, diabetes insipidus, and brain edema.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of ULTRAVIST Injection. 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.
- Adverse reactions reported in foreign postmarketing surveillance and other trials with the use of ULTRAVIST Injection include:
Cardiac arrest, ventricular fibrillation, atrial fibrillation, tachycardia, palpitations, congestive heart failure, myocardial infarction, angina pectoris;
Vertigo, tinnitus;
Hyperthyroidism, thyrotoxic crisis, hypothyroidism;
Mydriasis, lacrimation disorder;
Dysphagia, swelling of salivary glands;
Anaphylactoid reaction (including fatal cases), respiratory arrest, anaphylactoid shock, angioedema, laryngeal edema, laryngospasm, bronchospasm, hypersensitivity;
Cerebral ischemia/infarction, paralysis, paresis, transient cortical blindness, aphasia, coma, unconsciousness, amnesia, hypotonia;
Renal failure, hematuria;
Pulmonary edema, acute respiratory distress syndrome, asthma;
Stevens-Johnson Syndrome, skin discoloration;
Vasospasm.
# Drug Interactions
- In patients taking biguanides (for example, metformin), acute alterations in renal function after iodinated contrast agents may precipitate lactic acidosis. Stop biguanides 48 hours before the contrast medium examination and withhold until 48 hours after the procedure.
- Patients on beta-blockers may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Because of the risk of hypersensitivity reactions, use caution when administering iodinated contrast agents to patients taking beta-blockers.
- Interleukins are associated with an increased prevalence of delayed hypersensitivity reactions after iodinated contrast agent administration. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria.
- Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be postponed in patients who have recently received a cholecystographic contrast agent.
- Do not mix other drugs with ULTRAVIST Injection.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies performed with iopromide in rats and rabbits at doses up to 3.7 g I/kg (2.2 times the maximum recommended dose for a 50 kg human, or approximately 0.7 times the human dose following normalization of the data to body surface area estimates) have revealed no evidence of direct harm to the fetus. Embryolethality was observed in rabbits that received 3.7 g I/kg, but this was considered to have been secondary to maternal toxicity. Adequate and well-controlled studies in pregnant women have not been conducted. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Iopromide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Iopromide during labor and delivery.
### Nursing Mothers
- It is not known whether ULTRAVIST Injection is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast agents are administered to nursing women because of potential adverse reaction, and consideration should be given to temporarily discontinuing nursing.
### Pediatric Use
- The safety and efficacy of ULTRAVIST Injection have been established in the pediatric population over 2 years of age. Use of ULTRAVIST Injection in these age groups is supported by evidence from adequate and well controlled studies of ULTRAVIST Injection in adults and additional safety data obtained in literature and other reports in a total of 274 pediatric patients. Of these, there were 131 children (2–12 years), 57 adolescents, and 86 children of unreported or other ages. There were 148 females, 94 males and 32 in whom gender was not reported. The racial distribution was: Caucasian 93 (33.9%), Black 1 (0.4%), Asian 6 (2.2%), and unknown 174 (63.5%). These patients were evaluated in intra-arterial coronary angiographic (n=60), intravenous contrast computerized tomography (CT) (n=87), excretory urography (n=99) and 28 other procedures.
- In these pediatric patients, a concentration of 300 mg I/mL was employed for intravenous contrast CT or excretory urography. A concentration of 370 mg I/mL was employed for intra-arterial and intracardiac administration in the radiographic evaluation of the heart cavities and major arteries. Most pediatric patients received initial volumes of 1–2 mL/kg.
- Optimal doses of ULTRAVIST Injection have not been established because different injection volumes, concentrations and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target vascular bed has not been established. The potential need for dose adjustment on the basis of immature renal function has not been established. In the pediatric population, the pharmacokinetic parameters have not been established.
- Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent include those with asthma, a sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or a serum creatinine greater than 1.5 mg/dL. The injection rates in small vascular beds, and the relationship of the dose by volume or concentration in small pediatric patients have not been established. Exercise caution in selecting the dose.
- Safety and effectiveness in pediatric patients below the age of two have not been established.
### Geriatic Use
- Middle-aged and elderly patients, without significantly impaired renal function, who received ULTRAVIST Injection in doses corresponding to 9–30 g iodine, had mean steady-state volumes of distribution that ranged between 30–40 L. Mean total and renal clearances were between 81–125 mL/min and 70–115 mL/min respectively in these patients, and were similar to the values found in the young volunteers. The distribution phase half-life in this patient population was 0.1 hour, the main elimination phase half-life was 2.3 hours, and the terminal elimination phase half-life was 40 hours. The urinary excretion (97% of the dose) and fecal excretion (2%) was comparable to that observed in young healthy volunteers, suggesting that, compared to the renal route, biliary and/or gastrointestinal excretion is not significant for iopromide.
### Gender
There is no FDA guidance on the use of Iopromide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Iopromide with respect to specific racial populations.
### Renal Impairment
- In patients with renal impairment, opacification of the calyces and pelves by iopromide may be delayed due to slower renal excretion of iopromide.
- A pharmacokinetic study in patients with mild (n=2), moderate (n=6), and severe (n=3) renal impairment was conducted. The total clearance of iopromide was decreased proportionately to the baseline decrease in creatinine clearance. The plasma AUC increased about 2-fold in patients with moderate renal impairment and 6-fold in patients with severe renal impairment compared to subjects with normal renal function. The terminal half-life increased from 2.2 hrs for subjects with normal renal function to 11.6 hrs in patients with severe renal impairment. The peak plasma concentration of iopromide was not influenced by the extent of renal impairment. Exercise caution and use the lowest necessary dose of ULTRAVIST in patients with renal dysfunction.
### Hepatic Impairment
There is no FDA guidance on the use of Iopromide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Iopromide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Iopromide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Iopromide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Iopromide in the drug label.
# Overdosage
## Acute Overdose
- The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.
- ULTRAVIST Injection binds negligibly to plasma or serum protein and can, therefore, be dialyzed.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Iopromide in the drug label.
# Pharmacology
## Mechanism of Action
- Iopromide is a nonionic, water soluble, tri-iodinated x-ray contrast agent for intravascular administration.
- Intravascular injection of iopromide opacifies those vessels in the path of flow of the contrast agent, permitting radiographic visualization of the internal structures until significant hemodilution occurs.
## Structure
- ULTRAVIST (iopromide) Injection is a nonionic, water soluble x-ray contrast agent for intravascular administration. Each bottle is to be used as a Pharmacy Bulk Package for dispensing multiple single dose preparations utilizing a suitable transfer device. The chemical name for iopromide is N,N'-Bis(2,3-dihydroxypropyl) –2,4,6–triiodo–5– [(methoxyacetyl)amino] –N-methyl–1,3-benzenedicarboxamide. Iopromide has a molecular weight of 791.12 (iodine content 48.12%).
- Iopromide has the following structural formula:
- ULTRAVIST Injection is a nonionic, sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer.
- ULTRAVIST Injection is available in three strengths:
- 240 mg I/mL provides 498.72 mg/mL iopromide,
- 300 mg I/mL provides 623.4 mg/mL iopromide,
- 370 mg I/mL provides 768.86 mg/mL iopromide.
- During the manufacture of ULTRAVIST Injection, sodium hydroxide or hydrochloric acid may be added for pH adjustment. ULTRAVIST Injection has a pH of 7.4 (6.5–8) at 25± 2°C, is sterilized by autoclaving and contains no preservatives.
- The iodine concentrations (mg I/mL) available have the following physicochemical properties:
- Solutions of ULTRAVIST Injection 240 mg I/mL, 300 mg I/mL and 370 mg I/mL have osmolalities from approximately 1.1 to 2.7 times that of plasma (285 mOsmol/kg water).
## Pharmacodynamics
- Following ULTRAVIST administration, the degree of contrast enhancement is directly related to the iodine content in the administered dose; peak iodine plasma levels occur immediately following rapid intravenous injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments.
- Intravascular Contrast: Contrast enhancement appears to be greatest immediately after bolus injections (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (that is, dynamic computed tomographic imaging).
- ULTRAVIST Injection may be visualized in the renal parenchyma within 30–60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1–3 minutes, with optimum contrast occurring within 5–15 minutes.
- In contrast CT, some performance characteristics are different in the brain and body. In contrast CT of the body, iodinated contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to any relative differences in extravascular diffusion between adjacent tissues.
- In the normal brain with an intact blood-brain barrier, contrast is generally due to the presence of iodinated contrast agent within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations and aneurysms, depends on the iodine content of the circulating blood pool.
- In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial brain tissue. The time to maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to 1 hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing medium within the lesion and outside the blood pool. The mechanism by which this occurs is not clear.
## Pharmacokinetics
- Distribution
- After intravenous administration to healthy young volunteers, plasma iopromide concentration time profile shows an initial distribution phase with a half-life of 0.24 hour; a main elimination phase with a half-life of 2 hours; and a terminal elimination phase with a half-life of 6.2 hours. The total volume of distribution at steady state is about 16 L suggesting distribution in to extracellular space. Plasma protein binding of iopromide is 1%.
- Iodinated contrast agents may cross the blood-brain barrier.
- Elimination
- The amounts excreted unchanged in urine represent 97% of the dose in young healthy subjects. Only 2% of the dose is recovered in the feces. Similar recoveries in urine and feces are observed in middle-aged and elderly patients. This finding suggests that, compared to the renal route, biliary and/or gastrointestinal excretion is not important for iopromide. During the slower terminal phase only 3% of the dose is eliminated; 97% of the dose is disposed of during the earlier phases, the largest part of which occurs during the main elimination phase. The ratio of the renal clearance of iopromide to the creatinine clearance is 0.82 suggesting that iopromide is mainly excreted by glomerular filtration. Additional tubular reabsorption is possible. Pharmacokinetics of iopromide at intravenous doses up to 80 g iodine, are dose proportionate and first order.
- The mean total and renal clearances are 107 mL/min and 104 mL/min, respectively.
- Metabolism
- Iopromide is not metabolized.
- Specific Populations
- A pharmacokinetic study was conducted in 11 patients with renal impairment.
## Nonclinical Toxicology
- Long-term animal studies have not been performed with iopromide to evaluate carcinogenic potential or effects on fertility. Iopromide was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes analysis of chromosomal aberrations, an in vivo mouse micro-nucleus assay, and in an in vivo mouse dominant lethal assay.
# Clinical Studies
ULTRAVIST Injection was administered to 708 patients; 1 patient was less than 18 years of age, 347 patients were between 18 and 59 years of age, and 360 patients were equal to or greater than 60 years of age; the mean age was 56.6 years (range 17–88). Of the 708 patients, 446 (63%) were male and 262 (37%) were female. The racial distribution was: Caucasian 463 (65.4%), Black 95 (13.4%), Hispanic 36 (5.1%), Asian 11 (1.6 %), and other or unknown 103 (14.5%). Efficacy assessment was based on the global evaluation of the quality of the radiographs by rating visualization as either excellent, good, poor, or no image, and on the ability to make a diagnosis. Five (5) intra-arterial and three (3) intravenous procedures were studied with 1 of 4 concentrations (370 mg I/mL, 300 mg I/mL, 240 mg I/mL, and 150 mg I/mL). These procedures were: aortography/visceral angiography, coronary arteriography and left ventriculography, cerebral arteriography, peripheral arteriography, intra-arterial digital subtraction angiography (IA-DSA), contrast computed tomography (CT) of head and body, excretory urography, and peripheral venography.
- Cerebral arteriography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg I/mL in 80 patients with conditions such as altered cerebrovascular perfusion and/or permeability occurring in central nervous system diseases due to various CNS disorders. Visualization ratings were good or excellent in 99% of the patients with ULTRAVIST Injection; a radiologic diagnosis was made in the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained.
- Coronary arteriography/left ventriculography was evaluated in two randomized, double-blind clinical trials and one unblinded, unrandomized clinical trial of ULTRAVIST Injection 370 mg I/mL in 106 patients with conditions such as altered coronary artery perfusion due to metabolic causes and in patients with conditions such as altered ventricular function. Visualization ratings were good or excellent in 99% or more of the patients a radiologic diagnosis was made in the majority of the patients. A confirmation of the radiologic findings by other diagnostic methods was not obtained.
- Aortography/visceral angiography was evaluated in two randomized, double-blind clinical trials in 78 patients with conditions such as altered aortic blood flow and/or visceral vascular disorders. Visualization ratings were good or excellent in the majority of the patients; a radiologic diagnosis was made in 99% of the patients with ULTRAVIST Injection. A confirmation of radiologic findings by other diagnostic methods was not obtained. The risks of renal arteriography could not be analyzed.
- Contrast CT of head and body was evaluated in three randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg I/ml in 95 patients with vascular disorders. Visualization ratings were good or excellent in 99% of the patients; a radiologic diagnosis was made in the majority of the patients. A confirmation of contrast CT findings by other diagnostic methods was not obtained.
- ULTRAVIST Injection was evaluated in a blinded reader trial for CT of the head and body. Among the 382 patients who were evaluated with ULTRAVIST Injection 370 mg I/mL, visualization ratings were good or excellent in approximately 97% of patients.
- Peripheral venography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 240 mg I/mL in 63 patients with disorders affecting venous drainage of the limbs. Visualization ratings were good or excellent in 100% of the patients; a radiologic diagnosis was made in the majority of the patients. A confirmation of radiologic findings by other diagnostic methods was not obtained.
- Similar studies were completed with comparable findings noted in intra-arterial digital subtraction angiography, peripheral arteriography and excretory urography.
# How Supplied
- ULTRAVIST Injection is a sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution available in three strengths.
- ULTRAVIST Injection 240 mg I/mL Pharmacy Bulk Package
- 10 x 200 mL fill/250 mL bottles 50419-342-21
- ULTRAVIST Injection 300 mg I/mL Pharmacy Bulk Package
- 10 x 200 mL fill/250 mL bottles 50419-344-21
- 8 x 500 mL bottles 50419-344-58
- 8 x 500 mL bottles (RFID) 50419-344-48
- ULTRAVIST Injection 370 mg I/mL Pharmacy Bulk Package
- 10 x 250 mL bottles 50419-346-25
- 8 x 500 mL bottles 50419-346-58
- 8 x 500 mL bottles (RFID) 50419-346-48
- Inspect contrast agents visually prior to use. Do not use if discolored, if particulate matter (including crystals) is present, or if containers are defective. As ULTRAVIST Injection is a highly concentrated solution, crystallization (milky-cloudy appearance and/or sediment at bottom, or floating crystals) may occur.
- As with all contrast agents, because of the potential for chemical incompatibility, do not mix or inject ULTRAVIST Injection in intravenous administration lines containing other drugs, solutions or total nutritional admixtures.
- Use sterile technique in all vascular injections involving contrast agents.
- Inject intravascularly administered iodinated contrast agents at or close to body temperature.
- If nondisposable equipment is used, take scrupulous care to prevent residual contamination with traces of cleansing agents.
- Withdraw contrast agents from their containers under strict aseptic conditions using only sterile syringes and transfer devices. Use immediately contrast agents which have been transferred into other delivery systems.
- Store the preparation at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) and protected from light.
- Directions for Proper Use of ULTRAVIST Injection PHARMACY BULK PACKAGE
- Perform the transfer of ULTRAVIST Injection from the PHARMACY BULK PACKAGE in a suitable work area, such as a laminar flow hood, utilizing aseptic technique.
- Penetrate the container closure only one time, utilizing a suitable transfer device.
- After initial puncture use the contents of the PHARMACY BULK PACKAGE within 10 hours.
- Discard any unused ULTRAVIST Injection 10 hours after the initial puncture of the bulk package.
## Storage
There is limited information regarding Iopromide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients receiving ULTRAVIST Injection to inform their physician or healthcare provider of the following:
- If they are pregnant
- If they are diabetic or if they have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or thyroid disorder
- If they are allergic to any drugs or food, or if they have immune, autoimmune or immune deficiency disorders. Also, if they have had any reaction to previous injections of dyes used for x-ray procedures
- All medications they are currently taking, including non-prescription (over-the-counter) drugs.
# Precautions with Alcohol
- Alcohol-Iopromide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ULTRAVIST®[1]
# Look-Alike Drug Names
There is limited information regarding Iopromide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Iopromide | |
65de2f5a8b21342db87e50a1877c6caca0afa0c2 | wikidoc | Iprindole | Iprindole
# Overview
Iprindole (Prondol, Galatur, Tertran), formerly known as pramindole, is a tricyclic antidepressant (TCA) used in Europe for the treatment of depression. It was introduced by Wyeth and has been used clinically since 1967. Notably, iprindole was the first second-generation antidepressant to be launched.
Iprindole is unique compared to most other TCAs in that it is a relatively weak inhibitor of the reuptake of serotonin and norepinephrine and instead acts predominantly as an antagonist of 5-HT2 receptors, hence its classification as 'second-generation'. Additionally, side effects of iprindole are much less prominent relative to other TCAs and it is well tolerated. However, iprindole's efficacy may not be as great as other TCAs, especially in regards to anxiety relief.
# Availability
Iprindole was sold under the trade name Prondol by Wyeth in the United Kingdom and Ireland for the indication of major depressive disorder, and has also been sold as Galatur and Tertran by Wyeth as well.
It has been discontinued throughout the world.
# Chemistry
On a structural level, iprindole differs from other TCAs in that it contains an indole nucleus, similarly to the heterocyclic antipsychotic oxypertine, and has an eight-membered and saturated third ring.
# Pharmacology
Iprindole acts as an antagonist (or inverse agonist) of the following receptors:
- 5-HT1A receptor (Kd = 2,800 nM)
- 5-HT2A receptor (Ki = 217 nM)
- 5-HT2C receptor (Ki = 206 nM)
- α1-adrenergic receptor (Kd = 2,300 nM)
- α2-adrenergic receptor (Kd = 8,600 nM)
- H1 receptor (Kd = 130 nM)
- H2 receptor (Kd = 1,980 nM)
- mACh receptors (Kd = 2,100 nM)
And as an inhibitor of the following transporters:
- SERT (Kd = 1,620 nM)
- NET (Kd = 1,262 nM)
- DAT (Kd = 6,530 nM)
It has negligible affinity (>10,000 nM) for β-adrenergic and sigma receptors.
# Dosage
Iprindole is used in doses of 30–180 mg daily.
# Side effects
Anticholinergic side effects such as dry mouth and constipation are either greatly reduced in comparison to imipramine and most other TCAs or fully lacking with iprindole. However, it still has potent antihistamine effects and therefore can produce sedation, though this is diminished relative to imipramine as well, perhaps due to iprindole lacking significant alpha-blocking properties.
# Contraindications
Iprindole has been associated with jaundice and hepatotoxicity and should not be taken by alcoholics or people with pre-existing liver disease. If such symptoms are encountered iprindole should be discontinued immediately.
# Interactions
Iprindole has been shown to be a potent inhibitor of the aromatic hydroxylation and/or N-dealkylation-mediated metabolism of many substances including, but not limited to octopamine, amphetamine, methamphetamine, fenfluramine, phenelzine, tranylcypromine, trimipramine, and fluoxetine, likely via inactivating cytochrome P450 enzymes. It also inhibits its own degradation.
On account of these interactions, caution should be used when combining iprindole with other drugs. As an example, when administered with amphetamine or methamphetamine, iprindole increases their brain concentrations and prolongs their half-lives by 2- to 3-fold, strongly augmenting both their physiological effects and neurotoxicity in the process.
# Overdose
In overdose, iprindole is much less toxic than most other TCAs and is considered relatively benign. For instance, between 1974 and 1985, only two deaths associated with iprindole were recorded in the United Kingdom, whereas 278 were reported for imipramine. However, it should be noted that imipramine is prescribed much more often than iprindole, and for that reason this comparison is likely not entirely representative of iprindole's true capacity for fatality in overdose. | Iprindole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Iprindole (Prondol, Galatur, Tertran), formerly known as pramindole, is a tricyclic antidepressant (TCA) used in Europe for the treatment of depression.[4][5][6] It was introduced by Wyeth and has been used clinically since 1967.[7] Notably, iprindole was the first second-generation antidepressant to be launched.[8]
Iprindole is unique compared to most other TCAs in that it is a relatively weak inhibitor of the reuptake of serotonin and norepinephrine and instead acts predominantly as an antagonist of 5-HT2 receptors, hence its classification as 'second-generation'.[9][10][11] Additionally, side effects of iprindole are much less prominent relative to other TCAs and it is well tolerated.[12] However, iprindole's efficacy may not be as great as other TCAs, especially in regards to anxiety relief.[9][13]
# Availability
Iprindole was sold under the trade name Prondol by Wyeth in the United Kingdom and Ireland for the indication of major depressive disorder,[14] and has also been sold as Galatur and Tertran by Wyeth as well.[15]
It has been discontinued throughout the world.[citation needed]
# Chemistry
On a structural level, iprindole differs from other TCAs in that it contains an indole nucleus, similarly to the heterocyclic antipsychotic oxypertine, and has an eight-membered and saturated third ring.[12][16]
# Pharmacology
Iprindole acts as an antagonist (or inverse agonist) of the following receptors:
- 5-HT1A receptor (Kd = 2,800 nM)[17]
- 5-HT2A receptor (Ki = 217 nM)[18][19][20][21]
- 5-HT2C receptor (Ki = 206 nM)[18][19][20][21]
- α1-adrenergic receptor (Kd = 2,300 nM)[22]
- α2-adrenergic receptor (Kd = 8,600 nM)[22][23]
- H1 receptor (Kd = 130 nM)[22][24][25][26]
- H2 receptor (Kd = 1,980 nM)[27]
- mACh receptors (Kd = 2,100 nM)[28][29][30]
And as an inhibitor of the following transporters:
- SERT (Kd = 1,620 nM)[31]
- NET (Kd = 1,262 nM)[31]
- DAT (Kd = 6,530 nM)[31]
It has negligible affinity (>10,000 nM) for β-adrenergic and sigma receptors.[32][33][34][35]
# Dosage
Iprindole is used in doses of 30–180 mg daily.[4][36]
# Side effects
Anticholinergic side effects such as dry mouth and constipation are either greatly reduced in comparison to imipramine and most other TCAs or fully lacking with iprindole.[12] However, it still has potent antihistamine effects and therefore can produce sedation, though this is diminished relative to imipramine as well, perhaps due to iprindole lacking significant alpha-blocking properties.[13]
# Contraindications
Iprindole has been associated with jaundice and hepatotoxicity and should not be taken by alcoholics or people with pre-existing liver disease.[7][37][38][39] If such symptoms are encountered iprindole should be discontinued immediately.
# Interactions
Iprindole has been shown to be a potent inhibitor of the aromatic hydroxylation and/or N-dealkylation-mediated metabolism of many substances including, but not limited to octopamine, amphetamine, methamphetamine, fenfluramine, phenelzine, tranylcypromine, trimipramine, and fluoxetine, likely via inactivating cytochrome P450 enzymes.[1][40][41][42][43][44] It also inhibits its own degradation.[43]
On account of these interactions, caution should be used when combining iprindole with other drugs.[1] As an example, when administered with amphetamine or methamphetamine, iprindole increases their brain concentrations and prolongs their half-lives by 2- to 3-fold, strongly augmenting both their physiological effects and neurotoxicity in the process.[45][46][47]
# Overdose
In overdose, iprindole is much less toxic than most other TCAs and is considered relatively benign.[48] For instance, between 1974 and 1985, only two deaths associated with iprindole were recorded in the United Kingdom, whereas 278 were reported for imipramine.[48] However, it should be noted that imipramine is prescribed much more often than iprindole, and for that reason this comparison is likely not entirely representative of iprindole's true capacity for fatality in overdose. | https://www.wikidoc.org/index.php/Iprindole | |
0f2f34e676979933f20c852e14df2e126b23e3c8 | wikidoc | Iron John | Iron John
"Iron John" is a German fairy tale found in the collections of the Brothers Grimm, tale number 136, about a wild man and a prince. (The original German title is Eisenhans, a compound of Eisen "iron" and Hans, like English John a common short form of the personal name Johannes) It represents Aarne-Thompson type 502, "The wild man as a helper".
Most people see the story as a parable about a boy maturing into adulthood. The story also became the basis for the book Iron John: A Book About Men which spawned the Men's Movement in the early 90's.
# Synopsis
A king sends a huntsmen into a forest nearby, and the huntsman never returns. The king sends more, each meeting with the same fate, until the king sends all his remaining huntsmen out as a group, but again, none return. The king proclaims the woods as dangerous and off-limits to all.
Some years later, a wandering explorer and his dog hears of these dangerous woods and asks permission to hunt in the forest, claiming that he might be able to discover the fate of the other hunters. As they come to a lake in the middle of the forest, the dog is almost dragged under by a huge arm. The hunter returns to the forest the next day with a group of men to empty the lake. They find a naked man with skin like iron and long shaggy hair all over his body. They capture him, and where he is locked in a cage in the courtyard as a curiosity. No one is allowed to set the wild man free, on penalty of death.
Years later the young prince is playing with a ball in the courtyard. He accidentally rolls it into the cage where the wild man picks it up and will only return it if he is set free. He states further that the only key to the cage is hidden beneath the queen’s pillow.
Though the prince hesitates at first, eventually he builds up the courage to sneak into his mother’s room and steal the key. He releases the wild man, who reveals his name to be Iron John (or Iron Hans, depending on the translation). The prince fears he will be killed for setting Iron John free, so Iron John agrees to take the prince with him into the forest.
As it turns out, Iron John is a powerful being and has many treasures he guards. He sets the prince to watch over his well, but warns him not to let anything touch it or fall in because it will turn instantly to gold. The prince obeys at first, but begins to play in the well, finally turning all his hair into gold. Disappointed in the boy’s failure, Iron John sends him away to experience poverty and struggle, but also tells the prince that if he ever needs anything, simply to call the name of Iron John three times.
The prince travels to a distant land and offers his services to its king. Since he is ashamed of his golden hair, he refuses to remove his cap before the king and is sent to assist the gardener.
When war comes to the kingdom, the prince sees his chance to make a name for himself. He calls upon Iron John who gives him a horse, armor, and a legion of iron warriors to fight alongside him. The prince successfully defends his new homeland, but returns all that he borrowed to Iron John before returning to his former position.
In celebration, the king announces a banquet and offers his daughter’s hand in marriage to any one of the knights who can catch a golden apple that will be thrown into their midst. The king hopes that the mysterious knight who saved the kingdom will show himself for such a prize.
Again the prince asks Iron John for help, and again Iron John disguises the prince as the mysterious knight. Though the prince catches the golden apple and escapes, and does so again on two more occasions, he is eventually found out. The prince is returned to his former station, marries the princess, and is happily reunited with his parents. Iron John too, comes to the wedding, but now without the hair or iron skin that made him frightening. He reveals he was under enchantment until he found someone worthy and pure of heart to set him free.
# Variants
This tale is known throughout Europe, in such variants as The Hairy Man. A more wide-spread variant, found in Europe, Asia, and Africa, opens with the prince for some reason being the servant of an evil being, where he gains the same gifts, and the tale proceeds as in this variant; one such tale is The Magician's Horse.
The oldest variant to be preserved is the Italian Guerrino and the Savage Man. Another such variant is Georgic and Merlin. | Iron John
"Iron John" is a German fairy tale found in the collections of the Brothers Grimm, tale number 136, about a wild man and a prince. (The original German title is Eisenhans, a compound of Eisen "iron" and Hans, like English John a common short form of the personal name Johannes) It represents Aarne-Thompson type 502, "The wild man as a helper".[1]
Most people see the story as a parable about a boy maturing into adulthood. The story also became the basis for the book Iron John: A Book About Men which spawned the Men's Movement in the early 90's.
# Synopsis
A king sends a huntsmen into a forest nearby, and the huntsman never returns. The king sends more, each meeting with the same fate, until the king sends all his remaining huntsmen out as a group, but again, none return. The king proclaims the woods as dangerous and off-limits to all.
Some years later, a wandering explorer and his dog hears of these dangerous woods and asks permission to hunt in the forest, claiming that he might be able to discover the fate of the other hunters. As they come to a lake in the middle of the forest, the dog is almost dragged under by a huge arm. The hunter returns to the forest the next day with a group of men to empty the lake. They find a naked man with skin like iron and long shaggy hair all over his body. They capture him, and where he is locked in a cage in the courtyard as a curiosity. No one is allowed to set the wild man free, on penalty of death.
Years later the young prince is playing with a ball in the courtyard. He accidentally rolls it into the cage where the wild man picks it up and will only return it if he is set free. He states further that the only key to the cage is hidden beneath the queen’s pillow.
Though the prince hesitates at first, eventually he builds up the courage to sneak into his mother’s room and steal the key. He releases the wild man, who reveals his name to be Iron John (or Iron Hans, depending on the translation). The prince fears he will be killed for setting Iron John free, so Iron John agrees to take the prince with him into the forest.
As it turns out, Iron John is a powerful being and has many treasures he guards. He sets the prince to watch over his well, but warns him not to let anything touch it or fall in because it will turn instantly to gold. The prince obeys at first, but begins to play in the well, finally turning all his hair into gold. Disappointed in the boy’s failure, Iron John sends him away to experience poverty and struggle, but also tells the prince that if he ever needs anything, simply to call the name of Iron John three times.
The prince travels to a distant land and offers his services to its king. Since he is ashamed of his golden hair, he refuses to remove his cap before the king and is sent to assist the gardener.
When war comes to the kingdom, the prince sees his chance to make a name for himself. He calls upon Iron John who gives him a horse, armor, and a legion of iron warriors to fight alongside him. The prince successfully defends his new homeland, but returns all that he borrowed to Iron John before returning to his former position.
In celebration, the king announces a banquet and offers his daughter’s hand in marriage to any one of the knights who can catch a golden apple that will be thrown into their midst. The king hopes that the mysterious knight who saved the kingdom will show himself for such a prize.
Again the prince asks Iron John for help, and again Iron John disguises the prince as the mysterious knight. Though the prince catches the golden apple and escapes, and does so again on two more occasions, he is eventually found out. The prince is returned to his former station, marries the princess, and is happily reunited with his parents. Iron John too, comes to the wedding, but now without the hair or iron skin that made him frightening. He reveals he was under enchantment until he found someone worthy and pure of heart to set him free.
# Variants
This tale is known throughout Europe, in such variants as The Hairy Man.[2] A more wide-spread variant, found in Europe, Asia, and Africa, opens with the prince for some reason being the servant of an evil being, where he gains the same gifts, and the tale proceeds as in this variant; one such tale is The Magician's Horse.[3]
The oldest variant to be preserved is the Italian Guerrino and the Savage Man.[4] Another such variant is Georgic and Merlin.[5] | https://www.wikidoc.org/index.php/Iron_John | |
3c810d1c19905ca68175f4b6874a54a5ce16381f | wikidoc | Iron lung | Iron lung
An iron lung is a large machine that enables a person to breathe when normal muscle control has been lost or the work of breathing exceeds the person's ability. It is a form of medical ventilator. Properly, it is called a negative pressure ventilator.
The person using the iron lung is placed into the central chamber, a cylindrical steel drum. A door allowing the head and neck to remain free is then closed, forming a sealed, air-tight compartment enclosing the rest of the person's body. Pumps that control airflow periodically decrease and increase the air pressure within the chamber, and particularly, on the chest. When the pressure falls below that within the lungs, the lungs expand and air from outside the chamber is sucked in via the person's nose and airways to keep the lungs filled; when the pressure rises above that within the lungs, the reverse occurs, and air is expelled. In this manner, the iron lung mimics the physiologic action of breathing: by periodically altering intrathoracic pressure, it causes air to flow in and out of the lungs. The iron lung is a form of non-invasive therapy.
The machine was invented by Philip Drinker and Louis Agassiz Shaw, of the Harvard School of Public Health, originally for treatment of coal gas poisoning. But it found its most famous use in the mid-1900s when victims of poliomyelitis (more commonly known as polio), stricken with paralysis (including of the diaphragm, the cone shaped muscle at the bottom of the rib-cage whose action controls intrathoracic pressure), became unable to breathe, and were placed in these steel chambers to survive. The first iron lung was used on October 12, 1928 at Children's Hospital, Boston, in a child unconscious from respiratory failure; her dramatic recovery, within seconds of being placed within the chamber, did much to popularize the "Drinker Respirator."
In 1931, inveterate tinkerer John Haven "Jack" Emerson unveiled an improved iron lung, which was smaller, cheaper, lighter, quieter, and much more reliable than Drinker's. Drinker and Harvard promptly sued Emerson for patent violations, which proved unwise. In the subsequent legal battles Emerson demonstrated that every aspect of Drinker's patents had been patented by others at earlier times. Emerson won the case, and Drinker's patents were declared invalid.
Entire hospital wards were filled with rows of Emerson iron lungs at the height of the polio outbreaks of the 1940s and 50s. With the success of the worldwide polio vaccination programs which have virtually eradicated the disease, and the advent of modern ventilators that control breathing via the direct intubation of the airway, the use of the iron lung has sharply declined.
The positive pressure ventilator, which instead blows air into the patient's lungs by intubation through the airway, was used for the first time in Blegdams Hospital, Copenhagen, Denmark during a polio outbreak in 1952. It proved a success and soon superseded the iron lung all over Europe.
The iron lung now has a marginal place in modern respiratory therapy. Most patients with paralysis of the breathing muscles use modern mechanical ventilators that push air into the airway with positive pressure. These are generally efficacious and have the advantage of not restricting patients' movements or caregivers' ability to examine the patients as significantly as an iron lung does. However, negative pressure ventilation is a truer approximation of normal physiological breathing and results in more normal distribution of air in the lungs. It may also be preferable in certain rare conditions, such as Ondine's curse, in which failure of the medullary respiratory centers at the base of the brain result in patients having no autonomic control of breathing. Thus, there are patients who still today use the older machines, often in their homes, despite the occasional difficulty in finding replacement parts.
Biphasic Cuirass Ventilation is a modern development of the iron lung, consisting of a wearable rigid upper-body shell (a cuirass) which functions as a negative pressure respirator. | Iron lung
An iron lung is a large machine that enables a person to breathe when normal muscle control has been lost or the work of breathing exceeds the person's ability. It is a form of medical ventilator. Properly, it is called a negative pressure ventilator.
The person using the iron lung is placed into the central chamber, a cylindrical steel drum. A door allowing the head and neck to remain free is then closed, forming a sealed, air-tight compartment enclosing the rest of the person's body. Pumps that control airflow periodically decrease and increase the air pressure within the chamber, and particularly, on the chest. When the pressure falls below that within the lungs, the lungs expand and air from outside the chamber is sucked in via the person's nose and airways to keep the lungs filled; when the pressure rises above that within the lungs, the reverse occurs, and air is expelled. In this manner, the iron lung mimics the physiologic action of breathing: by periodically altering intrathoracic pressure, it causes air to flow in and out of the lungs. The iron lung is a form of non-invasive therapy.
The machine was invented by Philip Drinker and Louis Agassiz Shaw, of the Harvard School of Public Health, originally for treatment of coal gas poisoning. But it found its most famous use in the mid-1900s when victims of poliomyelitis (more commonly known as polio), stricken with paralysis (including of the diaphragm, the cone shaped muscle at the bottom of the rib-cage whose action controls intrathoracic pressure), became unable to breathe, and were placed in these steel chambers to survive. The first iron lung was used on October 12, 1928 at Children's Hospital, Boston, in a child unconscious from respiratory failure; her dramatic recovery, within seconds of being placed within the chamber, did much to popularize the "Drinker Respirator."[1]
In 1931, inveterate tinkerer John Haven "Jack" Emerson unveiled an improved iron lung, which was smaller, cheaper, lighter, quieter, and much more reliable than Drinker's.[2] Drinker and Harvard promptly sued Emerson for patent violations, which proved unwise. In the subsequent legal battles Emerson demonstrated that every aspect of Drinker's patents had been patented by others at earlier times. Emerson won the case, and Drinker's patents were declared invalid.
Entire hospital wards were filled with rows of Emerson iron lungs at the height of the polio outbreaks of the 1940s and 50s. With the success of the worldwide polio vaccination programs which have virtually eradicated the disease, and the advent of modern ventilators that control breathing via the direct intubation of the airway, the use of the iron lung has sharply declined.
The positive pressure ventilator, which instead blows air into the patient's lungs by intubation through the airway, was used for the first time in Blegdams Hospital, Copenhagen, Denmark during a polio outbreak in 1952.[3] It proved a success and soon superseded the iron lung all over Europe.
The iron lung now has a marginal place in modern respiratory therapy. Most patients with paralysis of the breathing muscles use modern mechanical ventilators that push air into the airway with positive pressure. These are generally efficacious and have the advantage of not restricting patients' movements or caregivers' ability to examine the patients as significantly as an iron lung does. However, negative pressure ventilation is a truer approximation of normal physiological breathing and results in more normal distribution of air in the lungs. It may also be preferable in certain rare conditions, such as Ondine's curse, in which failure of the medullary respiratory centers at the base of the brain result in patients having no autonomic control of breathing. Thus, there are patients who still today use the older machines, often in their homes, despite the occasional difficulty in finding replacement parts.
Biphasic Cuirass Ventilation is a modern development of the iron lung, consisting of a wearable rigid upper-body shell (a cuirass) which functions as a negative pressure respirator. | https://www.wikidoc.org/index.php/Iron_lung | |
e6cbe5678c979f8295fba0d08d5d6cd52087a9a3 | wikidoc | Isobutane | Isobutane
Isobutane, also known as methylpropane or 2-methylpropane, is an alkane, isomeric with butane. Recent concerns with depletion of the ozone layer by freon gases have led to increased use of isobutane as a gas for refrigeration systems, especially in domestic refrigerators and freezers, and as a propellant in aerosol sprays. When used as a refrigerant or a propellant, isobutane is also known as R-600a. It is used as a feedstock in the petrochemical industry, for example in the synthesis of isooctane.
# Nomenclature
Isobutane is the trivial name retained by the International Union of Pure and Applied Chemistry (IUPAC) in its 1993 Recommendations for the Nomenclature of Organic Chemistry.
Methylpropane is the systematic name. The substituent number (2-) is unnecessary because there is no isomer of this molecule with methylpropane as part of its name. | Isobutane
Template:Chembox new
Isobutane, also known as methylpropane or 2-methylpropane, is an alkane, isomeric with butane. Recent concerns with depletion of the ozone layer by freon gases have led to increased use of isobutane as a gas for refrigeration systems, especially in domestic refrigerators and freezers, and as a propellant in aerosol sprays. When used as a refrigerant or a propellant, isobutane is also known as R-600a. It is used as a feedstock in the petrochemical industry, for example in the synthesis of isooctane.[1]
# Nomenclature
Isobutane is the trivial name retained by the International Union of Pure and Applied Chemistry (IUPAC) in its 1993 Recommendations for the Nomenclature of Organic Chemistry.[2]
Methylpropane is the systematic name. The substituent number (2-) is unnecessary because there is no isomer of this molecule with methylpropane as part of its name. | https://www.wikidoc.org/index.php/Isobutane | |
131fceeb5c5f8698ad7f20576b28cec3ae0e2713 | wikidoc | Isochoric | Isochoric
An isochoric process, also called an isometric process or an isovolumetric process, is a process during which volume remains constant. The name is derived from the Greek isos, "equal", and khora, "place."
If an ideal gas is used in an isochoric process, and the quantity of gas stays constant, then the increase in energy is proportional to an increase in temperature and pressure. Take for example a gas heated in a rigid container: the pressure and temperature of the gas will increase, but the volume will remain the same.
In the ideal Otto cycle we found an example of an isochoric process when we assume an instantaneous burning of the gasoline-air mixture in an internal combustion engine car. There is an increase in the temperature and the pressure of the gas inside the piston while the volume remains the same.
# Equations
If the volume stays constant (\Delta V = 0 ), this implies that the process does no pressure-volume work, since such work is defined by
where P is pressure (no minus sign; this is work done by the system).
By applying the first law of thermodynamics, we can deduce that \Delta U the change in the system's internal energy, is
for an isochoric process: all the heat being transferred to the system is added to the system's internal energy, U. If the quantity of gas stays constant, then this increase in energy is proportional to an increase in temperature,
where CV is molar specific heat for constant volume.
On a pressure volume diagram, an isochoric process appears as a straight vertical line. Its thermodynamic conjugate, an isobaric process would appear as a straight horizontal line. | Isochoric
An isochoric process, also called an isometric process or an isovolumetric process, is a process during which volume remains constant. The name is derived from the Greek isos, "equal", and khora, "place."
If an ideal gas is used in an isochoric process, and the quantity of gas stays constant, then the increase in energy is proportional to an increase in temperature and pressure. Take for example a gas heated in a rigid container: the pressure and temperature of the gas will increase, but the volume will remain the same.
In the ideal Otto cycle we found an example of an isochoric process when we assume an instantaneous burning of the gasoline-air mixture in an internal combustion engine car. There is an increase in the temperature and the pressure of the gas inside the piston while the volume remains the same.
# Equations
If the volume stays constant (<math>\Delta V = 0 </math>), this implies that the process does no pressure-volume work, since such work is defined by
where P is pressure (no minus sign; this is work done by the system).
By applying the first law of thermodynamics, we can deduce that <math> \Delta U </math> the change in the system's internal energy, is
for an isochoric process: all the heat being transferred to the system is added to the system's internal energy, U. If the quantity of gas stays constant, then this increase in energy is proportional to an increase in temperature,
where CV is molar specific heat for constant volume.
On a pressure volume diagram, an isochoric process appears as a straight vertical line. Its thermodynamic conjugate, an isobaric process would appear as a straight horizontal line. | https://www.wikidoc.org/index.php/Isochoric | |
d8a05d9a05c5a89e7e1e1bf4540e11e7a1775f1f | wikidoc | Isoindole | Isoindole
Isoindole in heterocyclic chemistry is a benzo fused pyrrole. The compound is an isomer of indole and its reduced form is an isoindoline.
In solution the non-aromatic tautomer is predominant:
and therefore the compound resembles a pyrrole more than a simple imine. Isoindoles are building blocks for phthalocyanines which are relevant as dyes
# Isoindole-1,3-diones
The commercially important phthalimide is an isoindole-1,3-dione with two carbonyl groups attached to the heterocyclic ring. Thalidomide is an infamous drug based on this framework. | Isoindole
Isoindole in heterocyclic chemistry is a benzo fused pyrrole.[1] The compound is an isomer of indole and its reduced form is an isoindoline.
In solution the non-aromatic tautomer is predominant:
and therefore the compound resembles a pyrrole more than a simple imine. Isoindoles are building blocks for phthalocyanines which are relevant as dyes
# Isoindole-1,3-diones
The commercially important phthalimide is an isoindole-1,3-dione with two carbonyl groups attached to the heterocyclic ring. Thalidomide is an infamous drug based on this framework. | https://www.wikidoc.org/index.php/Isoindole | |
0fedbac69267fb56199c28a856d26ce20cb1b618 | wikidoc | Terpenoid | Terpenoid
The terpenoids, sometimes referred to as isoprenoids, are a large and diverse class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures which differ from one another not only in functional groups, but also in their basic carbon skeletons. These lipids can be found in all classes of living things, and are the largest group of natural products.
Plant terpenoids are extensively used for their aromatic qualities. They play a role in traditional herbal remedies and are under investigation for antibacterial, antineoplastic and other pharmaceutical effects.
Terpenoids contribute to the scent of eucalyptus, the flavors of cinnamon, cloves and ginger and the color of yellow flowers. Well-known terpenoids include citral, menthol, camphor and the cannabinoids found in the Cannabis plant.
The steroids and sterols in animals are biologically produced from terpenoid precursors. Sometimes terpenoids are added to proteins, e.g. to enhance their attachment to the cell membrane; this is known as isoprenylation.
Many of these are substrates for plant Cytochrome P450.
# Structure and classification
Terpenes are hydrocarbons resulting from the combination of several isoprene units. Terpenoids can be thought of as modified terpenes, where methyl groups have been moved or removed, or oxygen atoms added. (Some authors use the term "terpene" more broadly, to include the terpenoids.) Just like terpenes, the terpenoids can be classified according to the number of isoprene units used:
- Monoterpenoids, 2 isoprene units
- Sesquiterpenoids, 3 isoprene units
- Diterpenoids, 4 isoprene units
- Sesterterpenoids, 5 isoprene units
- Triterpenoids, 6 isoprene units
- Tetraterpenoids, 8 isoprene units
- Polyterpenoids with a larger number of isoprene units
Terpenoids can also be classified according to the number of cyclic structures they contain.
# Biosynthesis
There are two metabolic pathways of creating terpenoids:
## Mevalonic acid pathway
Many organisms manufacture terpenoids through the HMG-CoA reductase pathway,
the pathway that also produces cholesterol. The reactions take place in the cytosol. The pathway was discovered in the 1950s.
## MEP/DOXP pathway
The 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate pathway (MEP/DOXP pathway), also known as non-mevalonate pathway or mevalonic acid independent pathway, takes place in the plastids of plants and apicomplexan protozoa as well as in many bacteria. It was discovered in the late 1980s.
Pyruvate and glyceraldehyde 3-phosphate are converted by DOXP synthase (Dxs) to 1-deoxy-D-xylulose 5-phosphate, and by DOXP reductase (Dxr, IspC) to 2-C-methyl-D-erythritol 4-phosphate (MEP). The subsequent three reaction steps catalyzed by 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase (YgbP, IspD), 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (YchB, IspE), and 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (YgbB, IspF) mediate the formation of 2-C-methyl-D-erythritol 2,4-cyclopyrophosphate (MEcPP). Finally, MEcPP is converted to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) by HMB-PP synthase (GcpE, IspG), and HMB-PP is converted to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) by HMB-PP reductase (LytB, IspH).
IPP and DMAPP are the end products in either pathway, and are the precursors of isoprene, monoterpenoids (10-carbon), diterpenoids (20-carbon), carotenoids (40-carbon), chlorophylls and plastoquinone-9 (45-carbon). Synthesis of all higher terpenoids proceeds via formation of geranyl pyrophosphate (GPP), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP).
Although both pathways, MVA and MEP, are mutually exclusive in most organisms, interactions between them have been reported in plants and few bacteria species. | Terpenoid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The terpenoids, sometimes referred to as isoprenoids, are a large and diverse class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. Most are multicyclic structures which differ from one another not only in functional groups, but also in their basic carbon skeletons. These lipids can be found in all classes of living things, and are the largest group of natural products.
Plant terpenoids are extensively used for their aromatic qualities. They play a role in traditional herbal remedies and are under investigation for antibacterial, antineoplastic and other pharmaceutical effects.
Terpenoids contribute to the scent of eucalyptus, the flavors of cinnamon, cloves and ginger and the color of yellow flowers. Well-known terpenoids include citral, menthol, camphor and the cannabinoids found in the Cannabis plant.
The steroids and sterols in animals are biologically produced from terpenoid precursors. Sometimes terpenoids are added to proteins, e.g. to enhance their attachment to the cell membrane; this is known as isoprenylation.
Many of these are substrates for plant Cytochrome P450.
# Structure and classification
Terpenes are hydrocarbons resulting from the combination of several isoprene units. Terpenoids can be thought of as modified terpenes, where methyl groups have been moved or removed, or oxygen atoms added. (Some authors use the term "terpene" more broadly, to include the terpenoids.) Just like terpenes, the terpenoids can be classified according to the number of isoprene units used:
- Monoterpenoids, 2 isoprene units
- Sesquiterpenoids, 3 isoprene units
- Diterpenoids, 4 isoprene units
- Sesterterpenoids, 5 isoprene units
- Triterpenoids, 6 isoprene units
- Tetraterpenoids, 8 isoprene units
- Polyterpenoids with a larger number of isoprene units
Terpenoids can also be classified according to the number of cyclic structures they contain.
# Biosynthesis
There are two metabolic pathways of creating terpenoids:
## Mevalonic acid pathway
Many organisms manufacture terpenoids through the HMG-CoA reductase pathway,
the pathway that also produces cholesterol. The reactions take place in the cytosol. The pathway was discovered in the 1950s.
## MEP/DOXP pathway
The 2-C-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate pathway (MEP/DOXP pathway), also known as non-mevalonate pathway or mevalonic acid independent pathway, takes place in the plastids of plants and apicomplexan protozoa as well as in many bacteria. It was discovered in the late 1980s.
Pyruvate and glyceraldehyde 3-phosphate are converted by DOXP synthase (Dxs) to 1-deoxy-D-xylulose 5-phosphate, and by DOXP reductase (Dxr, IspC) to 2-C-methyl-D-erythritol 4-phosphate (MEP). The subsequent three reaction steps catalyzed by 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase (YgbP, IspD), 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase (YchB, IspE), and 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (YgbB, IspF) mediate the formation of 2-C-methyl-D-erythritol 2,4-cyclopyrophosphate (MEcPP). Finally, MEcPP is converted to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) by HMB-PP synthase (GcpE, IspG), and HMB-PP is converted to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) by HMB-PP reductase (LytB, IspH).
IPP and DMAPP are the end products in either pathway, and are the precursors of isoprene, monoterpenoids (10-carbon), diterpenoids (20-carbon), carotenoids (40-carbon), chlorophylls and plastoquinone-9 (45-carbon). Synthesis of all higher terpenoids proceeds via formation of geranyl pyrophosphate (GPP), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP).
Although both pathways, MVA and MEP, are mutually exclusive in most organisms, interactions between them have been reported in plants and few bacteria species. | https://www.wikidoc.org/index.php/Isoprenoid | |
85c36b984aeafcd6750bff14b8f3203169830683 | wikidoc | Iva annua | Iva annua
# Overview
Iva annua, sumpweed or marshelder, is an herbaceous annual plant native to much of North America.
# Uses
Iva annua var. macrocarpa was formerly cultivated by Native Americans in the central eastern United States and specifically the indigenous peoples of the Kansas City Hopewell culture in present day Missouri and Illinois, for its edible seed. As the author Jared Diamond notes, the edible parts contain 32 percent protein and 45 percent oil.
However, like its relative ragweed, Diamond notes that sumpweed possesses many objectionable qualities which include being a severe allergen, possessing "a strong odor objectionable to some people and that handling it can cause skin irritation." For these reasons Diamond believes that it was abandoned once more pleasant alternatives (like corn) were available, and by the time Europeans arrived in the Americas, had long disappeared as a crop.
# Notes
- ↑ Jared Diamond (2003). Guns, Germs and Steel. New York: Norton. p. 151..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} | Iva annua
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Iva annua, sumpweed or marshelder, is an herbaceous annual plant native to much of North America.
# Uses
Iva annua var. macrocarpa was formerly cultivated by Native Americans in the central eastern United States and specifically the indigenous peoples of the Kansas City Hopewell culture in present day Missouri and Illinois, for its edible seed. As the author Jared Diamond notes, the edible parts contain 32 percent protein and 45 percent oil.
However, like its relative ragweed, Diamond notes that sumpweed possesses many objectionable qualities which include being a severe allergen, possessing "a strong odor objectionable to some people and that handling it can cause skin irritation." For these reasons Diamond believes that it was abandoned once more pleasant alternatives (like corn) were available, and by the time Europeans arrived in the Americas, had long disappeared as a crop.[1]
# Notes
- ↑ Jared Diamond (2003). Guns, Germs and Steel. New York: Norton. p. 151..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}
# External links
- "Iva annua L." MissouriPlants.com. External link in |publisher= (help) Includes photographs.
Template:Agri-stub | https://www.wikidoc.org/index.php/Iva_annua | |
7a77340aca0f39eaa040d92a0ff2b419bdf06629 | wikidoc | Ivacaftor | Ivacaftor
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# Overview
Ivacaftor is a cystic fibrosis transmembrane conductance regulator that is FDA approved for the treatment of cystic fibrosis. Common adverse reactions include headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: One 150 mg tablet taken orally every 12 hours (300 mg total daily dose) with fat-containing food. Examples of appropriate fat-containing foods include eggs, butter, peanut butter, cheese pizza,
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ivacaftor in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ivacaftor in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosage: One 150 mg tablet taken orally every 12 hours (300 mg total daily dose) with fat-containing food. Examples of appropriate fat-containing foods include eggs, butter, peanut butter, cheese pizza,
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ivacaftor in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ivacaftor in pediatric patients.
# Contraindications
None
# Warnings
- Elevated transaminases have been reported in patients with CF receiving Ivacaftor. It is recommended that ALT and AST be assessed prior to initiating Ivacaftor every 3 months during the first year of treatment, and annually thereafter. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming Ivacaftor dosing.
- Use of Ivacaftor with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of Ivacaftor Therefore, co-administration of Ivacaftor with strong CYP3A inducers (e.g., rifampin, St. John's Wort) is not recommended.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The overall safety profile of Ivacaftor is based on pooled data from three placebo-controlled clinical trials conducted in 353 patients with CF who had a G551D mutation in the CFTR gene (Trials 1 and 2) or were homozygous for the F508del mutation (Trial 3). In addition, an 8-week crossover design trial (Trial 4) involving 39 patients with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene was conducted. Patients treated with Ivacaftor in these trials were between the ages of 6 and 57 years.
- Of the 353 patients included in the pooled analyses of patients with CF who had either a G551D mutation or were homozygous for the F508del mutation in the CFTR gene, 50% of patients were female and 97% were Caucasian; 221 received Ivacaftor and 132 received placebo from 16 to 48 weeks. The proportion of patients who prematurely discontinued study drug due to adverse reactions was 2% for Ivacaftor-treated patients and 5% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in Ivacaftor-treated patients included abdominal pain, increased hepatic enzymes, and hypoglycemia.
- The most common adverse reactions in the 221 patients treated with Ivacaftor were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea]] (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%).
- The incidence of adverse reactions below is based upon two double-blind, placebo-controlled, 48-week clinical trials (Trials 1 and 2) in a total of 213 patients with CF ages 6 to 53 who have a G551D mutation in the CFTR gene and who were treated with Ivacaftor 150 mg orally or placebo twice daily. Table 1 shows adverse reactions occurring in ≥8% of Ivacaftor-treated patients with CF who have a G551D mutation in the CFTR gene that also occurred at a higher rate than in the placebo-treated patients in the two double-blind, placebo-controlled trials.
Adverse reactions in the 48-week clinical trials that occurred in the Ivacaftor group at a frequency of 4 to 7% where rates exceeded that in the placebo group include:
- Infections and infestations: rhinitis
- Investigations: aspartate aminotransferase increased, bacteria in sputum, blood glucose increased, hepatic enzyme increased
- Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, myalgia
- Nervous system disorders: sinus headache
- Respiratory, thoracic and mediastinal disorders: pharyngeal erythema, pleuritic pain, sinus congestion, wheezing.
- Skin and subcutaneous tissue disorders: acne
- Laboratory abnormalities:
Transaminase Elevations: During 48-week placebo-controlled clinical studies, the incidence of maximum transaminase (ALT or AST) >8, >5 or >3 × ULN was 2%, 3% and 6% in Ivacaftor-treated patients and 2%, 2% and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5 %) on Ivacaftor permanently discontinued treatment for elevated transaminases, all >8 × ULN. Two patients treated with Ivacaftor were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo.
- Transaminase Elevations: During 48-week placebo-controlled clinical studies, the incidence of maximum transaminase (ALT or AST) >8, >5 or >3 × ULN was 2%, 3% and 6% in Ivacaftor-treated patients and 2%, 2% and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5 %) on Ivacaftor permanently discontinued treatment for elevated transaminases, all >8 × ULN. Two patients treated with Ivacaftor were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo.
## Postmarketing Experience
There is limited information regarding Ivacaftor Postmarketing Experience in the drug label.
# Drug Interactions
- Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure measured as area under the curve (AUC) by 8.5-fold. Based on simulations of these results, a reduction of the Ivacaftor dose to 150 mg twice a week is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin. Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the Ivacaftor dose to 150 mg once daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.
- Co-administration of Ivacaftor with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, food containing grapefruit or Seville oranges should be avoided during treatment with Ivacaftor.
- Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's Wort is not recommended.
## Potential for ivacaftor to affect other drugs
- Ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of Ivacaftor may increase systemic exposure of drugs that are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse events. Therefore, caution and appropriate monitoring are recommended when co-administering Ivacaftor with CYP3A and/or P-gp substrates, such as digoxin, cyclosporine, and tacrolimus.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies of Ivacaftor in pregnant women. Ivacaftor was not teratogenic in rats at approximately 6 times the maximum recommended human dose (MRHD) (based on summed AUCs for ivacaftor and its metabolites at a maternal dose of 200 mg/kg/day). Ivacaftor was not teratogenic in rabbits at approximately 12 times the MRHD (on an ivacaftor AUC basis at a maternal dose of 100 mg/kg/day, respectively). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. Because animal reproduction studies are not always predictive of human response, Ivacaftor should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ivacaftor in women who are pregnant.
### Labor and Delivery
- Ivacaftor is excreted into the milk of lactating female rats. Excretion of ivacaftor into human milk is probable. There are no human studies that have investigated the effects of ivacaftor on breast-fed infants. Caution should be exercised when Ivacaftor is administered to a nursing woman.
### Nursing Mothers
There is no FDA guidance on the use of Ivacaftor in women who are nursing.
### Pediatric Use
- The safety and efficacy of Ivacaftor in patients 6 to 17 years of age with CF who have a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene has been demonstrated.
- The safety and efficacy of Ivacaftor in patients with CF younger than age 6 years have not been established.
### Geriatic Use
- CF is largely a disease of children and young adults. Clinical trials of Ivacaftor did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.
### Gender
- The effect of gender on Ivacaftor pharmacokinetics was evaluated using population pharmacokinetics of data from clinical studies of Ivacaftor No dose adjustments are necessary based on gender.
### Race
There is no FDA guidance on the use of Ivacaftor with respect to specific racial populations.
### Renal Impairment
- Ivacaftor has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is necessary for patients with mild to moderate renal impairment; however, caution is recommended while using Ivacaftor in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.
- Ivacaftor has not been studied in patients with mild, moderate or severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or in patients with end-stage renal disease. No dose adjustments are recommended for mild and moderate renal impairment patients because of minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine in a human PK study); however, caution is recommended when administering Ivacaftor to patients with severe renal impairment or end-stage renal disease.
### Hepatic Impairment
- No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose of 150 mg once daily is recommended in patients with moderate hepatic impairment (Child-Pugh Class B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C) but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a dose of 150 mg once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment.
- Patients with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax, but an approximately two-fold increase in ivacaftor AUC0-∞ compared with healthy subjects matched for demographics. Based on simulations of these results, a reduced Ivacaftor dose of 150 mg once daily is recommended for patients with moderate hepatic impairment. The impact of mild hepatic impairment (Child-Pugh Class A) on pharmacokinetics of ivacaftor has not been studied, but the increase in ivacaftor AUC0-∞ is expected to be less than two-fold. Therefore, no dose adjustment is necessary for patients with mild hepatic impairment. The impact of severe hepatic impairment (Child-Pugh Class C, score 10-15) on pharmacokinetics of ivacaftor has not been studied. The magnitude of increase in exposure in these patients is unknown but is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, Ivacaftor should be used with caution in patients with severe hepatic impairment at a dose of 150 mg given once daily or less frequently.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ivacaftor in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ivacaftor in patients who are immunocompromised.
### Patients with CF who are Homozygous for the F508del Mutation in the CFTR Gene
- Efficacy results from a double-blind, placebo-controlled trial in patients with CF who are homozygous for the F508del mutation in the CFTR gene showed no statistically significant difference in forced expiratory volume exhaled in one second (FEV1) over 16 weeks of Ivacaftor treatment compared to placebo. Therefore, Ivacaftor should not be used in patients homozygous for the F508del mutation in the CFTR gene.
# Administration and Monitoring
### Administration
There is limited information regarding Ivacaftor Administration in the drug label.
### Monitoring
There is limited information regarding Ivacaftor Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ivacaftor and IV administrations.
# Overdosage
- There have been no reports of overdose with Ivacaftor. The highest single dose used in a clinical study was 800 mg in a solution formulation without any treatment-related adverse events.
- The highest repeated dose was 450 mg (in a tablet formulation) every 12 hours for 4.5 days (9 doses) in a trial evaluating the effect of Ivacaftor on ECGs in healthy subjects. Adverse events reported at a higher incidence compared to placebo included dizziness and diarrhea.
- No specific antidote is available for overdose with Ivacaftor Treatment of overdose with Ivacaftor consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
# Pharmacology
## Mechanism of Action
- Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein.
- In vitro, ivacaftor increased CFTR-mediated transepithelial current (IT) in rodent cells expressing the G551D-CFTR protein following addition of a cyclic adenosine monophosphate (cAMP) agonist with an EC50 of 100 ± 47 nM; however, ivacaftor did not increase IT in the absence of cAMP agonist. Ivacaftor also increased IT in human bronchial epithelial cells expressing G551D-CFTR protein following addition of a cAMP agonist by 10-fold with an EC50 of 236 ± 200 nM. Ivacaftor increased the open probability of G551D-CFTR protein in single channel patch clamp experiments using membrane patches from rodent cells expressing G551D-CFTR protein by 6-fold versus untreated cells after addition of PKA and ATP. In addition to G551D-CFTR, ivacaftor increased the channel-open probability of other mutant CFTR forms expressed in rodent cells, resulting in enhanced CFTR-mediated IT. These mutant CFTR forms included G178R-, S549N-, S549R-, G551S-, G970R-, G1244E-, S1251N-, S1255P-, and G1349D-CFTR. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.
## Structure
- Its molecular formula is C24H28N2O3 and its molecular weight is 392.49. Ivacaftor has the following structural formula:
## Pharmacodynamics
- Changes in sweat chloride response to Ivacaftor were evaluated in four clinical trials. In two randomized, double-blind, placebo-controlled clinical trials in patients with a G551D mutation in the CFTR gene, one in patients 12 and older (Trial 1) and the other in patients 6-11 years of age (Trial 2), the treatment difference (between Ivacaftor and placebo) in mean change in sweat chloride from baseline through Week 24 was -48 mmol/L (95% CI -51, -45) and -54 mmol/L (95% CI -62, -47), respectively. These changes persisted through 48 weeks. In a 16-week randomized, double-blind, placebo-controlled, parallel-group clinical trial in patients with CF age 12-years and older who were homozygous for the F508del mutation in the CFTR gene (Trial 3), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -3 mmol/L (95% CI -6, -0.2). In a two-part, randomized, double-blind, placebo-controlled, crossover clinical trial in patients with CF who had a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene (Trial 4), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -49 mmol/L (95% CI -57, -41). In Trial 4, mean changes in sweat chloride for the mutations for which Ivacaftor is indicated ranged from -51 to -78, whereas the range for individual subjects with the G970R mutations was -1 to -11 mmol/L. There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1).
- The effect of multiple doses of ivacaftor 150 mg and 450 mg twice daily on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia's correction method (QTcF) was below 10 ms, the threshold for regulatory concern.
## Pharmacokinetics
- The pharmacokinetics of ivacaftor is similar between healthy adult volunteers and patients with CF.
After oral administration of a single 150 mg dose to healthy volunteers in a fed state, peak plasma concentrations (Tmax) occurred at approximately 4 hours, and the mean (±SD) for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively.
- After every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.
- The exposure of ivacaftor increased approximately 2- to 4-fold when given with food containing fat. Therefore, Ivacaftor should be administered with fat-containing food. Examples of fat-containing foods include eggs, butter, peanut butter, and cheese pizza. The median (range) Tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.
- Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells. The mean apparent volume of distribution (Vz/F) of ivacaftor after a single dose of 275 mg of Ivacaftor in the fed state was similar for healthy subjects and patients with CF. After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.
- Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.
- Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose. The mean apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.
## Nonclinical Toxicology
There is limited information regarding Ivacaftor Nonclinical Toxicology in the drug label.
# Clinical Studies
### Trials in Patients with CF who have a G551D Mutation in the CFTR Gene
- Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, crossover trial in 39 adult (mean age 31 years) Caucasian patients with CF who had FEV1 ≥40% predicted. Twenty patients with median predicted FEV1 at baseline of 56% (range: 42% to 109%) received Ivacaftor 25, 75, 150 mg or placebo every 12 hours for 14 days and 19 patients with median predicted FEV1 at baseline of 69% (range: 40% to 122%) received Ivacaftor 150, 250 mg or placebo every 12 hours for 28 days. The selection of the 150 mg every 12 hours dose was primarily based on nominal improvements in lung function (pre-dose FEV1) and changes in pharmacodynamic parameters (sweat chloride and nasal potential difference). The twice-daily dosing regimen was primarily based on an apparent terminal plasma half-life of approximately 12 hours. Selection of the 150 mg dose of Ivacaftor for children 6 to 11 years of age was based on achievement of comparable pharmacokinetics as those observed for adult patients.
- The efficacy of Ivacaftor in patients with CF who have a G551D mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled clinical trials in 213 clinically stable patients with CF (109 receiving Ivacaftor 150 mg twice daily). All eligible patients from these trials were rolled over into an open-label extension study.
- Trial 1 evaluated 161 patients with CF who were 12 years of age or older (mean age 26 years) with FEV1 at screening between 40-90% predicted . Trial 2 evaluated 52 patients who were 6 to 11 years of age (mean age 9 years) with FEV1 at screening between 40-105% predicted . Patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the upper limit of normal were excluded.
- Patients in both trials were randomized 1:1 to receive either 150 mg of Ivacaftor or placebo every 12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies (e.g., tobramycin, dornase alfa). The use of inhaled hypertonic saline was not permitted. The primary efficacy endpoint in both studies was improvement in lung function as determined by the mean absolute change from baseline in percent predicted pre-dose FEV1 through 24 weeks of treatment.
- In both studies, treatment with Ivacaftor resulted in a significant improvement in FEV1. The treatment difference between Ivacaftor and placebo for the mean absolute change in percent predicted FEV1 from baseline through Week 24 was 10.6 percentage points (P < 0.0001) in Trial 1 and 12.5 percentage points (P < 0.0001) in Trial 2 (Figure 3). These changes persisted through 48 weeks. Improvements in percent predicted FEV1 were observed regardless of age, disease severity, sex, and geographic region.
- Other efficacy variables included absolute change in sweat chloride from baseline to Week 24, time to first pulmonary exacerbation through Week 48 (Trial 1 only), absolute change in weight from baseline to Week 48, and improvement in cystic fibrosis symptoms including relevant respiratory symptoms such as cough, sputum production, and difficulty breathing. For the purpose of the study, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Patients treated with Ivacaftor demonstrated statistically significant improvements in risk of pulmonary exacerbations, CF symptoms (in Trial 1 only), and gain in body weight (Table 2). Weight data, when expressed as body mass index normalized for age and sex in patients <20 years of age, was consistent with absolute change from baseline in weight.
### Trial in Patients with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R Mutation in the CFTR Gene
- The efficacy and safety of Ivacaftor in patients with CF who have a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene were evaluated in a two-part, randomized, double-blind, placebo-controlled, crossover design clinical trial in 39 patients with CF (Trial 4). Patients who completed Part 1 of this trial continued into the 16-week open-label Part 2 of the study. The mutations studied were G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D. for efficacy in patients with a G551D mutation.
- Patients were 6 years of age or older (mean age 23 years) with FEV1 ≥40% at screening . Patients with evidence of colonization with Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the upper limit of normal at screening were excluded.
- Patients were randomized 1:1 to receive either 150 mg of Ivacaftor or placebo every 12 hours with food containing fat for 8 weeks in addition to their prescribed CF therapies during the first treatment period and crossed over to the other treatment for the second 8 weeks. The two 8-week treatment periods were separated by a 4- to 8-week washout period. The use of inhaled hypertonic saline was not permitted.
- The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through 8 weeks of treatment. Other efficacy variables included absolute change from baseline in sweat chloride through 8 weeks of treatment, absolute change from baseline in body mass index (BMI) at 8 weeks of treatment (including body weight at 8 weeks), and improvement in cystic fibrosis symptoms (including relevant respiratory symptoms such as cough, sputum production, and difficulty breathing) through 8 weeks of treatment. For the overall population of the 9 mutations studied, treatment with Ivacaftor compared to placebo resulted in significant improvement in percent predicted FEV1 , BMI , and cystic fibrosis respiratory symptom score ; however, there was a high degree of variability of efficacy responses among the 9 mutations (Table 3). Based on clinical and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established.
### Trial in Patients Homozygous for the F508del Mutation in the CFTR Gene
- Trial 3 was a 16-week randomized, double-blind, placebo-controlled, parallel-group trial in 140 patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥40% predicted. Patients were randomized 4:1 to receive Ivacaftor 150 mg (n=112) every twelve hours or placebo (n=28) in addition to their prescribed CF therapies. The mean age of patients enrolled was 23 years and the mean baseline FEV1 was 79% predicted (range 40% to 129%). As in Trials 1 and 2, patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the upper limit of normal were excluded. The use of inhaled hypertonic saline was not permitted.
- The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline through Week 16 in percent predicted FEV1. Treatment with Ivacaftor resulted in no improvement in FEV1 relative to placebo in patients with CF homozygous for the F508del mutation in the CFTR gene . There were no meaningful differences between patients treated with Ivacaftor compared to placebo for secondary endpoints (change in CF symptoms, change in weight, or change in sweat chloride concentration).
# How Supplied
## Storage
Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ivacaftor Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Ivacaftor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Kalydeco
# Look-Alike Drug Names
There is limited information regarding Ivacaftor Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ivacaftor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Ivacaftor is a cystic fibrosis transmembrane conductance regulator that is FDA approved for the treatment of cystic fibrosis. Common adverse reactions include headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: One 150 mg tablet taken orally every 12 hours (300 mg total daily dose) with fat-containing food. Examples of appropriate fat-containing foods include eggs, butter, peanut butter, cheese pizza,
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ivacaftor in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ivacaftor in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosage: One 150 mg tablet taken orally every 12 hours (300 mg total daily dose) with fat-containing food. Examples of appropriate fat-containing foods include eggs, butter, peanut butter, cheese pizza,
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ivacaftor in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ivacaftor in pediatric patients.
# Contraindications
None
# Warnings
- Elevated transaminases have been reported in patients with CF receiving Ivacaftor. It is recommended that ALT and AST be assessed prior to initiating Ivacaftor every 3 months during the first year of treatment, and annually thereafter. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming Ivacaftor dosing.
- Use of Ivacaftor with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of Ivacaftor Therefore, co-administration of Ivacaftor with strong CYP3A inducers (e.g., rifampin, St. John's Wort) is not recommended.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The overall safety profile of Ivacaftor is based on pooled data from three placebo-controlled clinical trials conducted in 353 patients with CF who had a G551D mutation in the CFTR gene (Trials 1 and 2) or were homozygous for the F508del mutation (Trial 3). In addition, an 8-week crossover design trial (Trial 4) involving 39 patients with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene was conducted. Patients treated with Ivacaftor in these trials were between the ages of 6 and 57 years.
- Of the 353 patients included in the pooled analyses of patients with CF who had either a G551D mutation or were homozygous for the F508del mutation in the CFTR gene, 50% of patients were female and 97% were Caucasian; 221 received Ivacaftor and 132 received placebo from 16 to 48 weeks. The proportion of patients who prematurely discontinued study drug due to adverse reactions was 2% for Ivacaftor-treated patients and 5% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in Ivacaftor-treated patients included abdominal pain, increased hepatic enzymes, and hypoglycemia.
- The most common adverse reactions in the 221 patients treated with Ivacaftor were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea]] (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%).
- The incidence of adverse reactions below is based upon two double-blind, placebo-controlled, 48-week clinical trials (Trials 1 and 2) in a total of 213 patients with CF ages 6 to 53 who have a G551D mutation in the CFTR gene and who were treated with Ivacaftor 150 mg orally or placebo twice daily. Table 1 shows adverse reactions occurring in ≥8% of Ivacaftor-treated patients with CF who have a G551D mutation in the CFTR gene that also occurred at a higher rate than in the placebo-treated patients in the two double-blind, placebo-controlled trials.
Adverse reactions in the 48-week clinical trials that occurred in the Ivacaftor group at a frequency of 4 to 7% where rates exceeded that in the placebo group include:
- Infections and infestations: rhinitis
- Investigations: aspartate aminotransferase increased, bacteria in sputum, blood glucose increased, hepatic enzyme increased
- Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, myalgia
- Nervous system disorders: sinus headache
- Respiratory, thoracic and mediastinal disorders: pharyngeal erythema, pleuritic pain, sinus congestion, wheezing.
- Skin and subcutaneous tissue disorders: acne
- Laboratory abnormalities:
Transaminase Elevations: During 48-week placebo-controlled clinical studies, the incidence of maximum transaminase (ALT or AST) >8, >5 or >3 × ULN was 2%, 3% and 6% in Ivacaftor-treated patients and 2%, 2% and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5 %) on Ivacaftor permanently discontinued treatment for elevated transaminases, all >8 × ULN. Two patients treated with Ivacaftor were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo.
- Transaminase Elevations: During 48-week placebo-controlled clinical studies, the incidence of maximum transaminase (ALT or AST) >8, >5 or >3 × ULN was 2%, 3% and 6% in Ivacaftor-treated patients and 2%, 2% and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5 %) on Ivacaftor permanently discontinued treatment for elevated transaminases, all >8 × ULN. Two patients treated with Ivacaftor were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo.
## Postmarketing Experience
There is limited information regarding Ivacaftor Postmarketing Experience in the drug label.
# Drug Interactions
- Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure measured as area under the curve (AUC) by 8.5-fold. Based on simulations of these results, a reduction of the Ivacaftor dose to 150 mg twice a week is recommended for co-administration with strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin. Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the Ivacaftor dose to 150 mg once daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.
- Co-administration of Ivacaftor with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, food containing grapefruit or Seville oranges should be avoided during treatment with Ivacaftor.
- Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's Wort is not recommended.
## Potential for ivacaftor to affect other drugs
- Ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of Ivacaftor may increase systemic exposure of drugs that are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse events. Therefore, caution and appropriate monitoring are recommended when co-administering Ivacaftor with CYP3A and/or P-gp substrates, such as digoxin, cyclosporine, and tacrolimus.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There are no adequate and well-controlled studies of Ivacaftor in pregnant women. Ivacaftor was not teratogenic in rats at approximately 6 times the maximum recommended human dose (MRHD) (based on summed AUCs for ivacaftor and its metabolites at a maternal dose of 200 mg/kg/day). Ivacaftor was not teratogenic in rabbits at approximately 12 times the MRHD (on an ivacaftor AUC basis at a maternal dose of 100 mg/kg/day, respectively). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. Because animal reproduction studies are not always predictive of human response, Ivacaftor should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ivacaftor in women who are pregnant.
### Labor and Delivery
- Ivacaftor is excreted into the milk of lactating female rats. Excretion of ivacaftor into human milk is probable. There are no human studies that have investigated the effects of ivacaftor on breast-fed infants. Caution should be exercised when Ivacaftor is administered to a nursing woman.
### Nursing Mothers
There is no FDA guidance on the use of Ivacaftor in women who are nursing.
### Pediatric Use
- The safety and efficacy of Ivacaftor in patients 6 to 17 years of age with CF who have a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene has been demonstrated.
- The safety and efficacy of Ivacaftor in patients with CF younger than age 6 years have not been established.
### Geriatic Use
- CF is largely a disease of children and young adults. Clinical trials of Ivacaftor did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.
### Gender
- The effect of gender on Ivacaftor pharmacokinetics was evaluated using population pharmacokinetics of data from clinical studies of Ivacaftor No dose adjustments are necessary based on gender.
### Race
There is no FDA guidance on the use of Ivacaftor with respect to specific racial populations.
### Renal Impairment
- Ivacaftor has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is necessary for patients with mild to moderate renal impairment; however, caution is recommended while using Ivacaftor in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.
- Ivacaftor has not been studied in patients with mild, moderate or severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or in patients with end-stage renal disease. No dose adjustments are recommended for mild and moderate renal impairment patients because of minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine in a human PK study); however, caution is recommended when administering Ivacaftor to patients with severe renal impairment or end-stage renal disease.
### Hepatic Impairment
- No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dose of 150 mg once daily is recommended in patients with moderate hepatic impairment (Child-Pugh Class B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C) but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a dose of 150 mg once daily or less frequently in patients with severe hepatic impairment after weighing the risks and benefits of treatment.
- Patients with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax, but an approximately two-fold increase in ivacaftor AUC0-∞ compared with healthy subjects matched for demographics. Based on simulations of these results, a reduced Ivacaftor dose of 150 mg once daily is recommended for patients with moderate hepatic impairment. The impact of mild hepatic impairment (Child-Pugh Class A) on pharmacokinetics of ivacaftor has not been studied, but the increase in ivacaftor AUC0-∞ is expected to be less than two-fold. Therefore, no dose adjustment is necessary for patients with mild hepatic impairment. The impact of severe hepatic impairment (Child-Pugh Class C, score 10-15) on pharmacokinetics of ivacaftor has not been studied. The magnitude of increase in exposure in these patients is unknown but is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, Ivacaftor should be used with caution in patients with severe hepatic impairment at a dose of 150 mg given once daily or less frequently.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ivacaftor in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ivacaftor in patients who are immunocompromised.
### Patients with CF who are Homozygous for the F508del Mutation in the CFTR Gene
- Efficacy results from a double-blind, placebo-controlled trial in patients with CF who are homozygous for the F508del mutation in the CFTR gene showed no statistically significant difference in forced expiratory volume exhaled in one second (FEV1) over 16 weeks of Ivacaftor treatment compared to placebo. Therefore, Ivacaftor should not be used in patients homozygous for the F508del mutation in the CFTR gene.
# Administration and Monitoring
### Administration
There is limited information regarding Ivacaftor Administration in the drug label.
### Monitoring
There is limited information regarding Ivacaftor Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ivacaftor and IV administrations.
# Overdosage
- There have been no reports of overdose with Ivacaftor. The highest single dose used in a clinical study was 800 mg in a solution formulation without any treatment-related adverse events.
- The highest repeated dose was 450 mg (in a tablet formulation) every 12 hours for 4.5 days (9 doses) in a trial evaluating the effect of Ivacaftor on ECGs in healthy subjects. Adverse events reported at a higher incidence compared to placebo included dizziness and diarrhea.
- No specific antidote is available for overdose with Ivacaftor Treatment of overdose with Ivacaftor consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
# Pharmacology
## Mechanism of Action
- Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein.
- In vitro, ivacaftor increased CFTR-mediated transepithelial current (IT) in rodent cells expressing the G551D-CFTR protein following addition of a cyclic adenosine monophosphate (cAMP) agonist with an EC50 of 100 ± 47 nM; however, ivacaftor did not increase IT in the absence of cAMP agonist. Ivacaftor also increased IT in human bronchial epithelial cells expressing G551D-CFTR protein following addition of a cAMP agonist by 10-fold with an EC50 of 236 ± 200 nM. Ivacaftor increased the open probability of G551D-CFTR protein in single channel patch clamp experiments using membrane patches from rodent cells expressing G551D-CFTR protein by 6-fold versus untreated cells after addition of PKA and ATP. In addition to G551D-CFTR, ivacaftor increased the channel-open probability of other mutant CFTR forms expressed in rodent cells, resulting in enhanced CFTR-mediated IT. These mutant CFTR forms included G178R-, S549N-, S549R-, G551S-, G970R-, G1244E-, S1251N-, S1255P-, and G1349D-CFTR. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.
## Structure
- Its molecular formula is C24H28N2O3 and its molecular weight is 392.49. Ivacaftor has the following structural formula:
## Pharmacodynamics
- Changes in sweat chloride response to Ivacaftor were evaluated in four clinical trials. In two randomized, double-blind, placebo-controlled clinical trials in patients with a G551D mutation in the CFTR gene, one in patients 12 and older (Trial 1) and the other in patients 6-11 years of age (Trial 2), the treatment difference (between Ivacaftor and placebo) in mean change in sweat chloride from baseline through Week 24 was -48 mmol/L (95% CI -51, -45) and -54 mmol/L (95% CI -62, -47), respectively. These changes persisted through 48 weeks. In a 16-week randomized, double-blind, placebo-controlled, parallel-group clinical trial in patients with CF age 12-years and older who were homozygous for the F508del mutation in the CFTR gene (Trial 3), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -3 mmol/L (95% CI -6, -0.2). In a two-part, randomized, double-blind, placebo-controlled, crossover clinical trial in patients with CF who had a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene (Trial 4), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -49 mmol/L (95% CI -57, -41). In Trial 4, mean changes in sweat chloride for the mutations for which Ivacaftor is indicated ranged from -51 to -78, whereas the range for individual subjects with the G970R mutations was -1 to -11 mmol/L. There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1).
- The effect of multiple doses of ivacaftor 150 mg and 450 mg twice daily on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia's correction method (QTcF) was below 10 ms, the threshold for regulatory concern.
## Pharmacokinetics
- The pharmacokinetics of ivacaftor is similar between healthy adult volunteers and patients with CF.
After oral administration of a single 150 mg dose to healthy volunteers in a fed state, peak plasma concentrations (Tmax) occurred at approximately 4 hours, and the mean (±SD) for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively.
- After every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.
- The exposure of ivacaftor increased approximately 2- to 4-fold when given with food containing fat. Therefore, Ivacaftor should be administered with fat-containing food. Examples of fat-containing foods include eggs, butter, peanut butter, and cheese pizza. The median (range) Tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.
- Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells. The mean apparent volume of distribution (Vz/F) of ivacaftor after a single dose of 275 mg of Ivacaftor in the fed state was similar for healthy subjects and patients with CF. After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.
- Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.
- Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose. The mean apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.
## Nonclinical Toxicology
There is limited information regarding Ivacaftor Nonclinical Toxicology in the drug label.
# Clinical Studies
### Trials in Patients with CF who have a G551D Mutation in the CFTR Gene
- Dose ranging for the clinical program consisted primarily of one double-blind, placebo-controlled, crossover trial in 39 adult (mean age 31 years) Caucasian patients with CF who had FEV1 ≥40% predicted. Twenty patients with median predicted FEV1 at baseline of 56% (range: 42% to 109%) received Ivacaftor 25, 75, 150 mg or placebo every 12 hours for 14 days and 19 patients with median predicted FEV1 at baseline of 69% (range: 40% to 122%) received Ivacaftor 150, 250 mg or placebo every 12 hours for 28 days. The selection of the 150 mg every 12 hours dose was primarily based on nominal improvements in lung function (pre-dose FEV1) and changes in pharmacodynamic parameters (sweat chloride and nasal potential difference). The twice-daily dosing regimen was primarily based on an apparent terminal plasma half-life of approximately 12 hours. Selection of the 150 mg dose of Ivacaftor for children 6 to 11 years of age was based on achievement of comparable pharmacokinetics as those observed for adult patients.
- The efficacy of Ivacaftor in patients with CF who have a G551D mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled clinical trials in 213 clinically stable patients with CF (109 receiving Ivacaftor 150 mg twice daily). All eligible patients from these trials were rolled over into an open-label extension study.
- Trial 1 evaluated 161 patients with CF who were 12 years of age or older (mean age 26 years) with FEV1 at screening between 40-90% predicted [mean FEV1 64% predicted at baseline (range: 32% to 98%)]. Trial 2 evaluated 52 patients who were 6 to 11 years of age (mean age 9 years) with FEV1 at screening between 40-105% predicted [mean FEV1 84% predicted at baseline (range: 44% to 134%)]. Patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the upper limit of normal were excluded.
- Patients in both trials were randomized 1:1 to receive either 150 mg of Ivacaftor or placebo every 12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies (e.g., tobramycin, dornase alfa). The use of inhaled hypertonic saline was not permitted. The primary efficacy endpoint in both studies was improvement in lung function as determined by the mean absolute change from baseline in percent predicted pre-dose FEV1 through 24 weeks of treatment.
- In both studies, treatment with Ivacaftor resulted in a significant improvement in FEV1. The treatment difference between Ivacaftor and placebo for the mean absolute change in percent predicted FEV1 from baseline through Week 24 was 10.6 percentage points (P < 0.0001) in Trial 1 and 12.5 percentage points (P < 0.0001) in Trial 2 (Figure 3). These changes persisted through 48 weeks. Improvements in percent predicted FEV1 were observed regardless of age, disease severity, sex, and geographic region.
- Other efficacy variables included absolute change in sweat chloride from baseline to Week 24, time to first pulmonary exacerbation through Week 48 (Trial 1 only), absolute change in weight from baseline to Week 48, and improvement in cystic fibrosis symptoms including relevant respiratory symptoms such as cough, sputum production, and difficulty breathing. For the purpose of the study, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Patients treated with Ivacaftor demonstrated statistically significant improvements in risk of pulmonary exacerbations, CF symptoms (in Trial 1 only), and gain in body weight (Table 2). Weight data, when expressed as body mass index normalized for age and sex in patients <20 years of age, was consistent with absolute change from baseline in weight.
### Trial in Patients with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R Mutation in the CFTR Gene
- The efficacy and safety of Ivacaftor in patients with CF who have a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene were evaluated in a two-part, randomized, double-blind, placebo-controlled, crossover design clinical trial in 39 patients with CF (Trial 4). Patients who completed Part 1 of this trial continued into the 16-week open-label Part 2 of the study. The mutations studied were G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D. for efficacy in patients with a G551D mutation.
- Patients were 6 years of age or older (mean age 23 years) with FEV1 ≥40% at screening [mean FEV1 at baseline 78% predicted (range: 43% to 119%)]. Patients with evidence of colonization with Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the upper limit of normal at screening were excluded.
- Patients were randomized 1:1 to receive either 150 mg of Ivacaftor or placebo every 12 hours with food containing fat for 8 weeks in addition to their prescribed CF therapies during the first treatment period and crossed over to the other treatment for the second 8 weeks. The two 8-week treatment periods were separated by a 4- to 8-week washout period. The use of inhaled hypertonic saline was not permitted.
- The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through 8 weeks of treatment. Other efficacy variables included absolute change from baseline in sweat chloride through 8 weeks of treatment, absolute change from baseline in body mass index (BMI) at 8 weeks of treatment (including body weight at 8 weeks), and improvement in cystic fibrosis symptoms (including relevant respiratory symptoms such as cough, sputum production, and difficulty breathing) through 8 weeks of treatment. For the overall population of the 9 mutations studied, treatment with Ivacaftor compared to placebo resulted in significant improvement in percent predicted FEV1 [10.7 through Week 8 (P < 0.0001)], BMI [0.66 kg/m2 at Week 8 (P < 0.0001)], and cystic fibrosis respiratory symptom score [9.6 through Week 8 (P = 0.0004)]; however, there was a high degree of variability of efficacy responses among the 9 mutations (Table 3). Based on clinical and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established.
### Trial in Patients Homozygous for the F508del Mutation in the CFTR Gene
- Trial 3 was a 16-week randomized, double-blind, placebo-controlled, parallel-group trial in 140 patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥40% predicted. Patients were randomized 4:1 to receive Ivacaftor 150 mg (n=112) every twelve hours or placebo (n=28) in addition to their prescribed CF therapies. The mean age of patients enrolled was 23 years and the mean baseline FEV1 was 79% predicted (range 40% to 129%). As in Trials 1 and 2, patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the upper limit of normal were excluded. The use of inhaled hypertonic saline was not permitted.
- The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline through Week 16 in percent predicted FEV1. Treatment with Ivacaftor resulted in no improvement in FEV1 relative to placebo in patients with CF homozygous for the F508del mutation in the CFTR gene [mean absolute change from baseline through Week 16 in percent predicted FEV1 was 1.5% and -0.2% for patients in the Ivacaftor and placebo-treated groups, respectively (P = 0.15)]. There were no meaningful differences between patients treated with Ivacaftor compared to placebo for secondary endpoints (change in CF symptoms, change in weight, or change in sweat chloride concentration).
# How Supplied
## Storage
Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ivacaftor Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Ivacaftor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Kalydeco
# Look-Alike Drug Names
There is limited information regarding Ivacaftor Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ivacaftor | |
1094b7db35d960c5cdff1c31b82053db2a3fd330 | wikidoc | Jamais vu | Jamais vu
In psychology, the term jamais vu (from the French language|French, meaning "never seen") is used to describe any familiar situation which is not recognized by the observer.
# Psychology
Often described as the opposite of déjà vu, jamais vu involves a sense of eeriness and the observer's impression of seeing the situation for the first time, despite rationally knowing that he or she has been in the situation before.
Jamais vu is more commonly explained as when a person momentarily doesn't recognize a word, person, or place that he/she already knows.
The phenomenon is often grouped with déjà vu and presque vu (together, the three are frequently referred to as "The Vus").
Jamais vu is sometimes associated with certain types of amnesia and epilepsy. With seizures, jamais vu can surface as an aura due to a partial seizure disorder that originates from the temporal lobe of the brain. It also can occur as a migraine aura.
The TimesOnline reports:
# Linguistics
From a linguistic perspective, the phenomenon that a word after frequent repetition seems to lose its meaning is connected with the very nature of words. A word as a unit of language has three characteristics:
- It has form, i.e. it is shaped out of sounds or, in the case of written language, out of letters (characters).
- It has function, which (among other things) means that it operates in a meaningful sentence.
- It has meaning, which implies that it refers to a certain unit of thought (a concept or an idea) within a context.
However, when a word is repeated over and over again, it is in fact only the form which is repeated. There is no sentence, so the function of the word is eliminated. Its meaning, too, is effectively eliminated, because there is no context. A few repetitions will leave the language user's memory and expectation intact: he remembers the meaning and expects a meaningful reference. Continued repetition, however, will more and more foreground the word form to the exclusion of function and meaning, until the word literally "makes no sense". It is not the word that is being repeated, but only one of its aspects: the word form.
# Related phenomena
- Déjà vu: remembering having seen something before. In French, this literally means 'already seen', though in usage it is basically equivalent to déjà vécu.
- Presque vu: almost, but not quite, remembering something. This is the "on the tip of my tongue" feeling. (Cf. the article on Déjà vu.) | Jamais vu
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In psychology, the term jamais vu (from the French language|French, meaning "never seen") is used to describe any familiar situation which is not recognized by the observer.
# Psychology
Often described as the opposite of déjà vu, jamais vu involves a sense of eeriness and the observer's impression of seeing the situation for the first time, despite rationally knowing that he or she has been in the situation before.
Jamais vu is more commonly explained as when a person momentarily doesn't recognize a word, person, or place that he/she already knows.[1]
The phenomenon is often grouped with déjà vu and presque vu (together, the three are frequently referred to as "The Vus").
Jamais vu is sometimes associated with certain types of amnesia and epilepsy. With seizures, jamais vu can surface as an aura due to a partial seizure disorder that originates from the temporal lobe of the brain. It also can occur as a migraine aura. [2]
The TimesOnline reports:
# Linguistics
From a linguistic perspective, the phenomenon that a word after frequent repetition seems to lose its meaning is connected with the very nature of words. A word as a unit of language has three characteristics:
- It has form, i.e. it is shaped out of sounds or, in the case of written language, out of letters (characters).
- It has function, which (among other things) means that it operates in a meaningful sentence.
- It has meaning, which implies that it refers to a certain unit of thought (a concept or an idea) within a context.
However, when a word is repeated over and over again, it is in fact only the form which is repeated. There is no sentence, so the function of the word is eliminated. Its meaning, too, is effectively eliminated, because there is no context. A few repetitions will leave the language user's memory and expectation intact: he remembers the meaning and expects a meaningful reference. Continued repetition, however, will more and more foreground the word form to the exclusion of function and meaning, until the word literally "makes no sense". It is not the word that is being repeated, but only one of its aspects: the word form.
# Related phenomena
- Déjà vu: remembering having seen something before. In French, this literally means 'already seen', though in usage it is basically equivalent to déjà vécu.
- Presque vu: almost, but not quite, remembering something. This is the "on the tip of my tongue" feeling. (Cf. the article on Déjà vu.) | https://www.wikidoc.org/index.php/Jamais_vu | |
7b0279570e0f64dbb6cab7827bbbeddca346f0bd | wikidoc | Jan Adams | Jan Adams
January Rudalgo Adams, known as "Dr. Jan Adams," is an American cosmetic surgeon from Middletown, Ohio who practices in Beverly Hills, California. He graduated from Harvard University and Ohio State University as a physician
He co-presents Cosmetic Surgery Live, a British television program and Plastic Surgery Before & After, on the Discovery Health Channel, and was a co-host on The Other Half, a male-centric syndicated clone of The View during the 2001-02 season.
He is the author of Everything Women of Color Should Know About Cosmetic Surgery, published by St Martin's Press in 2000 (ISBN 0 312 25310 9). He has also appeared on The Oprah Winfrey Show.
Adams was the plastic surgeon who performed surgery on Donda West, the mother of rapper Kanye West. Donda West died the day following her surgery. There is speculation as to whether a pre-existing medical condition made it unsafe for her to undergo this procedure.
Records also indicate that in 2001, two malpractice lawsuits against Adams ended in judgments of $217,337 and $250,000, respectively
In a 2006 legal case, Adams was found guilty of driving with a blood-alcohol level of .08 or greater, and he pleaded no contest in 2003 to driving under the influence, according to medical records.
On Tuesday, November 20, 2007, Dr. Adams walked off the set of Larry King Live while on the air, taking off his microphone and ear piece. He told Larry King he did not wish to answer any questions, citing a request by the West family for privacy. He said "I have a tremendous amount of love and respect for the West family. They asked me not to go on. And I've said from the very beginning, I don't have a side in this." | Jan Adams
January Rudalgo Adams, known as "Dr. Jan Adams," is an American cosmetic surgeon from Middletown, Ohio who practices in Beverly Hills, California. He graduated from Harvard University and Ohio State University as a physician [1]
He co-presents Cosmetic Surgery Live, a British television program and Plastic Surgery Before & After, on the Discovery Health Channel, and was a co-host on The Other Half, a male-centric syndicated clone of The View during the 2001-02 season.
He is the author of Everything Women of Color Should Know About Cosmetic Surgery, published by St Martin's Press in 2000 (ISBN 0 312 25310 9). He has also appeared on The Oprah Winfrey Show. [2]
Adams was the plastic surgeon who performed surgery on Donda West, the mother of rapper Kanye West. Donda West died the day following her surgery. There is speculation as to whether a pre-existing medical condition made it unsafe for her to undergo this procedure. [3]
Records also indicate that in 2001, two malpractice lawsuits against Adams ended in judgments of $217,337 and $250,000, respectively [3]
In a 2006 legal case, Adams was found guilty of driving with a blood-alcohol level of .08 or greater, and he pleaded no contest in 2003 to driving under the influence, according to medical records.[citation needed]
On Tuesday, November 20, 2007, Dr. Adams walked off the set of Larry King Live while on the air, taking off his microphone and ear piece. He told Larry King he did not wish to answer any questions, citing a request by the West family for privacy. He said "I have a tremendous amount of love and respect for the West family. They asked me not to go on. And I've said from the very beginning, I don't have a side in this."[4] | https://www.wikidoc.org/index.php/Jan_Adams | |
f13c7a34a5bdba3b4938f07d28e0b2e2f4ce3473 | wikidoc | Jasmonate | Jasmonate
The jasmonates (JAs) are a group of plant hormones which help regulate plant growth and development. Jasmonates include jasmonic acid and its esters, such as methyl jasmonate (MeJa). Like the related prostaglandin hormones found in mammals, the jasmonates are cyclopentanone derivatives which are derived biosynthetically from fatty acids. They are biosynthesized from linolenic acid by the octadecanoid pathway.
The level of JA in plants varies as a function of tissue and cell type, developmental stage, and in response to several different environmental stimuli. High levels of JA are also found in flowers and pericarp tissues of developing reproductive structures and in the chloroplasts of illuminated plants; JA levels also increase rapidly in response to mechanical perturbations such as tendril coiling and when plants suffer wounding.
Demonstrated roles of JA in planta include:
- JA and MeJA inhibit the germination of nondormant seeds and stimulate the germination of dormant seeds
- High levels of JA encourage the accumulation on storage proteins; genes encoding vegetative storage proteins are JA responsive and tuberonic acid (a JA derivative) has been proposed to play a role in the formation of tubers
- JA application can induce chlorosis and inhibition of genes encoding proteins involved in photosynthesis, although the purpose of this response is unknown it is proposed that this response to JA could help reduce the plant's capacity for carbon assimilation under conditions of excess light or carbon
- The role of JA accumulation in flowers and fruit is unknown, however it may be related to fruit ripening (via ethylene), fruit carotenoid composition, and expression of genes encoding seed and vegetative storage proteins
- JA plays a role in insect and disease resistance, many genes during plant defense are induced by JA; JA and ethylene may act together in defense response | Jasmonate
The jasmonates (JAs) are a group of plant hormones which help regulate plant growth and development. Jasmonates include jasmonic acid and its esters, such as methyl jasmonate (MeJa). Like the related prostaglandin hormones found in mammals, the jasmonates are cyclopentanone derivatives which are derived biosynthetically from fatty acids. They are biosynthesized from linolenic acid by the octadecanoid pathway.
The level of JA in plants varies as a function of tissue and cell type, developmental stage, and in response to several different environmental stimuli.[1] High levels of JA are also found in flowers and pericarp tissues of developing reproductive structures and in the chloroplasts of illuminated plants;[1] JA levels also increase rapidly in response to mechanical perturbations such as tendril coiling and when plants suffer wounding.[2][3]
Demonstrated roles of JA in planta include:
- JA and MeJA inhibit the germination of nondormant seeds and stimulate the germination of dormant seeds[1]
- High levels of JA encourage the accumulation on storage proteins; genes encoding vegetative storage proteins are JA responsive and tuberonic acid (a JA derivative) has been proposed to play a role in the formation of tubers[4][5]
- JA application can induce chlorosis and inhibition of genes encoding proteins involved in photosynthesis, although the purpose of this response is unknown it is proposed that this response to JA could help reduce the plant's capacity for carbon assimilation under conditions of excess light or carbon[1]
- The role of JA accumulation in flowers and fruit is unknown, however it may be related to fruit ripening (via ethylene), fruit carotenoid composition, and expression of genes encoding seed and vegetative storage proteins[1]
- JA plays a role in insect and disease resistance, many genes during plant defense are induced by JA; JA and ethylene may act together in defense response[6] | https://www.wikidoc.org/index.php/Jasmonate | |
82b9fee364880d53fe2b5c4e14291a0402b49481 | wikidoc | Jellyfish | Jellyfish
Jellyfish are marine invertebrates belonging to the class Scyphozoa of the phylum Cnidaria. They can be found in every ocean in the world and even in some fresh water. The name "jellyfish" is also applied to some close relatives of true scyphozoans, such as the Hydrozoa and the Cubozoa. Jellyfish live in groups called 'Hermadenisis'.
# Anatomy and morphology
The body of an adult jellyfish consists of a bell shape producing jelly and enclosing its internal structure, from which tentacles are suspended. Each tentacle is covered with cells called cnidocytes, that can sting or kill other animals. Most jellyfish use these cells to secure prey or for defense. Others, such as the Rhizostomae, do not have tentacles at all. They have many small eyes on their bell which give them a 360° field of vision.
Jellyfish lack basic sensory organs and a brain, but their nervous systems and rhopalia allow them to perceive stimuli, such as light and odor, and respond quickly. They feed on small fish and zooplankton that become caught in their tentacles. Most jellyfish are passive drifters and slow swimmers, as their shape is not hydrodynamic. Instead, they move so as to create a current forcing the prey within reach of their tentacles. They do this by rhythmically opening and closing their bell-like body. Their digestive system is incomplete: the same orifice is used to take in food and expel waste.
The body of an adult is made up of 94–98% water. The bell consists of a layer of epidermis, gastrodermis, and a thick, intervening layer called mesoglea that produces most of the jelly.
## Body systems
A jellyfish detects the touch of other animals using a nervous system called a "nerve net", located in its epidermis. Touch stimuli are conducted by nerve rings, through the rhopalial lappet, located around the animal's body, to the nerve cells. Jellyfish also have ocelli: light-sensitive organs that do not form images but are used to determine up from down, responding to sunlight shining on the water's surface.
Jellyfish don't have specialized digestive, osmoregulatory, central nervous, respiratory, or circulatory systems. They digest using the gastrodermal lining of the gastrovascular cavity, where nutrients are absorbed. They do not need a respiratory system since their skin is thin enough that the body is oxygenated by diffusion. They have limited control over movement and mostly free-float, but can use the hydrostatic skeleton of the water pouch to accomplish vertical movement through pulsations of the disc-like body.
The outer side of a jellyfish is lined with a jelly-like material called ectoplasm (ecto meaning outer and plasm meaning living matter). The ectoplasm typically contains a smaller amount of protein granules and other organic compounds than inner cytoplasm, also referred to as endoplasm (endo meaning inner).
## Jellyfish blooms
Many species of jellyfish are capable of congregating into large swarms or "blooms", consisting of hundreds of individuals. The formation of these blooms is a complex process that depends on ocean currents, nutrients, temperature and ambient oxygen concentrations. Jellyfish sometimes mass breed during blooms. During such times of rapid population expansion, some people will raise ecological concerns about the potential noxious effects of a jellyfish "outbreak".
According to Claudia Mills of the University of Washington, the frequency of jellyfish blooms may be attributed to humans' impact on marine systems. She says that the breeding jellyfish may merely be filling ecological niches formerly occupied by overfished creatures. Jellyfish researcher Marsh Youngbluth further clarifies that "jellyfish feed on the same kinds of prey as adult and young fishes, so if fish are removed from the equation, jellyfish are likely to move in."
Increased nutrients in the water, ascribed to agricultural runoff, have also been cited as an antecedent to the proliferation of jellyfish. Monty Graham, of the Dauphin Island Sea Lab in Alabama, says that "ecosystems in which there are high levels of nutrients ... provide nourishment for the small organisms on which jellyfish feed. In waters where there is eutrophication, low oxygen levels often result, favoring jellyfish as they thrive in less oxygen-rich water than fish can tolerate. The fact that jellyfish are increasing is a symptom of something happening in the ecosystem."
By sampling sea life in a heavily fished region off the coast of Namibia, researchers found that jellyfish have overtaken fish in terms of biomass. The findings represent a careful, quantitative analysis of what has been called a "jellyfish explosion" following intense fishing in the area in the last few decades. The findings were reported by Andrew Brierley of the University of St. Andrews and his colleagues in the July 12, 2006 issue of the journal Current Biology.
Areas which have been seriously affected by jellyfish blooms include the northern Gulf of Mexico. In that case, Graham states, "Moon jellies have formed a kind of gelatinous net that stretches from end to end across the gulf."
## Life history
Most jellyfish pass through two distinct life history phases (body forms) during their life cycle. The first is the polypoid stage, when the jellyfish takes the form of either a sessile stalk which catches passing food, or a similar free-floating configuration. The polyp's mouth and tentacles face upwards, reminiscent of the hydroid stage of the somewhat closely related anthozoan polyps, also of the phylum Cnidaria.
In the second stage, the jellyfish is known as a medusa. Medusae have a radially symmetric, umbrella-shaped body called a bell. The medusa's tentacles are fringe-like protrusions from the border of the bell. (Medusa is also the word for jellyfish in Romanian, Hebrew, Croatian, Spanish, French, Italian, Hungarian, Russian and Bulgarian.)
Jellyfish are dioecious; that is, they are either male or female. In most cases, to reproduce, a male releases his sperm into the surrounding water. The sperm then swims into the mouth of the female, allowing the fertilization of the ova. However, moon jellies use a different process. The eggs become lodged in pits on the oral arms, which form a temporary brood chamber to accommodate fertilization.
After fertilization and initial growth, a larval form, called the planula, develops from the egg. The planula is a small larva covered with cilia. It settles onto a firm surface and develops into a polyp. The polyp is cup-shaped with tentacles surrounding a single orifice, resembling a tiny sea anemone. After an interval of growth, the polyp begins reproducing asexually by budding and is called a segmenting polyp, or a scyphistome. New scyphistomae may be produced by budding or new, immature jellies called ephyra may be formed. Many jellyfish species are capable of producing new medusae by budding directly from the medusan stage.
Most jellyfish have a lifespan of two and a half months; few live longer than six months but one species can live as long as 30 years and another species, T. nutricula, is effectively immortal.
# Etymology and taxonomic history
Since jellyfish are not fish, some people consider the term "jellyfish" a misnomer, and instead use the term "jellies" or "sea jellies". The word "jellyfish" is also often used to denote either hydrozoans or the box jellyfish, the cubozoans. The class name, Scyphozoa, comes from the Greek word skyphos, denoting a kind of drinking cup and alluding to the cup shape of the organism.
A group of jellyfish is often called a "smack".
# Importance to humans
## Culinary uses
Jellyfish are an important source of food to the Chinese community and in many Asian countries. Only jellyfish belonging to the order Rhizostomeae are harvested for food. Rhizostomes, especially Rhopilema esculentum in China (Chinese name: 海蜇 hǎizhē) and Stomolophus meleagris (cannonball jellyfish) in the United States, are favoured because they are typically larger and have more rigid bodies than other scyphozoans. Furthermore, their toxins are innocuous to humans.
Traditional processing methods, carried out by a Jellyfish Master, involve a 20 to 40 day multi-phase procedure in which the umbrella and oral arms are treated with a mixture of table salt and alum, and compressed. The gonads and mucous membranes are removed prior to salting. Processing reduces liquidation, off-odors and the growth of spoilage organisms, and makes the jellyfish drier and more acidic, producing a "crunchy and crispy texture." Jellyfish prepared this way retain 7-10% of their original, raw weight, and the processed product contains approximately 95% water and 4-5% protein, making it a relatively low calorie food. Freshly processed jellyfish has a white, creamy color and turns yellow or brown during prolonged storage.
In China, processed jellyfish are desalted by soaking in water overnight and eaten cooked or raw. The dish is often served shredded with a dressing of oil, soy sauce, vinegar and sugar, or as a salad with vegetables. In Japan, cured jellyfish are rinsed, cut into strips and served with vinegar as an appetizer. Desalted, ready-to-eat products are also available.
Fisheries have begun harvesting cannonball jellyfish along the southern Atlantic coast of the United States and in the Gulf of Mexico for export to Asian nations.
## In biotechnology
In 1961, green fluorescent protein (GFP) was discovered in the jellyfish Aequorea victoria by scientists studying bioluminescence. This protein has since become a quite useful tool in biology. Its use is mainly for scientists studying in which tissues genes are expressed. The technique, using genetic engineering, fuses the gene of interest to the gene of GFP. The fused DNA is then put into a cell, to generate either a cell line or (via IVF techniques) an entire animal bearing the gene. In the cell or animal, the artificial gene gets turned on in the same tissues and the same time as the normal gene. But instead of making the normal protein, the gene makes GFP. One can then find out what tissues express that protein -- or at what stage of development -- by shining light on the animal or cell, and looking for the green fluorescence. The fluorescence shows where the gene of interest is expressed. Jellyfish are also harvested for their collagen, which can be used for a variety of scientific applications including the treatment of rheumatoid arthritis.
## In captivity
Jellyfish are commonly displayed in aquaria in many countries. Often the tank's background is blue and the animals are illuminated by side light to produce a high contrast effect. In natural conditions, many jellies are so transparent that they are almost impossible to see.
Holding jellyfish in captivity presents other problems. For one, they are not adapted to closed spaces. They depend on currents to transport them from place to place. To compensate for this, professional exhibits feature precise water flows, typically in circular tanks to prevent specimens from becoming trapped in corners. The Monterey Bay Aquarium uses a modified version of the kreisel (German for "spinning top") for this purpose.
## Toxicity to humans
When stung by a jellyfish, first aid may be needed immediately. The stings of true Scyphozoan jellyfish are not generally deadly, though species of the completely separate class Cubozoa (box jellyfish) such as the famous and especially toxic Irukandji can be fatal. However, even nonfatal jellyfish stings are known to be extremely painful. Serious stings may cause anaphylaxis and may result in death. Hence, people stung by jellyfish must get out of the water to avoid drowning. In serious cases, advanced professional care must be sought. This care may include administration of an antivenin and other supportive care such as required to treat the symptoms of anaphylactic shock.
There are three goals of first aid for uncomplicated jellyfish stings: prevent injury to rescuers, inactivate the nematocysts, and remove any tentacles stuck on the patient. To prevent injury to rescuers, barrier clothing should be worn. This protection may include anything from panty hose to wet suits to full-body sting-proof suits. Inactivating the nematocysts, or stinging cells, prevents further injection of venom into the patient.
Vinegar (3 to 10% aqueous acetic acid) should be applied for box jellyfish stings. Vinegar, however, is not recommended for Portuguese Man o' War stings. In the case of stings on or around the eyes, vinegar may be placed on a towel and dabbed around the eyes, but not in them. Salt water may also be used in case vinegar is not readily available. Fresh water should not be used if the sting occurred in salt water, as a change in pH can cause the release of additional venom. Rubbing the wound, or using alcohol, spirits, ammonia, or urine will encourage the release of venom and should be avoided. Though often not available, a shower or bath as hot as can be tolerated can neutralize stings. However, if hypothermia is suspected this method may cause other serious complications.
Once deactivated, the stinging cells must be removed. This can be accomplished by picking off tentacles left on the body. First aid providers should be careful to use gloves or another readily available barrier device to prevent personal injury, and to follow standard universal precautions. After large pieces of the jellyfish are removed, shaving cream may be applied to the area and a knife edge, safety razor, or credit card may be used to take away any remaining nematocysts.
Beyond initial first aid, antihistamines such as diphenhydramine (Benadryl) may be used to control skin irritation (pruritus). To remove the venom in the skin, apply a paste of baking soda and water and apply a cloth covering on the sting. If possible, reapply paste every 15-20 minutes. Ice can be applied to stop the spread of venom until either of these is available. | Jellyfish
Jellyfish are marine invertebrates belonging to the class Scyphozoa of the phylum Cnidaria. They can be found in every ocean in the world and even in some fresh water. The name "jellyfish" is also applied to some close relatives of true scyphozoans, such as the Hydrozoa and the Cubozoa. Jellyfish live in groups called 'Hermadenisis'.
# Anatomy and morphology
The body of an adult jellyfish consists of a bell shape producing jelly and enclosing its internal structure, from which tentacles are suspended. Each tentacle is covered with cells called cnidocytes, that can sting or kill other animals. Most jellyfish use these cells to secure prey or for defense. Others, such as the Rhizostomae, do not have tentacles at all. They have many small eyes on their bell which give them a 360° field of vision.
Jellyfish lack basic sensory organs and a brain, but their nervous systems and rhopalia allow them to perceive stimuli, such as light and odor, and respond quickly. They feed on small fish and zooplankton that become caught in their tentacles. Most jellyfish are passive drifters and slow swimmers, as their shape is not hydrodynamic. Instead, they move so as to create a current forcing the prey within reach of their tentacles. They do this by rhythmically opening and closing their bell-like body. Their digestive system is incomplete: the same orifice is used to take in food and expel waste.
The body of an adult is made up of 94–98% water. The bell consists of a layer of epidermis, gastrodermis, and a thick, intervening layer called mesoglea that produces most of the jelly.
## Body systems
A jellyfish detects the touch of other animals using a nervous system called a "nerve net", located in its epidermis. Touch stimuli are conducted by nerve rings, through the rhopalial lappet, located around the animal's body, to the nerve cells. Jellyfish also have ocelli: light-sensitive organs that do not form images but are used to determine up from down, responding to sunlight shining on the water's surface.
Jellyfish don't have specialized digestive, osmoregulatory, central nervous, respiratory, or circulatory systems. They digest using the gastrodermal lining of the gastrovascular cavity, where nutrients are absorbed. They do not need a respiratory system since their skin is thin enough that the body is oxygenated by diffusion. They have limited control over movement and mostly free-float, but can use the hydrostatic skeleton of the water pouch to accomplish vertical movement through pulsations of the disc-like body.
The outer side of a jellyfish is lined with a jelly-like material called ectoplasm (ecto meaning outer and plasm meaning living matter). The ectoplasm typically contains a smaller amount of protein granules and other organic compounds than inner cytoplasm, also referred to as endoplasm (endo meaning inner).
## Jellyfish blooms
Many species of jellyfish are capable of congregating into large swarms or "blooms", consisting of hundreds of individuals. The formation of these blooms is a complex process that depends on ocean currents, nutrients, temperature and ambient oxygen concentrations. Jellyfish sometimes mass breed during blooms. During such times of rapid population expansion, some people will raise ecological concerns about the potential noxious effects of a jellyfish "outbreak".
According to Claudia Mills of the University of Washington, the frequency of jellyfish blooms may be attributed to humans' impact on marine systems. She says that the breeding jellyfish may merely be filling ecological niches formerly occupied by overfished creatures. Jellyfish researcher Marsh Youngbluth further clarifies that "jellyfish feed on the same kinds of prey as adult and young fishes, so if fish are removed from the equation, jellyfish are likely to move in."
Increased nutrients in the water, ascribed to agricultural runoff, have also been cited as an antecedent to the proliferation of jellyfish. Monty Graham, of the Dauphin Island Sea Lab in Alabama, says that "ecosystems in which there are high levels of nutrients ... provide nourishment for the small organisms on which jellyfish feed. In waters where there is eutrophication, low oxygen levels often result, favoring jellyfish as they thrive in less oxygen-rich water than fish can tolerate. The fact that jellyfish are increasing is a symptom of something happening in the ecosystem."[1]
By sampling sea life in a heavily fished region off the coast of Namibia, researchers found that jellyfish have overtaken fish in terms of biomass. The findings represent a careful, quantitative analysis of what has been called a "jellyfish explosion" following intense fishing in the area in the last few decades. The findings were reported by Andrew Brierley of the University of St. Andrews and his colleagues in the July 12, 2006 issue of the journal Current Biology.
Areas which have been seriously affected by jellyfish blooms include the northern Gulf of Mexico. In that case, Graham states, "Moon jellies have formed a kind of gelatinous net that stretches from end to end across the gulf."[1]
## Life history
Most jellyfish pass through two distinct life history phases (body forms) during their life cycle. The first is the polypoid stage, when the jellyfish takes the form of either a sessile stalk which catches passing food, or a similar free-floating configuration. The polyp's mouth and tentacles face upwards, reminiscent of the hydroid stage of the somewhat closely related anthozoan polyps, also of the phylum Cnidaria.
In the second stage, the jellyfish is known as a medusa. Medusae have a radially symmetric, umbrella-shaped body called a bell. The medusa's tentacles are fringe-like protrusions from the border of the bell. (Medusa is also the word for jellyfish in Romanian, Hebrew, Croatian, Spanish, French, Italian, Hungarian, Russian and Bulgarian.)
Jellyfish are dioecious; that is, they are either male or female. In most cases, to reproduce, a male releases his sperm into the surrounding water. The sperm then swims into the mouth of the female, allowing the fertilization of the ova. However, moon jellies use a different process. The eggs become lodged in pits on the oral arms, which form a temporary brood chamber to accommodate fertilization.
After fertilization and initial growth, a larval form, called the planula, develops from the egg. The planula is a small larva covered with cilia. It settles onto a firm surface and develops into a polyp. The polyp is cup-shaped with tentacles surrounding a single orifice, resembling a tiny sea anemone. After an interval of growth, the polyp begins reproducing asexually by budding and is called a segmenting polyp, or a scyphistome. New scyphistomae may be produced by budding or new, immature jellies called ephyra may be formed. Many jellyfish species are capable of producing new medusae by budding directly from the medusan stage.
Most jellyfish have a lifespan of two and a half months; few live longer than six months but one species can live as long as 30 years and another species, T. nutricula, is effectively immortal.
# Etymology and taxonomic history
Since jellyfish are not fish, some people consider the term "jellyfish" a misnomer, and instead use the term "jellies" or "sea jellies". The word "jellyfish" is also often used to denote either hydrozoans or the box jellyfish, the cubozoans. The class name, Scyphozoa, comes from the Greek word skyphos, denoting a kind of drinking cup and alluding to the cup shape of the organism.
A group of jellyfish is often called a "smack". [2]
# Importance to humans
## Culinary uses
Jellyfish are an important source of food to the Chinese community and in many Asian countries.[3] Only jellyfish belonging to the order Rhizostomeae are harvested for food. Rhizostomes, especially Rhopilema esculentum in China (Chinese name: 海蜇 hǎizhē) and Stomolophus meleagris (cannonball jellyfish) in the United States, are favoured because they are typically larger and have more rigid bodies than other scyphozoans. Furthermore, their toxins are innocuous to humans.[3]
Traditional processing methods, carried out by a Jellyfish Master, involve a 20 to 40 day multi-phase procedure in which the umbrella and oral arms are treated with a mixture of table salt and alum, and compressed.[3] The gonads and mucous membranes are removed prior to salting. Processing reduces liquidation, off-odors and the growth of spoilage organisms, and makes the jellyfish drier and more acidic, producing a "crunchy and crispy texture."[3] Jellyfish prepared this way retain 7-10% of their original, raw weight, and the processed product contains approximately 95% water and 4-5% protein, making it a relatively low calorie food.[3] Freshly processed jellyfish has a white, creamy color and turns yellow or brown during prolonged storage.
In China, processed jellyfish are desalted by soaking in water overnight and eaten cooked or raw. The dish is often served shredded with a dressing of oil, soy sauce, vinegar and sugar, or as a salad with vegetables.[3] In Japan, cured jellyfish are rinsed, cut into strips and served with vinegar as an appetizer.[3][4] Desalted, ready-to-eat products are also available.[3]
Fisheries have begun harvesting cannonball jellyfish along the southern Atlantic coast of the United States and in the Gulf of Mexico for export to Asian nations.[3]
## In biotechnology
In 1961, green fluorescent protein (GFP) was discovered in the jellyfish Aequorea victoria by scientists studying bioluminescence. This protein has since become a quite useful tool in biology. Its use is mainly for scientists studying in which tissues genes are expressed. The technique, using genetic engineering, fuses the gene of interest to the gene of GFP. The fused DNA is then put into a cell, to generate either a cell line or (via IVF techniques) an entire animal bearing the gene. In the cell or animal, the artificial gene gets turned on in the same tissues and the same time as the normal gene. But instead of making the normal protein, the gene makes GFP. One can then find out what tissues express that protein -- or at what stage of development -- by shining light on the animal or cell, and looking for the green fluorescence. The fluorescence shows where the gene of interest is expressed.[5] Jellyfish are also harvested for their collagen, which can be used for a variety of scientific applications including the treatment of rheumatoid arthritis.
## In captivity
Jellyfish are commonly displayed in aquaria in many countries. Often the tank's background is blue and the animals are illuminated by side light to produce a high contrast effect. In natural conditions, many jellies are so transparent that they are almost impossible to see.
Holding jellyfish in captivity presents other problems. For one, they are not adapted to closed spaces. They depend on currents to transport them from place to place. To compensate for this, professional exhibits feature precise water flows, typically in circular tanks to prevent specimens from becoming trapped in corners. The Monterey Bay Aquarium uses a modified version of the kreisel (German for "spinning top") for this purpose.
## Toxicity to humans
When stung by a jellyfish, first aid may be needed immediately. The stings of true Scyphozoan jellyfish are not generally deadly, though species of the completely separate class Cubozoa (box jellyfish) such as the famous and especially toxic Irukandji can be fatal. However, even nonfatal jellyfish stings are known to be extremely painful. Serious stings may cause anaphylaxis and may result in death. Hence, people stung by jellyfish must get out of the water to avoid drowning. In serious cases, advanced professional care must be sought. This care may include administration of an antivenin and other supportive care such as required to treat the symptoms of anaphylactic shock.
There are three goals of first aid for uncomplicated jellyfish stings: prevent injury to rescuers, inactivate the nematocysts, and remove any tentacles stuck on the patient. To prevent injury to rescuers, barrier clothing should be worn. This protection may include anything from panty hose to wet suits to full-body sting-proof suits. Inactivating the nematocysts, or stinging cells, prevents further injection of venom into the patient.
Vinegar (3 to 10% aqueous acetic acid) should be applied for box jellyfish stings.[6][7] Vinegar, however, is not recommended for Portuguese Man o' War stings.[6] In the case of stings on or around the eyes, vinegar may be placed on a towel and dabbed around the eyes, but not in them. Salt water may also be used in case vinegar is not readily available.[6][8] Fresh water should not be used if the sting occurred in salt water, as a change in pH can cause the release of additional venom. Rubbing the wound, or using alcohol, spirits, ammonia, or urine will encourage the release of venom and should be avoided.[9] Though often not available, a shower or bath as hot as can be tolerated can neutralize stings. However, if hypothermia is suspected this method may cause other serious complications.
Once deactivated, the stinging cells must be removed. This can be accomplished by picking off tentacles left on the body.[9] First aid providers should be careful to use gloves or another readily available barrier device to prevent personal injury, and to follow standard universal precautions. After large pieces of the jellyfish are removed, shaving cream may be applied to the area and a knife edge, safety razor, or credit card may be used to take away any remaining nematocysts.[10]
Beyond initial first aid, antihistamines such as diphenhydramine (Benadryl) may be used to control skin irritation (pruritus).[10] To remove the venom in the skin, apply a paste of baking soda and water and apply a cloth covering on the sting. If possible, reapply paste every 15-20 minutes. Ice can be applied to stop the spread of venom until either of these is available. | https://www.wikidoc.org/index.php/Jellyfish | |
63d8eecb3b95d7290c994859e05285b562fd85a0 | wikidoc | Jequirity | Jequirity
The Jequirity, also called Crab's Eye, Rosary Pea, 'John Crow' Bead, Precatory bean or Indian Licorice (Abrus precatorius), is a legume with long, pinnate-leafleted leaves. Their seeds are often used as beads and in percussion instruments. The seed is highly poisonous but is unlikely to harm if swallowed raw and unbroken, as they have a hard seed coat.
The toxin present in Abrus precatorius is a close relative to ricin called abrin. It is a dimer consisting of two protein subunits, termed A and B. The B chain facillitates abrin's entry into a cell by bonding to certain transport proteins on cell membranes, which then transport the toxin into the cell. Once inside the cell, the A chain prevents protein synthesis by inactivating the 26S subunit of the ribosome. One molecule of abrin will inactivate up to 1,500 ribosomes per second. Symptoms are identical to those of ricin, except that the fatal dose of ricin is approximately 75 times greater than the fatal dose of abrin. Abrin can kill with a circulating amount of less than 3 μg (micrograms).
The seeds of Abrus precatorius are much valued in native jewelry for their bright coloration. The third of the bean with the hilum (attachment scar) is black, while the rest is bright red, suggesting a ladybug. Jewelry-making with jequirity seeds is dangerous, and there have been cases of death by a finger-prick while boring the seeds for beadwork. However, it has long been a symbol of love in China. | Jequirity
The Jequirity, also called Crab's Eye, Rosary Pea, 'John Crow' Bead, Precatory bean or Indian Licorice (Abrus precatorius), is a legume with long, pinnate-leafleted leaves. Their seeds are often used as beads and in percussion instruments. The seed is highly poisonous but is unlikely to harm if swallowed raw and unbroken, as they have a hard seed coat.
The toxin present in Abrus precatorius is a close relative to ricin called abrin. It is a dimer consisting of two protein subunits, termed A and B. The B chain facillitates abrin's entry into a cell by bonding to certain transport proteins on cell membranes, which then transport the toxin into the cell. Once inside the cell, the A chain prevents protein synthesis by inactivating the 26S subunit of the ribosome. One molecule of abrin will inactivate up to 1,500 ribosomes per second. Symptoms are identical to those of ricin, except that the fatal dose of ricin is approximately 75 times greater than the fatal dose of abrin. Abrin can kill with a circulating amount of less than 3 μg (micrograms).
The seeds of Abrus precatorius are much valued in native jewelry for their bright coloration. The third of the bean with the hilum (attachment scar) is black, while the rest is bright red, suggesting a ladybug. Jewelry-making with jequirity seeds is dangerous, and there have been cases of death by a finger-prick while boring the seeds for beadwork. However, it has long been a symbol of love in China. | https://www.wikidoc.org/index.php/Jequirity | |
ec8660bbb2c722a773ae0cf61b16dce4007482a4 | wikidoc | Jiaogulan | Jiaogulan
Gynostemma pentaphyllum, also called jiaogulan (Template:Zh-cp) is an herbaceous vine of the family Cucurbitaceae (cucumber or gourd family) indigenous to the southern reaches of China, southern Korea and Japan. Jiaogulan is best known as an herbal medicine reputed to have powerful antioxidant and adaptogenic effects that increase longevity.
# Range
Jiaogulan is a vine hardy to USDA zone 8 in which it may grow as a short lived perennial plant. It can be grown as an annual in most temperate climates, in well-drained soil with full sun. The plant is dioecious, meaning each plant exists either as male or female, thus if seeds are desired both a male and female plant must be grown. Unlike most of the Cucurbitaceae, jiaogulan does not show toxicity.
# Uses
Jiaogulan is consumed primarily as a tea, and is also used as a natural sweetener in Japan. It is known as an adaptogen and antioxidant and has been found to increase superoxide dismutase (SOD) which is a powerful endogenous cellular antioxidant. Studies have found it increases the activities of macrophages, T lymphocytes and natural killer cells and that it acts as a tumor inhibitor. Due to its adaptogenic effects it is frequently referred to as "Southern Ginseng," although it is not closely related to true Panax ginseng. Its adaptogenic constituents include the triterpenoid saponins gypenosides which are closely structurally related to the ginsenosides from the well-known medicinal plant ginseng. It has been shown to lower cholesterol levels in human studies.
The plant is best known for its use as an herbal medicine in traditional Chinese medicine, although its inclusion in Wu Qi-Jun's 1848 botany book Zhi Wu Ming Shi Tu Kao Chang Bian discusses a few medicinal uses and seems to be the earliest known documentation of the herb. Prior to that, Jiaogulan was cited as a survival food in Zu Xio's 1406 book Materia Medica for Famine. Until recently it was a locally known herb used primarily in regions of southern China. It is described by the local inhabitants as the immortality herb, because people within the Guizhou Province, where jiaogulan tea is drunk regularly, have a history of living to a very old age. Most research has been done since the 1960s when the Chinese realized that it might be an inexpensive source for adaptogenic compounds, taking pressure off of ginseng stock.
Adaptogenic herbs are nontoxic in normal doses, produce a nonspecific defensive response to stress, and have a normalizing influence on the body. They normalize the hypothalamic-pituitary-adrenal axis (HPA axis). As defined, adaptogens constitute a new class of natural, homeostatic metabolic regulators. However they are also functional at the level of allostasis which is a more dynamic reaction to long term stress, lacking the fixed reference points of homeostasis. Jiaogulan is a calming adaptogen which is also useful in formula with codonopsis for jet lag and altitude sickness.
# Alternate names
Western languages such as English and German commonly refer to the plant as jiaogulan. Other names include:
- Chinese: xiancao (仙草, literally "immortal grass"; more accurately "herb of immortality")
- English: five-leaf ginseng, poor man's ginseng, miracle grass, fairy herb, sweet tea vine, gospel herb
- Japanese: amachazuru (kanji: 甘茶蔓; hiragana: あまちゃずる; literally amacha=sweet, cha=tea, zuru=vine)
- Korean language: dungkulcha (덩굴차) or dolwe (돌외)
- Latin: Gynostemma pentaphyllum or Vitis pentaphyllum
- Thai: jiaogulan (เจียวกู่หลาน)
- Vietnamese: Giảo cổ lam
One U.S.-based company markets jiaogulan under the name "Panta". At least one U.S. company markets jiaogulan under the name "Penta Concentrate" for lowering cholesterol. | Jiaogulan
Gynostemma pentaphyllum, also called jiaogulan (Template:Zh-cp) is an herbaceous vine of the family Cucurbitaceae (cucumber or gourd family) indigenous to the southern reaches of China, southern Korea and Japan. Jiaogulan is best known as an herbal medicine reputed to have powerful antioxidant and adaptogenic effects that increase longevity.
# Range
Jiaogulan is a vine hardy to USDA zone 8 in which it may grow as a short lived perennial plant. It can be grown as an annual in most temperate climates, in well-drained soil with full sun. The plant is dioecious, meaning each plant exists either as male or female, thus if seeds are desired both a male and female plant must be grown. Unlike most of the Cucurbitaceae, jiaogulan does not show toxicity.
# Uses
Jiaogulan is consumed primarily as a tea, and is also used as a natural sweetener in Japan[citation needed]. It is known as an adaptogen and antioxidant and has been found to increase superoxide dismutase (SOD) which is a powerful endogenous cellular antioxidant. Studies have found it increases the activities of macrophages, T lymphocytes and natural killer cells and that it acts as a tumor inhibitor.[1] Due to its adaptogenic effects it is frequently referred to as "Southern Ginseng," although it is not closely related to true Panax ginseng. Its adaptogenic constituents include the triterpenoid saponins gypenosides which are closely structurally related to the ginsenosides from the well-known medicinal plant ginseng. It has been shown to lower cholesterol levels in human studies.[2]
The plant is best known for its use as an herbal medicine in traditional Chinese medicine, although its inclusion in Wu Qi-Jun's 1848 botany book Zhi Wu Ming Shi Tu Kao Chang Bian discusses a few medicinal uses and seems to be the earliest known documentation of the herb. Prior to that, Jiaogulan was cited as a survival food in Zu Xio's 1406 book Materia Medica for Famine. Until recently it was a locally known herb used primarily in regions of southern China. It is described by the local inhabitants as the immortality herb, because people within the Guizhou Province, where jiaogulan tea is drunk regularly, have a history of living to a very old age.[3][4] Most research has been done since the 1960s when the Chinese realized that it might be an inexpensive source for adaptogenic compounds, taking pressure off of ginseng stock.
Adaptogenic herbs are nontoxic in normal doses, produce a nonspecific defensive response to stress, and have a normalizing influence on the body. They normalize the hypothalamic-pituitary-adrenal axis (HPA axis). As defined, adaptogens constitute a new class of natural, homeostatic metabolic regulators.[3] However they are also functional at the level of allostasis which is a more dynamic reaction to long term stress, lacking the fixed reference points of homeostasis.[5] Jiaogulan is a calming adaptogen which is also useful in formula with codonopsis for jet lag and altitude sickness.[4]
# Alternate names
Western languages such as English and German commonly refer to the plant as jiaogulan. Other names include:[6]
- Chinese: xiancao (仙草, literally "immortal grass"; more accurately "herb of immortality")
- English: five-leaf ginseng, poor man's ginseng, miracle grass, fairy herb, sweet tea vine, gospel herb
- Japanese: amachazuru (kanji: 甘茶蔓; hiragana: あまちゃずる; literally amacha=sweet, cha=tea, zuru=vine)
- Korean language: dungkulcha (덩굴차) or dolwe (돌외)
- Latin: Gynostemma pentaphyllum or Vitis pentaphyllum
- Thai: jiaogulan (เจียวกู่หลาน)
- Vietnamese: Giảo cổ lam
One U.S.-based company markets jiaogulan under the name "Panta". At least one U.S. company markets jiaogulan under the name "Penta Concentrate" for lowering cholesterol.[7][8] | https://www.wikidoc.org/index.php/Jiaogulan | |
91b07e7d98d18467da7b1e1c1daccf370a503a6e | wikidoc | Jintropin | Jintropin
Jintropin is the brand name for a synthetic human growth hormone product, which is made by the Chinese company GeneScience. Jintropin is used to treat GH deficiency and a few other legitimate disorders (see Growth hormone treatment). It also has a number of controversial uses (see HGH controversies).
# Legal status
Jintropin is approved for use in China. It is not approved for sale or import in the United States or Australia. Since early 2007, GeneScience has stated on its website that it does not ship Jintropin out of China, but the United States accuses the company of supplying human growth hormone smuggled into the U.S.
## Sylvester Stallone
Sylvester Stallone was found guilty of importing 48 vials of Jintropin into Australia on a 2007 trip to promote the film Rocky Balboa. He was ordered to pay a A$12,975 fine.
## GeneScience indicted
In September 2007, a U.S. federal grand jury indicted GeneScience and its CEO, Lei Jin, on charges of smuggling. U.S. authorities say that Jin imported illegal growth hormone into the country and marketed the drugs through web sites under the brand name "Jinotropin." | Jintropin
Jintropin is the brand name for a synthetic human growth hormone product, which is made by the Chinese company GeneScience.[1] Jintropin is used to treat GH deficiency and a few other legitimate disorders (see Growth hormone treatment). It also has a number of controversial uses (see HGH controversies).
# Legal status
Jintropin is approved for use in China. It is not approved for sale or import in the United States[2] or Australia.[3] Since early 2007, GeneScience has stated on its website that it does not ship Jintropin out of China,[2][4] but the United States accuses the company of supplying human growth hormone smuggled into the U.S.[5]
## Sylvester Stallone
Sylvester Stallone was found guilty of importing 48 vials of Jintropin into Australia on a 2007 trip to promote the film Rocky Balboa. He was ordered to pay a A$12,975 fine.[3]
## GeneScience indicted
In September 2007, a U.S. federal grand jury indicted GeneScience and its CEO, Lei Jin, on charges of smuggling. U.S. authorities say that Jin imported illegal growth hormone into the country and marketed the drugs through web sites under the brand name "Jinotropin."[5] | https://www.wikidoc.org/index.php/Jintropin | |
60d714b3259de18757ab0dbe41462fee6a80f02b | wikidoc | Jon Sudbø | Jon Sudbø
# Overview
Jon Sudbø (born May 3, 1961) is a dentist and formerly a consultant oncologist and medical researcher at The Radium Hospital in Oslo, Norway. Having earlier been licenced as a dentist and a physician, he earned a doctorate (dr. med.) in 2001. Until February 2006 he was an associate Professor at the University of Oslo. In November, 2006 his license to practice medicine and dentistry were revoked, and on December 19, 2006, the faculty board at the faculty of medicine at the University of Oslo decided to revoke his doctorate.
Recently he gained a limited authorization to work as a dentist, and is currently working in Seljord, Telemark.
# Scandal
In January 2006 it was revealed that his October 2005 fast track submission to The Lancet was based upon fraudulent patient data. The article had suggested that non-COX2-NSAIDs like ibuprofen diminish the risk of oral cancer in smokers. However, it turned out that the whole patient material was fictional.
The Norwegian newspaper Dagbladet reported that of the 908 subjects in the Lancet study 250 had the same birthday.
Sudbø has later acknowledged that he has used fictional data in at least two more
papers, published in the New England Journal of Medicine and the Journal of Clinical Oncology.
An independent Commission of Inquiry led by Swedish Professor Anders Ekbom, that also included a member from the U.S. National Cancer Institute, was set up by Rikshospitalet and the University of Oslo to discern the details of the fraud. They were also to try to identify the role of the co-authors, which included, among others, Jon Sudbø's brother, wife and Andrew J. Dannenberg, who was listed as the senior author on the article.
In May 2006, Norwegian and Swedish media reported that the committee was investigating some 60 scientists from 6 countries, and a total of 38 articles.
The commission reported on 30 June 2006 . The commission deemed much of Sudbø's work invalid because of manipulation and fabrication of raw data: of the 38 articles he had published since 1993, 15 were condemned as fraudulent, including his doctoral dissertation. Because of this, the dissertation and the other fraudulent articles will be rescinded. The commission also criticised the co-authors of Sudbø's papers. Professor Anders Ekbom, the Chair of the Commission, said: "One explanation of this catastrophe was that Sudbø was a lone wolf. Few or anyone had insight into his work". However, the commission found no evidence that any of his co-authors had taken part in the fraud or otherwise been party to the deceit (although Sudbø's supervisor accepted criticism for lack of vigilance and follow-up).
In November 2006 his authorization as a physician and a dentist was revoked by the Norwegian Board of Health Supervision.
# Effects of fraud
Rikshospitalet and the University were both criticised for "a lack of preliminary control and organization with a view to the researcher's PhD project". The hospital was also criticised for "a lack of training and consciousness-raising in respect of the researcher and other employees with a view to the rules for handling patient material, preliminary assessments of research projects and authorship" and for "a lack of leadership and routines designed to expose and deal with non-conformance with its rules of procedure".
The fraud may also has international effects. The commission could not rule out that Sudbø's false conclusions could have had an impact on cancer patients around the world, because his findings were used by other scientists and incorporated into cancer treatments, although Sudbø's solicitor Erling O. Lyngtveit had said on behalf of his client that none of the fraudulent articles had had any consequences for patients . Norway's scientific reputation could also be damaged by the affair, and "massive lawsuits" may be imminent from the national and international organisations that funded Sudbø's fraudulent papers.
According to the Norwegian news website Depesjer ("Dispatches"), scientific experts they consulted felt that Sudbø's co-authors were "severely exploited", but also that closer observations of the Vancouver guidelines and other rules by co-authors would "hamper future attempts at publishing fabricated material" . Dr. Atle Klovning, a leading European authority on evidence-based medicine, said in the article that Sudbø's co-authors had probably not lived up to their responsibilities according to the Vancouver rules. | Jon Sudbø
# Overview
Jon Sudbø (born May 3, 1961) is a dentist and formerly a consultant oncologist and medical researcher at The Radium Hospital in Oslo, Norway. Having earlier been licenced as a dentist and a physician, he earned a doctorate (dr. med.) in 2001. Until February 2006 he was an associate Professor at the University of Oslo. In November, 2006 his license to practice medicine and dentistry were revoked, and on December 19, 2006, the faculty board at the faculty of medicine at the University of Oslo decided to revoke his doctorate.
[1][2] Recently he gained a limited authorization to work as a dentist, and is currently working in Seljord, Telemark.
# Scandal
In January 2006 it was revealed that his October 2005 fast track submission to The Lancet was based upon fraudulent patient data. The article had suggested that non-COX2-NSAIDs like ibuprofen diminish the risk of oral cancer in smokers.[3] However, it turned out that the whole patient material was fictional.
The Norwegian newspaper Dagbladet reported that of the 908 subjects in the Lancet study 250 had the same birthday.[4]
Sudbø has later acknowledged that he has used fictional data in at least two more
papers, published in the New England Journal of Medicine and the Journal of Clinical Oncology.
An independent Commission of Inquiry led by Swedish Professor Anders Ekbom, that also included a member from the U.S. National Cancer Institute, was set up by Rikshospitalet and the University of Oslo to discern the details of the fraud. They were also to try to identify the role of the co-authors, which included, among others, Jon Sudbø's brother, wife and Andrew J. Dannenberg, who was listed as the senior author on the article.
In May 2006, Norwegian and Swedish media reported that the committee was investigating some 60 scientists from 6 countries, and a total of 38 articles.[5]
The commission reported on 30 June 2006 [1]. The commission deemed much of Sudbø's work invalid because of manipulation and fabrication of raw data: of the 38 articles he had published since 1993, 15 were condemned as fraudulent, including his doctoral dissertation.[6] Because of this, the dissertation and the other fraudulent articles will be rescinded. The commission also criticised the co-authors of Sudbø's papers. Professor Anders Ekbom, the Chair of the Commission, said: "One explanation of this catastrophe was that Sudbø was a lone wolf. Few or anyone had insight into his work". However, the commission found no evidence that any of his co-authors had taken part in the fraud or otherwise been party to the deceit (although Sudbø's supervisor accepted criticism for lack of vigilance and follow-up).
In November 2006 his authorization as a physician and a dentist was revoked by the Norwegian Board of Health Supervision.
# Effects of fraud
Rikshospitalet and the University were both criticised for "a lack of preliminary control and organization with a view to the researcher's [Sudbø's] PhD project". The hospital was also criticised for "a lack of training and consciousness-raising in respect of the researcher and other employees with a view to the rules for handling patient material, preliminary assessments of research projects and authorship" and for "a lack of leadership and routines designed to expose and deal with non-conformance with its rules of procedure".
The fraud may also has international effects.[7] The commission could not rule out that Sudbø's false conclusions could have had an impact on cancer patients around the world, because his findings were used by other scientists and incorporated into cancer treatments, although Sudbø's solicitor Erling O. Lyngtveit had said on behalf of his client that none of the fraudulent articles had had any consequences for patients [2]. Norway's scientific reputation could also be damaged by the affair, and "massive lawsuits" may be imminent from the national and international organisations that funded Sudbø's fraudulent papers.
According to the Norwegian news website Depesjer ("Dispatches"), scientific experts they consulted felt that Sudbø's co-authors were "severely exploited", but also that closer observations of the Vancouver guidelines and other rules by co-authors would "hamper future attempts at publishing fabricated material" [3]. Dr. Atle Klovning, a leading European authority on evidence-based medicine, said in the article that Sudbø's co-authors had probably not lived up to their responsibilities according to the Vancouver rules. | https://www.wikidoc.org/index.php/Jon_Sudb%C3%B8 | |
b3e5ead6262885592ee2ac30018e5aab08fa2551 | wikidoc | Junk food | Junk food
Junk food is a term describing food that is unhealthy and/or has poor nutritional value, according to the Food Standards Agency (UK). The term is believed to have been coined by Michael Jacobson, director of the Center for Science in the Public Interest, in 1972. The term has since become common usage.
Junk food often contains high levels of saturated fat, salt, or sugar and numerous food additives such as monosodium glutamate and tartrazine; at the same time, it is lacking in proteins, vitamins and fibre, among other healthy attributes. It is popular with suppliers because it is relatively cheap to manufacture, has a long shelf life and may not require refrigeration. It is popular with American consumers because it is easy to purchase, requires little or no preparation, is convenient to consume and has lots of flavor. Consumption of junk food in America, has been associated with obesity, heart disease, Type 2 diabetes and dental cavities. There is also concern about the targeting of marketing to children.
# Classification
What constitutes unhealthy food may be confusing and, according to critics, includes elements of class snobbery, cultural influence and moral judgement. For example, fast food in North America, such as hamburgers and french fries supplied by companies such as McDonald's, KFC and Pizza Hut are often perceived as junk food, whereas the same meals supplied by more up-market outlets such as California Pizza Kitchen or Nando's are not, despite often having the same or worse nutritional content. Some foods that are considered ethnic or traditional are not generally considered junk food, such as falafel, pakora, gyoza or chicharron, though all of these foods have little nutritional value and are usually high in fat from being fried in oil. Other foods such as white rice, roast potatoes and processed white bread are not considered junk food despite having limited nutritional content compared to wholegrain foods. Similarly, breakfast cereals are often regarded as healthy but may have high levels of sugar, salt and fat.
Some types of chips that are said to be "junk food" may actually be partially harmful because they may contain polyunsaturated and monounsaturated fats. It should also be understood that the detrimental effects of the empty calories may outweigh the benefits of the unsaturated fats. These foods tend to be high in sodium, which may contribute in causing hypertension (high blood pressure) in some people.
# Marketing
During 2006 in the United Kingdom following a high profile media campaign by the chef Jamie Oliver and a threat of court action from the National Heart Forum, the UK advertising regulator and competition authority, Ofcom, launched a consultation on advertising of foods to children. The Food Standards Agency was one of many respondents. As a result a ban on advertising during children's television programmes and programmes aimed at young people was announced. The ban also includes marketing using celebrities, cartoon characters and health or nutrition claims. Some schools have tried to ban junk food. | Junk food
Template:Globalize/USA
Junk food is a term describing food that is unhealthy and/or has poor nutritional value, according to the Food Standards Agency (UK). The term is believed to have been coined by Michael Jacobson, director of the Center for Science in the Public Interest, in 1972.[1] The term has since become common usage.
Junk food often contains high levels of saturated fat, salt, or sugar and numerous food additives such as monosodium glutamate and tartrazine; at the same time, it is lacking in proteins, vitamins and fibre, among other healthy attributes. It is popular with suppliers because it is relatively cheap to manufacture, has a long shelf life and may not require refrigeration. It is popular with American consumers because it is easy to purchase, requires little or no preparation, is convenient to consume and has lots of flavor. Consumption of junk food in America, has been associated with obesity, heart disease, Type 2 diabetes and dental cavities. There is also concern about the targeting of marketing to children.
# Classification
What constitutes unhealthy food may be confusing and, according to critics, includes elements of class snobbery, cultural influence and moral judgement. For example, fast food in North America, such as hamburgers and french fries supplied by companies such as McDonald's, KFC and Pizza Hut are often perceived as junk food, whereas the same meals supplied by more up-market outlets such as California Pizza Kitchen or Nando's are not, despite often having the same or worse nutritional content.[1] Some foods that are considered ethnic or traditional are not generally considered junk food, such as falafel, pakora, gyoza or chicharron, though all of these foods have little nutritional value and are usually high in fat from being fried in oil. Other foods such as white rice, roast potatoes and processed white bread are not considered junk food despite having limited nutritional content compared to wholegrain foods. Similarly, breakfast cereals are often regarded as healthy but may have high levels of sugar, salt and fat.[2]
Some types of chips that are said to be "junk food" may actually be partially harmful because they may contain polyunsaturated and monounsaturated fats. It should also be understood that the detrimental effects of the empty calories may outweigh the benefits of the unsaturated fats[citation needed]. These foods tend to be high in sodium, which may contribute in causing hypertension (high blood pressure) in some people.
# Marketing
During 2006 in the United Kingdom following a high profile media campaign by the chef Jamie Oliver and a threat of court action from the National Heart Forum[3], the UK advertising regulator and competition authority, Ofcom, launched a consultation on advertising of foods to children.[4] The Food Standards Agency was one of many respondents.[5] As a result a ban on advertising during children's television programmes and programmes aimed at young people was announced.[6] The ban also includes marketing using celebrities, cartoon characters and health or nutrition claims. Some schools have tried to ban junk food. | https://www.wikidoc.org/index.php/Junk_Food | |
ff5ac7045183c3fd76700c74817d7461582c6599 | wikidoc | Junk page | Junk page
Synonyms / Brand Names:
# Dosing and Administration
FDA Package Insert Resources
Indications, Contraindications, Side Effects, Drug Interactions, etc.
Calculate Creatine Clearance
On line calculator of your patients Cr Cl by a variety of formulas.
Convert pounds to Kilograms
On line calculator of your patients weight in pounds to Kg for dosing estimates.
Publication Resources
Recent articles, WikiDoc State of the Art Review, Textbook Information
Trial Resources
Ongoing Trials, Trial Results
Guidelines & Evidence Based Medicine Resources
US National Guidelines, Cochrane Collaboration, etc.
Media Resources
Slides, Video, Images, MP3, Podcasts, etc.
Patient Resources
Discussion Groups, Handouts, Blogs, News, etc.
International Resources
en Español
# FDA Package Insert Resources
Indications
Contraindications
Side Effects
Drug Interactions
Precautions
Overdose
Instructions for Administration
How Supplied
Pharmacokinetics and Molecular Data
FDA label
FDA on Junk page
Return to top
# Publication Resources
Most Recent Articles on Junk page
Review Articles on Junk page
Articles on Junk page in N Eng J Med, Lancet, BMJ
WikiDoc State of the Art Review
Textbook Information on Junk page
Return to top
# Trial Resources
Ongoing Trials with Junk page at Clinical Trials.gov
Trial Results with Junk page
Return to top
# Guidelines & Evidence Based Medicine Resources
US National Guidelines Clearinghouse on Junk page
Cochrane Collaboration on Junk page
Cost Effectiveness of Junk page
Return to top
# Media Resources
Powerpoint Slides on Junk page
Images of Junk page
Podcasts & MP3s on Junk page
Videos on Junk page
Return to top
# Patient Resources
Patient Information from National Library of Medicine
Patient Resources on Junk page
Discussion Groups on Junk page
Patient Handouts on Junk page
Blogs on Junk page
Junk page in the News
Junk page in the Marketplace
Return to top
# International Resources
Junk page en Español
Return to top
Adapted from the FDA Package Insert. | Junk page
Synonyms / Brand Names:
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Dosing and Administration
FDA Package Insert Resources
Indications, Contraindications, Side Effects, Drug Interactions, etc.
Calculate Creatine Clearance
On line calculator of your patients Cr Cl by a variety of formulas.
Convert pounds to Kilograms
On line calculator of your patients weight in pounds to Kg for dosing estimates.
Publication Resources
Recent articles, WikiDoc State of the Art Review, Textbook Information
Trial Resources
Ongoing Trials, Trial Results
Guidelines & Evidence Based Medicine Resources
US National Guidelines, Cochrane Collaboration, etc.
Media Resources
Slides, Video, Images, MP3, Podcasts, etc.
Patient Resources
Discussion Groups, Handouts, Blogs, News, etc.
International Resources
en Español
# FDA Package Insert Resources
Indications
Contraindications
Side Effects
Drug Interactions
Precautions
Overdose
Instructions for Administration
How Supplied
Pharmacokinetics and Molecular Data
FDA label
FDA on Junk page
Return to top
# Publication Resources
Most Recent Articles on Junk page
Review Articles on Junk page
Articles on Junk page in N Eng J Med, Lancet, BMJ
WikiDoc State of the Art Review
Textbook Information on Junk page
Return to top
# Trial Resources
Ongoing Trials with Junk page at Clinical Trials.gov
Trial Results with Junk page
Return to top
# Guidelines & Evidence Based Medicine Resources
US National Guidelines Clearinghouse on Junk page
Cochrane Collaboration on Junk page
Cost Effectiveness of Junk page
Return to top
# Media Resources
Powerpoint Slides on Junk page
Images of Junk page
Podcasts & MP3s on Junk page
Videos on Junk page
Return to top
# Patient Resources
Patient Information from National Library of Medicine
Patient Resources on Junk page
Discussion Groups on Junk page
Patient Handouts on Junk page
Blogs on Junk page
Junk page in the News
Junk page in the Marketplace
Return to top
# International Resources
Junk page en Español
Return to top
Adapted from the FDA Package Insert. | https://www.wikidoc.org/index.php/Junk_page | |
e121a88d7e34f3ee7cb8dda2331deb95218dbc44 | wikidoc | KIAA0895L | KIAA0895L
Uncharacterized protein KIAA0895-like also known as LOC653319, is a protein that in humans is encoded by the KIAA0895L gene.
# Gene
KIAA0895L is located at q22.1 on chromosome 16 of the human genome. Its genomic DNA consists of 8,379 base pairs. KIAA0895L is located between EXOC3L and E2F4 on the right, and NOL3 and HSF4 on the left. The promoter for KIAA0895L is located on chromosome 16 and spans 67217367-67218383bp.
KIAA0895L was first documented by the Mammalian Gene Collection Program Team in 2002. There are several patents on KIAA0895L, two of those being patent US 6943241 and patent EP1308459.
# Species distribution
KIAA0895L orthologs can be found in all mammals. It is not found in plants, archaea, or fungi. KIAA0895L has a single paralog, known as KIAA0895.
The known orthologs of KIAA0895L are listed below:
- Chimpanzee – LOC741288
- Rhesus monkey – LOC696623
- Dog – LOC489765
- Horse – LOC100053028
- Giant panda – PANDA_006923
- Cow – LOC512420
- Norway rat – LOC688736
- Zebra finch – LOC100223241
- Chicken – LOC415660
- Mouse – LOC74356
- Opossum – LOC100019983
- Puffer fish – Unnamed
- Sea squirt – LOC100177006
- Platypus – LOC100078127
- Zebrafish – LOC562097
- Frog – LOC100135412
- Sea urchin – KIAA0895
- Ciliated protozoa – TTherm_01042050
- Plasmodium – PY05482
- Trichoplax adherens – TRIADDRAFT_62861
- Kordia – KAOT1_03617
# Structure
KIAA0895L is composed of 471 amino acids (53.5kDa). A proline-rich region was also revealed at 14-65 amino acids. There is also an area of low complexity at 2913-2917 bp in the 3’ UTR region. There is a conserved domain of unknown function, known as DUF1704, located at 1390-2083 bp.
# Predicted post translational modifications
The following is a list of predicted post translational modifications found for KIAA0895L. These are predicted in all mammalian orthologs in the public sequence database.
# Interacting proteins
No proteins that interact with KIAA0895L or its homolog have yet been identified.
# Tissue distribution
KIAA0895L is expressed in many tissues of the body such as brain, testis, mammary glands, bladder, and the eye.
# Clinical significance
KIAA0895L has been shown to be up regulated in lymphoblastoid cells from males with autism that is caused by an expansion of a CGG repeat in the promoter region of the fragile X mental retardation 1 gene located at Xq27.3 as well as in cells with a 15q11-q13 mutation.
# Notes and references
- ↑ "Entrez Gene: KIAA0895-like"..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}
- ↑ Genecards bin/cards/carddisp.pl?gene=KIAA0895L&search=KIAA0895L
- ↑ NCBI
- ↑ NCBI Entrez Gene
- ↑ UCSC Genome Bioinformatics
- ↑ Genomatix
- ↑ Strausberg RL, Feingold EA, Grouse LH, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- ↑ BLAST (Basic Local Alignment Search Tool)
- ↑ KEGG
- ↑ KEGG
- ↑ SDBC(San Diego Supercomputer Center Biology Workbench)
- ↑ Higgins DG, Bleasby AJ, Fuchs R (April 1992). "CLUSTAL V: improved software for multiple sequence alignment". Comput. Appl. Biosci. 8 (2): 189–91. doi:10.1093/bioinformatics/8.2.189. PMID 1591615.
- ↑ Genecards bin/cards/carddisp.pl?gene=KIAA0895L&search=KIAA0895L
- ↑ KEGG(Kyoto Encyclopedia of Genes and Genomes)
- ↑ Dotlet(My Hits)
- ↑ Junier T, Pagni M (February 2000). "Dotlet: diagonal plots in a web browser". Bioinformatics. 16 (2): 178–9. doi:10.1093/bioinformatics/16.2.178. PMID 10842741.
- ↑ BLAST(Basic Local Alignment Search Tool)
- ↑ Swiss Institute of Bioinformatics, ExPASy
- ↑ Genecards
- ↑ NCBI GEO (National Center for Biotechnology Information Gene Expression Omnibus)
- ↑ Nishimura Y, Martin CL, Vazquez-Lopez A, Spence SJ, Alvarez-Retuerto AI, Sigman M, Steindler C, Pellegrini S, Schanen NC, Warren ST, Geschwind DH (July 2007). "Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways". Hum. Mol. Genet. 16 (14): 1682–98. doi:10.1093/hmg/ddm116. PMID 17519220. | KIAA0895L
Uncharacterized protein KIAA0895-like also known as LOC653319, is a protein that in humans is encoded by the KIAA0895L gene.[1]
# Gene
KIAA0895L is located at q22.1 on chromosome 16 of the human genome.[2] Its genomic DNA consists of 8,379 base pairs.[3] KIAA0895L is located between EXOC3L and E2F4 on the right, and NOL3 and HSF4 on the left.[4] The promoter for KIAA0895L is located on chromosome 16 and spans 67217367-67218383bp.[5][6]
KIAA0895L was first documented by the Mammalian Gene Collection Program Team in 2002.[7] There are several patents on KIAA0895L, two of those being patent US 6943241 and patent EP1308459.[8]
# Species distribution
KIAA0895L orthologs can be found in all mammals.[9] It is not found in plants, archaea, or fungi. KIAA0895L has a single paralog, known as KIAA0895.[10]
The known orthologs of KIAA0895L are listed below:[11][12]
- Chimpanzee – LOC741288
- Rhesus monkey – LOC696623
- Dog – LOC489765
- Horse – LOC100053028
- Giant panda – PANDA_006923
- Cow – LOC512420
- Norway rat – LOC688736
- Zebra finch – LOC100223241
- Chicken – LOC415660
- Mouse – LOC74356
- Opossum – LOC100019983
- Puffer fish – Unnamed
- Sea squirt – LOC100177006
- Platypus – LOC100078127
- Zebrafish – LOC562097
- Frog – LOC100135412
- Sea urchin – KIAA0895
- Ciliated protozoa – TTherm_01042050
- Plasmodium – PY05482
- Trichoplax adherens – TRIADDRAFT_62861
- Kordia – KAOT1_03617
# Structure
KIAA0895L is composed of 471 amino acids (53.5kDa).[13] A proline-rich region was also revealed at 14-65 amino acids.[14] There is also an area of low complexity at 2913-2917 bp in the 3’ UTR region.[15][16] There is a conserved domain of unknown function, known as DUF1704, located at 1390-2083 bp.[17]
# Predicted post translational modifications
The following is a list of predicted post translational modifications found for KIAA0895L.[18] These are predicted in all mammalian orthologs in the public sequence database.
# Interacting proteins
No proteins that interact with KIAA0895L or its homolog have yet been identified.
# Tissue distribution
KIAA0895L is expressed in many tissues of the body such as brain, testis, mammary glands, bladder, and the eye.[19]
# Clinical significance
KIAA0895L has been shown to be up regulated[20] in lymphoblastoid cells from males with autism that is caused by an expansion of a CGG repeat in the promoter region of the fragile X mental retardation 1 gene located at Xq27.3[21] as well as in cells with a 15q11-q13 mutation.
# Notes and references
- ↑ "Entrez Gene: KIAA0895-like"..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}
- ↑ Genecards bin/cards/carddisp.pl?gene=KIAA0895L&search=KIAA0895L
- ↑ NCBI
- ↑ NCBI Entrez Gene
- ↑ UCSC Genome Bioinformatics
- ↑ Genomatix
- ↑ Strausberg RL, Feingold EA, Grouse LH, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- ↑ BLAST (Basic Local Alignment Search Tool)
- ↑ KEGG
- ↑ KEGG
- ↑ SDBC(San Diego Supercomputer Center Biology Workbench)
- ↑ Higgins DG, Bleasby AJ, Fuchs R (April 1992). "CLUSTAL V: improved software for multiple sequence alignment". Comput. Appl. Biosci. 8 (2): 189–91. doi:10.1093/bioinformatics/8.2.189. PMID 1591615.
- ↑ Genecards bin/cards/carddisp.pl?gene=KIAA0895L&search=KIAA0895L
- ↑ KEGG(Kyoto Encyclopedia of Genes and Genomes)
- ↑ Dotlet(My Hits)
- ↑ Junier T, Pagni M (February 2000). "Dotlet: diagonal plots in a web browser". Bioinformatics. 16 (2): 178–9. doi:10.1093/bioinformatics/16.2.178. PMID 10842741.
- ↑ BLAST(Basic Local Alignment Search Tool)
- ↑ Swiss Institute of Bioinformatics, ExPASy [1]
- ↑ Genecards
- ↑ NCBI GEO (National Center for Biotechnology Information Gene Expression Omnibus)[2]
- ↑ Nishimura Y, Martin CL, Vazquez-Lopez A, Spence SJ, Alvarez-Retuerto AI, Sigman M, Steindler C, Pellegrini S, Schanen NC, Warren ST, Geschwind DH (July 2007). "Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways". Hum. Mol. Genet. 16 (14): 1682–98. doi:10.1093/hmg/ddm116. PMID 17519220. | https://www.wikidoc.org/index.php/KIAA0895L | |
5884b41adaabc51d7c9955b04af10ad8d09ea354 | wikidoc | KIAA1211L | KIAA1211L
KIAA1211L is a protein that in humans is encoded by the KIAA1211L gene. It is highly expressed in the brain (Cerebral Cortex). Furthermore, it is localized to the microtubules and the centrosomes and is subcellularly located in the nucleus. Finally, KIAA1211L is associated with certain mental disorders and various cancers.
# Gene
KIAA1211L is a protein-coding gene. The table above presents the gene’s alias, location, size and accession number.
# mRNA
There are 11 splice isoforms of the gene KIAA1211L. The validated isoform has 10 exons.
# Protein
The table above presents the protein’s alias, size, and accession number. The KIAA1211L protein is proline rich and asparagine, isoleucine, phenylalanine, and tyrosine poor.
## Domains and motifs
The KIAA1211L protein has one domain called the DUF4592 motif and spans amino acids 131-239. This domain is highly conserved among the KIAA1211L orthologs.The DUF4592 motif is depicted in both the conceptual translation and schematic figures.
## Post translational modifications
KIAA1211L is phosphorylated at the Ser92 and Ser490 amino acids. The KIAA1211L protein is also predicted to have five different SUMOylation sites located at Lys134, Lys375, Lys866, Lys874, and Lys914. Both the phosphorylated sites and the SUMOylation sites are depicted in the conceptual translation and schematic figures.
## Secondary structure
The KIAA1211L protein predicted secondary structure is composed of 50% alpha helixes, 8.9% beta sheets, and 17.9% turns. The high number of turns is consistent with the fact that KIAA1211L is proline rich.
## Subcellular location
The KIAA1211L protein is predicted to be located in the nucleus. The orthologs, including the elephant shark, horse, rock dove, and chimp, are also predicted to be located in the nucleus. The nuclear location signal is located on amino acids 25-43 which is depicted in both the conceptual translation and schematic figures. . This signal is conserved throughout the orthologs. Additionally, this location (amino acids 24-43) is positively charged, probably due to the high amount of lysine at this location. Finally, it is predicted that KIAA1211L is mainly localized to the microtubules and centrosome and sometimes localized to the cytokinetic bridge.
# Expression
The gene is highly expressed in the brain (Cerebral Cortex). The KIAA1211L protein is located in many different tissue types, including the brain, the hippocampus, the lung, breast carcinoma, the islets of Langerhans, the pancreas, the kidney, and 38 other tissues. Additionally, it is expressed an average amount compared to other human proteins.
## Regulation of transcription
The promoter region of KIAA1211L is approximately 1340 base pairs with various predicted transcription factors. The glial cells missing homolog 1 and the oligodendrocyte lineage transcription factors are notable because KIAA1211L is highly expressed in the brain. Furthermore, the Estrogen-related receptor alpha is also a notable transcription factor due to KIAA1211L's low expression levels when estrogen receptors are knocked down. Furthermore, KIAA1211L is predicted to be SUMOylated. The 3' UTR of KIAA1211L is predicted to be a targeted by miRNA-132, which is depicted in the conceptual translation figure.
# Function
## Interacting proteins
Glycogen Synthase Kinase 3 Beta (GSK3B)
GSK3B is a protein kinase that regulates transcription factors and microtubules. As such, it phosphorylates proteins, decreasing their ability to bind and stabilize microtubules. The proteins it phosphorylates are the principle components of neurofibrillary tangles in Alzheimer disease. The protein is needed for the establishment of neuronal polarity and axon outgrowth and phosphorylates proteins in neuroblastoma cells. Furthermore, it is associated with bipolar disease and is active in breast cancer cells.
As such, the predicted interaction between KIAA1211L and GSK3B is likely because KIAA1211L is highly expressed in the brain, associated with bipolar disorder and breast cancer, and is localized on the microtubules. The interaction between GSK3B and KIAA1211L was predicted using anti bait coimmunoprecipitation, pull down, tandem affinity purification, fluorescence polarization spectroscopy, protein kinases assay, two hybrid, and confocal microscopy experiments.
KIAA1211L protein is also predicted to interact with Alpha-synuclein (SNCA), E3 Ubiquitin-Protein Ligase Mdm2 (MDM2), Serine/Threonine-Protein Kinase PAK 1 (PAK 1), and DNA Replication Factor Cdt1 (CDT1).
## Clinical significance
KIAA1211L is associated with depression, bipolar disorder, and schizophrenia. Additionally, KIAA1211L is associated with various cancers including ovarian, breast, etc.
# Homology
## Paralogs
KIAA1211 is the paralog to KIAA1211L. KIAA1211 is located on chromosome 4 and has 1233 amino acids. It's percent identity to KIAA1211L is 21%. The KIAA1211 has an ortholog in the bacteria Proteus vulgarism, indicating the paralog duplicated 4290 million years ago, before KIAA1211L.
## Orthologs
Below is the table of various KIAA1211L orthologs. It includes closely, intermediately, and distantly related orthologs. The most distant ortholog is the elephant shark, indicating KIAA1211L duplicated 473 MYA. The amino acids conserved among all the KIAA1211L orthologs are depicted in the conceptual translation.
## Phylogeny
The KIAA1211L gene is similar and conserved in mammals, birds, reptiles, amphibians, and fish. It is not conserved in bacteria, archaea, protists, plants, fungus, trichoplax, and invertebrates.
# Citations
- ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 1.5 "KIAA1211L KIAA1211 like - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-23..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}
- ↑ Jump up to: 2.0 2.1 2.2 "Cell atlas - KIAA1211L - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2017-04-23.
- ↑ Jump up to: 3.0 3.1 3.2 3.3 "GenScript Protein Subcellular Location Prediction Tool".
- ↑ Jump up to: 4.0 4.1 4.2 Spurrell, C. H. (2013). "Identifying New Genes for Inherited Breast Cancer by Exome Sequencing".
- ↑ Jump up to: 5.0 5.1 5.2 Iwamoto, K; Kakiuchi, C; Bundo, M; Ikeda, K; Kato, T (April 2004). "Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders". Mol Psychiatry. 9 (4): 406–416. doi:10.1038/sj.mp.4001437.
- ↑ Jump up to: 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Database, GeneCards Human Gene. "KIAA1211L Gene - GeneCards | K121L Protein | K121L Antibody". www.genecards.org. Retrieved 2017-02-24.
- ↑ Jump up to: 7.0 7.1 "Homo sapiens KIAA1211 like (KIAA1211L), mRNA - Nucleotide - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-23.
- ↑ Jump up to: 8.0 8.1 8.2 8.3 8.4 8.5 Workbench, NCSA Biology. "SDSC Biology Workbench". workbench.sdsc.edu. Retrieved 2017-04-23.
- ↑ "Genatlas sheet". genatlas.medecine.univ-paris5.fr. Retrieved 2017-04-23.
- ↑ "Pfam: Family: DUF4592 (PF15262)". pfam.xfam.org. Retrieved 2017-04-23.
- ↑ "Homo sapiens KIAA1211 like (KIAA1211L), mRNA - Nucleotide - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-23.
- ↑ Jump up to: 12.0 12.1 "SUMOplot™ Analysis Program | Abgent". www.abgent.com. Retrieved 2017-04-23.
- ↑ Kumar, Prof. T. Ashok. "BioGem.Org - Ashok Kumar's Bioinformatics Portal... | Home". www.biogem.org. Retrieved 2017-04-23.
- ↑ "Tissue expression of KIAA1211L - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2017-04-23.
- ↑ "KIAA1211L protein abundance in PaxDb". pax-db.org. Retrieved 2017-04-23.
- ↑ Jump up to: 16.0 16.1 16.2 "Genomatix - NGS Data Analysis & Personalized Medicine". www.genomatix.de. Retrieved 2017-05-07.
- ↑ Al Saleh, S (2011). "Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells". PLoS One. 6.
- ↑ Alvarez-Saavedra, M (2010). "MicroRNA-132-Dependent Post-Transcriptional Regulation of Clock Entrainment Physiology Via Modulation of Chromatin Remodeling and Translational Control Gene Targets". University of Ottawa.
- ↑ Jump up to: 19.0 19.1 19.2 19.3 19.4 "GSK3B - Glycogen synthase kinase-3 beta - Homo sapiens (Human) - GSK3B gene & protein". www.uniprot.org. Retrieved 2017-04-23.
- ↑ Database, GeneCards Human Gene. "GSK3B Gene - GeneCards | GSK3B Protein | GSK3B Antibody". www.genecards.org. Retrieved 2017-04-23.
- ↑ Jump up to: 21.0 21.1 "IntAct". www.ebi.ac.uk. Retrieved 2017-04-23.
- ↑ Database, GeneCards Human Gene. "KIAA1211 Gene - GeneCards | K1211 Protein | K1211 Antibody". www.genecards.org. Retrieved 2017-04-23.
- ↑ Myers and Miller (1989). "CABIOS". 4: 11–17.
- ↑ "kiaa1211l KIAA1211 like - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-02-24.
- ↑ "TimeTree :: The Timescale of Life". www.timetree.org. Retrieved 2017-02-24.
- ↑ Jump up to: 26.0 26.1 "BLAST: Basic Local Alignment Search Tool". blast.ncbi.nlm.nih.gov. Retrieved 2017-04-23.
- ↑ "TimeTree :: The Timescale of Life". www.timetree.org. Retrieved 2017-04-23.
- ↑ EMBL-EBI. "EMBOSS Needle < Pairwise Sequence Alignment < EMBL-EBI". www.ebi.ac.uk. Retrieved 2017-04-23. | KIAA1211L
KIAA1211L is a protein that in humans is encoded by the KIAA1211L gene. It is highly expressed in the brain (Cerebral Cortex).[1] Furthermore, it is localized to the microtubules and the centrosomes and is subcellularly located in the nucleus.[2][3] Finally, KIAA1211L is associated with certain mental disorders and various cancers.[4][5]
# Gene
KIAA1211L is a protein-coding gene.[6] The table above presents the gene’s alias, location, size and accession number.
# mRNA
There are 11 splice isoforms of the gene KIAA1211L.[1] The validated isoform has 10 exons.[1]
# Protein
The table above presents the protein’s alias, size, and accession number. The KIAA1211L protein is proline rich and asparagine, isoleucine, phenylalanine, and tyrosine poor.[8]
## Domains and motifs
The KIAA1211L protein has one domain called the DUF4592 motif and spans amino acids 131-239.[10] This domain is highly conserved among the KIAA1211L orthologs.The DUF4592 motif is depicted in both the conceptual translation and schematic figures.
## Post translational modifications
KIAA1211L is phosphorylated at the Ser92 and Ser490 amino acids.[11] The KIAA1211L protein is also predicted to have five different SUMOylation sites located at Lys134, Lys375, Lys866, Lys874, and Lys914.[12] Both the phosphorylated sites and the SUMOylation sites are depicted in the conceptual translation and schematic figures.
## Secondary structure
The KIAA1211L protein predicted secondary structure is composed of 50% alpha helixes, 8.9% beta sheets, and 17.9% turns.[13] The high number of turns is consistent with the fact that KIAA1211L is proline rich.[8]
## Subcellular location
The KIAA1211L protein is predicted to be located in the nucleus.[3] The orthologs, including the elephant shark, horse, rock dove, and chimp, are also predicted to be located in the nucleus.[3] The nuclear location signal is located on amino acids 25-43 which is depicted in both the conceptual translation and schematic figures. .[3] This signal is conserved throughout the orthologs. Additionally, this location (amino acids 24-43) is positively charged, probably due to the high amount of lysine at this location.[8] Finally, it is predicted that KIAA1211L is mainly localized to the microtubules and centrosome and sometimes localized to the cytokinetic bridge.[2]
# Expression
The gene is highly expressed in the brain (Cerebral Cortex).[1] The KIAA1211L protein is located in many different tissue types, including the brain, the hippocampus, the lung, breast carcinoma, the islets of Langerhans, the pancreas, the kidney, and 38 other tissues.[14] Additionally, it is expressed an average amount compared to other human proteins.[15]
## Regulation of transcription
The promoter region of KIAA1211L is approximately 1340 base pairs with various predicted transcription factors.[16] The glial cells missing homolog 1 and the oligodendrocyte lineage transcription factors are notable because KIAA1211L is highly expressed in the brain.[16][1] Furthermore, the Estrogen-related receptor alpha is also a notable transcription factor due to KIAA1211L's low expression levels when estrogen receptors are knocked down.[17][16] Furthermore, KIAA1211L is predicted to be SUMOylated.[12] The 3' UTR of KIAA1211L is predicted to be a targeted by miRNA-132, which is depicted in the conceptual translation figure.[18]
# Function
## Interacting proteins
Glycogen Synthase Kinase 3 Beta (GSK3B)
GSK3B is a protein kinase that regulates transcription factors and microtubules.[19] As such, it phosphorylates proteins, decreasing their ability to bind and stabilize microtubules.[19] The proteins it phosphorylates are the principle components of neurofibrillary tangles in Alzheimer disease.[19] The protein is needed for the establishment of neuronal polarity and axon outgrowth and phosphorylates proteins in neuroblastoma cells.[19] Furthermore, it is associated with bipolar disease and is active in breast cancer cells.[19][20]
As such, the predicted interaction between KIAA1211L and GSK3B is likely because KIAA1211L is highly expressed in the brain, associated with bipolar disorder and breast cancer, and is localized on the microtubules.[1][2][4][5] The interaction between GSK3B and KIAA1211L was predicted using anti bait coimmunoprecipitation, pull down, tandem affinity purification, fluorescence polarization spectroscopy, protein kinases assay, two hybrid, and confocal microscopy experiments.[21]
KIAA1211L protein is also predicted to interact with Alpha-synuclein (SNCA), E3 Ubiquitin-Protein Ligase Mdm2 (MDM2), Serine/Threonine-Protein Kinase PAK 1 (PAK 1), and DNA Replication Factor Cdt1 (CDT1).[21]
## Clinical significance
KIAA1211L is associated with depression, bipolar disorder, and schizophrenia.[5] Additionally, KIAA1211L is associated with various cancers including ovarian, breast, etc.[4]
# Homology
## Paralogs
KIAA1211 is the paralog to KIAA1211L. KIAA1211 is located on chromosome 4 and has 1233 amino acids.[22] It's percent identity to KIAA1211L is 21%.[23] The KIAA1211 has an ortholog in the bacteria Proteus vulgarism, indicating the paralog duplicated 4290 million years ago, before KIAA1211L.[24][25]
## Orthologs
Below is the table of various KIAA1211L orthologs. It includes closely, intermediately, and distantly related orthologs. The most distant ortholog is the elephant shark, indicating KIAA1211L duplicated 473 MYA. The amino acids conserved among all the KIAA1211L orthologs are depicted in the conceptual translation.
## Phylogeny
The KIAA1211L gene is similar and conserved in mammals, birds, reptiles, amphibians, and fish. It is not conserved in bacteria, archaea, protists, plants, fungus, trichoplax, and invertebrates.
# Citations
- ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 1.5 "KIAA1211L KIAA1211 like [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-23..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}
- ↑ Jump up to: 2.0 2.1 2.2 "Cell atlas - KIAA1211L - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2017-04-23.
- ↑ Jump up to: 3.0 3.1 3.2 3.3 "GenScript Protein Subcellular Location Prediction Tool".
- ↑ Jump up to: 4.0 4.1 4.2 Spurrell, C. H. (2013). "Identifying New Genes for Inherited Breast Cancer by Exome Sequencing".
- ↑ Jump up to: 5.0 5.1 5.2 Iwamoto, K; Kakiuchi, C; Bundo, M; Ikeda, K; Kato, T (April 2004). "Molecular characterization of bipolar disorder by comparing gene expression profiles of postmortem brains of major mental disorders". Mol Psychiatry. 9 (4): 406–416. doi:10.1038/sj.mp.4001437.
- ↑ Jump up to: 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Database, GeneCards Human Gene. "KIAA1211L Gene - GeneCards | K121L Protein | K121L Antibody". www.genecards.org. Retrieved 2017-02-24.
- ↑ Jump up to: 7.0 7.1 "Homo sapiens KIAA1211 like (KIAA1211L), mRNA - Nucleotide - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-23.
- ↑ Jump up to: 8.0 8.1 8.2 8.3 8.4 8.5 Workbench, NCSA Biology. "SDSC Biology Workbench". workbench.sdsc.edu. Retrieved 2017-04-23.
- ↑ "Genatlas sheet". genatlas.medecine.univ-paris5.fr. Retrieved 2017-04-23.
- ↑ "Pfam: Family: DUF4592 (PF15262)". pfam.xfam.org. Retrieved 2017-04-23.
- ↑ "Homo sapiens KIAA1211 like (KIAA1211L), mRNA - Nucleotide - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-04-23.
- ↑ Jump up to: 12.0 12.1 "SUMOplot™ Analysis Program | Abgent". www.abgent.com. Retrieved 2017-04-23.
- ↑ Kumar, Prof. T. Ashok. "BioGem.Org - Ashok Kumar's Bioinformatics Portal... | Home". www.biogem.org. Retrieved 2017-04-23.
- ↑ "Tissue expression of KIAA1211L - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2017-04-23.
- ↑ "KIAA1211L protein abundance in PaxDb". pax-db.org. Retrieved 2017-04-23.
- ↑ Jump up to: 16.0 16.1 16.2 "Genomatix - NGS Data Analysis & Personalized Medicine". www.genomatix.de. Retrieved 2017-05-07.
- ↑ Al Saleh, S (2011). "Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells". PLoS One. 6.
- ↑ Alvarez-Saavedra, M (2010). "MicroRNA-132-Dependent Post-Transcriptional Regulation of Clock Entrainment Physiology Via Modulation of Chromatin Remodeling and Translational Control Gene Targets". University of Ottawa.
- ↑ Jump up to: 19.0 19.1 19.2 19.3 19.4 "GSK3B - Glycogen synthase kinase-3 beta - Homo sapiens (Human) - GSK3B gene & protein". www.uniprot.org. Retrieved 2017-04-23.
- ↑ Database, GeneCards Human Gene. "GSK3B Gene - GeneCards | GSK3B Protein | GSK3B Antibody". www.genecards.org. Retrieved 2017-04-23.
- ↑ Jump up to: 21.0 21.1 "IntAct". www.ebi.ac.uk. Retrieved 2017-04-23.
- ↑ Database, GeneCards Human Gene. "KIAA1211 Gene - GeneCards | K1211 Protein | K1211 Antibody". www.genecards.org. Retrieved 2017-04-23.
- ↑ Myers and Miller (1989). "CABIOS". 4: 11–17.
- ↑ "kiaa1211l KIAA1211 like [Callorhinchus milii (elephant shark)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-02-24.
- ↑ "TimeTree :: The Timescale of Life". www.timetree.org. Retrieved 2017-02-24.
- ↑ Jump up to: 26.0 26.1 "BLAST: Basic Local Alignment Search Tool". blast.ncbi.nlm.nih.gov. Retrieved 2017-04-23.
- ↑ "TimeTree :: The Timescale of Life". www.timetree.org. Retrieved 2017-04-23.
- ↑ EMBL-EBI. "EMBOSS Needle < Pairwise Sequence Alignment < EMBL-EBI". www.ebi.ac.uk. Retrieved 2017-04-23. | https://www.wikidoc.org/index.php/KIAA1211L | |
933dd8b78bf8c1190b058fe2872c7377bfb38b09 | wikidoc | Keratin 1 | Keratin 1
Keratin 1 is a member of the keratin family. It is specifically expressed in the spinous and granular layers of the epidermis with family member keratin 10. Mutations in this gene have been associated with the variants of bullous congenital ichthyosiform erythroderma in which the palms and soles of the feet are affected.
This gene, of the keratin family, is formed by type II cytokeratins set in pairs in a heterotypic chain, which are shown throughout the differentiation of epithelial tissues. This type II cytokeratin is specifically expressed in the spinous and granular layers of the epidermis. Connections between mutations in the Keratin family and bullous congenital ichthyosiform erythroderma have been made, on account of type II cytokeratins being found clustered in a region of chromosomes 12q12-q13.
# Interactions
Keratin 1 has been shown to interact with Desmoplakin and PRKCE. | Keratin 1
Keratin 1 is a member of the keratin family. It is specifically expressed in the spinous and granular layers of the epidermis with family member keratin 10. Mutations in this gene have been associated with the variants of bullous congenital ichthyosiform erythroderma in which the palms and soles of the feet are affected.
This gene, of the keratin family, is formed by type II cytokeratins set in pairs in a heterotypic chain, which are shown throughout the differentiation of epithelial tissues. This type II cytokeratin is specifically expressed in the spinous and granular layers of the epidermis. Connections between mutations in the Keratin family and bullous congenital ichthyosiform erythroderma have been made, on account of type II cytokeratins being found clustered in a region of chromosomes 12q12-q13.[1]
# Interactions
Keratin 1 has been shown to interact with Desmoplakin[2] and PRKCE.[3] | https://www.wikidoc.org/index.php/KRT1 | |
b1e71bf5224f47a439ca65fd7fa2c2a2726586f5 | wikidoc | Keratin 5 | Keratin 5
Keratin 5, also known as KRT5, K5, or CK5, is a protein that is encoded in humans by the KRT5 gene. It dimerizes with keratin 14 and forms the intermediate filaments (IF) that make up the cytoskeleton of basal epithelial cells. This protein is involved in several diseases including epidermolysis bullosa simplex and breast and lung cancers.
# Structure
Keratin 5, like other members of the keratin family, is an intermediate filament protein. These polypeptides are characterized by a 310 residue central rod domain that consists of four alpha helix segments (helix 1A, 1B, 2A, and 2B) connected by three short linker regions (L1, L1-2, and L2). The ends of the central rod domain, which are called the helix initiation motif (HIM) and the helix termination motif (HTM), are highly conserved. They are especially important for helix stabilization, heterodimer formation, and filament formation. Lying on either side of the central rod are variable, non-helical head and tail regions which protrude from the IF surface and provide specificity to different IF polypeptides.
IF central rods contain heptad repeats (repeating seven residue patterns) of hydrophobic resides that allow two different IF proteins to intertwine into a coiled-coil formation via hydrophobic interactions. These heterodimers are formed between specific pairs of type I (acidic) and type II (basic) keratin. K5, a type II keratin, pairs with the type I keratin K14. The coiled-coil dimers undergo stepwise assembly and combine in an antiparallel manner, forming end-to-end interactions with other coiled-coils to form large 10 nm intermediate filaments.
# Function
Keratin 5 (and K14) are expressed primarily in basal keratinocytes in the epidermis, specifically in the stratified epithelium lining the skin and digestive tract. Keratin intermediate filaments make up the cytoskeletal scaffold within epithelial cells, which contributes to the cell architecture and provides the cells with the ability to withstand mechanical, and non-mechanical, stresses. K5/K14 keratin pairs are able to undergo extensive bundling due to the non-helical tail of K15 acting as a weak cross-linker at the intermediate filament surface. This bundling increases the elasticity, and therefore the mechanical resilience, of the intermediate filaments.
K5/K14 intermediate filaments are anchored to the desmosomes of basal cells via desmoplakin and plakophilin-1, connecting the cells to their neighbours. At the hemidesmosome, plectin and BPAG1 associate with transmembrane proteins α6β4 integrin, a type of cell adhesion molecule, and BP180/collagen XVII, linking K5/K14 filaments in the basal cells to the basal lamina.
# Clinical relevance
## Epidermolysis bullosa simplex
Epidermolysis bullosa simplex (EBS) is an inherited skin blistering disorder associated with mutations in either K5 or K14. EBS-causing mutations are primarily missense mutations, but a small number of cases arise from insertions or deletions. Their mechanism of action is dominant negative interference, with the mutated keratin proteins interfering with the structure and integrity of the cytoskeleton. This cytoskeletal disorganization also leads to a loss of anchorage to the hemidesmosomes and desmosomes, causing basal cells to lose their linkage with the basal lamina and each other.
The severity of EBS has been observed to be dependent upon the position of the mutation within the protein, as well as the type of keratin (K5 or K14) that contains the mutation. Mutations that occur at either of the two 10-15 residue “hotspot” regions located on either end of the central rod domain (HIM and HTM) tend to coincide with more severe forms of EBS, whereas mutations at other spots usually result in milder symptoms. Since the “hotspot” regions contain the initiation and termination sequences of the alpha-helical rod, mutations at these spots usually have a larger effect on helix stabilization and heterodimer formation. Additionally, mutations in K5 tend to result in more severe symptoms than mutations in K14, possibly due to greater steric interference.
## Cancer
Keratin 5 serves as a biomarker for several different types of cancer, including breast and lung cancers.
Basal-like breast cancers tend to have poorer outcomes than other types of breast cancer due to a lack of targeted therapies. These breast cancers do not express human epidermal growth factor receptor-2 or receptors for estrogen or progesterone, making them immune to Trastuzumab/Herceptin and hormonal therapies , which are very effective against other breast cancer types. Due to the fact that K5 expression is only seen in basal cells, it serves as an important biomarker for screening patients with basal-like breast cancers to ensure that they are not receiving ineffective treatment.
Studies on lung cancer have also shown that squamous cell carcinomas give rise to tumors with elevated K5 levels, and that they are more likely to arise from stem cells expressing K5 than from those cells without K5 expression. K5 also serves as a marker of mesothelioma, and can be used to distinguish mesothelioma from pulmonary adenocarcinoma. Similarly, it can be used to distinguish papilloma, which is positive for K5, from papillary carcinoma, which is K5 negative. It can also serve as a marker of basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, and thymoma.
The expression of K5 is linked to the intermediate phenotype of cells undergoing the epithelial-mesenchymal transition (EMT). This process has a large role in tumor progression and metastasis since it helps enable tumor cells to travel throughout the body and colonize distant sites. K5 may therefore be useful in the identification of basal cell metastases. | Keratin 5
Keratin 5, also known as KRT5, K5, or CK5, is a protein that is encoded in humans by the KRT5 gene.[1][2][3] It dimerizes with keratin 14 and forms the intermediate filaments (IF) that make up the cytoskeleton of basal epithelial cells.[4][5] This protein is involved in several diseases including epidermolysis bullosa simplex and breast and lung cancers.[5][6][7]
# Structure
Keratin 5, like other members of the keratin family, is an intermediate filament protein. These polypeptides are characterized by a 310 residue central rod domain that consists of four alpha helix segments (helix 1A, 1B, 2A, and 2B) connected by three short linker regions (L1, L1-2, and L2).[4] The ends of the central rod domain, which are called the helix initiation motif (HIM) and the helix termination motif (HTM), are highly conserved. They are especially important for helix stabilization, heterodimer formation, and filament formation.[8] Lying on either side of the central rod are variable, non-helical head and tail regions which protrude from the IF surface and provide specificity to different IF polypeptides.[4]
IF central rods contain heptad repeats (repeating seven residue patterns) of hydrophobic resides that allow two different IF proteins to intertwine into a coiled-coil formation via hydrophobic interactions.[4] These heterodimers are formed between specific pairs of type I (acidic) and type II (basic) keratin. K5, a type II keratin, pairs with the type I keratin K14.[9] The coiled-coil dimers undergo stepwise assembly and combine in an antiparallel manner, forming end-to-end interactions with other coiled-coils to form large 10 nm intermediate filaments.[4][10]
# Function
Keratin 5 (and K14) are expressed primarily in basal keratinocytes in the epidermis, specifically in the stratified epithelium lining the skin and digestive tract.[5][9] Keratin intermediate filaments make up the cytoskeletal scaffold within epithelial cells, which contributes to the cell architecture and provides the cells with the ability to withstand mechanical, and non-mechanical, stresses.[5][10][11] K5/K14 keratin pairs are able to undergo extensive bundling due to the non-helical tail of K15 acting as a weak cross-linker at the intermediate filament surface. This bundling increases the elasticity, and therefore the mechanical resilience, of the intermediate filaments.[11]
K5/K14 intermediate filaments are anchored to the desmosomes of basal cells via desmoplakin and plakophilin-1, connecting the cells to their neighbours.[12] At the hemidesmosome, plectin and BPAG1 associate with transmembrane proteins α6β4 integrin, a type of cell adhesion molecule, and BP180/collagen XVII, linking K5/K14 filaments in the basal cells to the basal lamina.[10]
# Clinical relevance
## Epidermolysis bullosa simplex
Epidermolysis bullosa simplex (EBS) is an inherited skin blistering disorder associated with mutations in either K5 or K14.[5][13] EBS-causing mutations are primarily missense mutations, but a small number of cases arise from insertions or deletions. Their mechanism of action is dominant negative interference, with the mutated keratin proteins interfering with the structure and integrity of the cytoskeleton.[5] This cytoskeletal disorganization also leads to a loss of anchorage to the hemidesmosomes and desmosomes, causing basal cells to lose their linkage with the basal lamina and each other.[10][12]
The severity of EBS has been observed to be dependent upon the position of the mutation within the protein, as well as the type of keratin (K5 or K14) that contains the mutation. Mutations that occur at either of the two 10-15 residue “hotspot” regions located on either end of the central rod domain (HIM and HTM) tend to coincide with more severe forms of EBS, whereas mutations at other spots usually result in milder symptoms. Since the “hotspot” regions contain the initiation and termination sequences of the alpha-helical rod, mutations at these spots usually have a larger effect on helix stabilization and heterodimer formation.[8][13] Additionally, mutations in K5 tend to result in more severe symptoms than mutations in K14, possibly due to greater steric interference.[13]
## Cancer
Keratin 5 serves as a biomarker for several different types of cancer, including breast and lung cancers.[6][7]
Basal-like breast cancers tend to have poorer outcomes than other types of breast cancer due to a lack of targeted therapies.[7][14][15] These breast cancers do not express human epidermal growth factor receptor-2 or receptors for estrogen or progesterone, making them immune to Trastuzumab/Herceptin and hormonal therapies , which are very effective against other breast cancer types. Due to the fact that K5 expression is only seen in basal cells, it serves as an important biomarker for screening patients with basal-like breast cancers to ensure that they are not receiving ineffective treatment.[14]
Studies on lung cancer have also shown that squamous cell carcinomas give rise to tumors with elevated K5 levels, and that they are more likely to arise from stem cells expressing K5 than from those cells without K5 expression.[6] K5 also serves as a marker of mesothelioma, and can be used to distinguish mesothelioma from pulmonary adenocarcinoma.[16] Similarly, it can be used to distinguish papilloma, which is positive for K5, from papillary carcinoma, which is K5 negative.[17] It can also serve as a marker of basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, and thymoma.[16]
The expression of K5 is linked to the intermediate phenotype of cells undergoing the epithelial-mesenchymal transition (EMT). This process has a large role in tumor progression and metastasis since it helps enable tumor cells to travel throughout the body and colonize distant sites. K5 may therefore be useful in the identification of basal cell metastases.[18] | https://www.wikidoc.org/index.php/KRT5 | |
43f35f4ef0cd19783be6806d270102c03bfbfe11 | wikidoc | Lopinavir | Lopinavir
Lopinavir (ABT-378) is an antiretroviral of the protease inhibitor class. It is marketed by Abbott as Kaletra®, a co-formulation with a sub-therapeutic dose of ritonavir, as a component of combination therapy to treat HIV/AIDS.
As of 2006, lopinavir/ritonavir forms part of the preferred combination for first-line therapy recommended by the US DHHS. It is available as capsules, tablets and oral solution.
# History
Lopinavir was developed by Abbott in an attempt to improve on the HIV resistance and serum protein-binding properties of the company's earlier protease inhibitor, ritonavir. Administered alone, lopinavir has insufficient bioavailability; however, like several HIV protease inhibitors, its blood levels are greatly increased by low doses of ritonavir, a potent inhibitor of cytochrome P450 3A4. Abbott therefore pursued a strategy of co-administering lopinavir with sub-therapeutic doses of ritonavir, and lopinavir is only marketed as a co-formulation with ritonavir. It is the first multi-drug capsule to contain a drug not available individually.
Lopinavir/ritonavir was approved by the US FDA on 15 September 2000, and in Europe in April 2001. Its patent will expire in the US on June 26, 2016.
# Pharmacology
Lopinavir is highly bound to plasma proteins (98-99%).
There are contradictory reports regarding lopinavir penetration into the CSF. Anecdotal reports state that lopinavir cannot be detected in the CSF; however, a study of paired CSF-plasma samples from 26 patients receiving lopinavir/ritonavir found lopinavir CSF levels above the IC50 in 77% of samples.
# Adverse effects
The most common adverse effects observed with lopinavir/ritonavir are diarrhea and nausea. In key clinical trials, moderate or severe diarrhea occurred in up to 27% of patients, and moderate/severe nausea in up to 16%. Other common adverse effects include abdominal pain, asthenia, headache, vomiting and, particularly in children, rash.
Raised liver enzymes and hyperlipidemia (both hypertriglyceridemia and hypercholesterolemia) are also commonly observed during lopinavir/ritonavir treatment.
# Access
As a result of high prices and the spread of HIV infection, the government of Thailand issued a compulsory license on 29 January 2007 to produce and/or import generic lopinavir/ritonavir. In response, Abbott Laboratories pulled registration for lopinavir and seven of their other new drugs in Thailand, citing the Thai government's lack of respect for patents.
Abbott's attitude has been denounced by several NGOs worldwide, including a netstrike initiated by Act Up-Paris and a public call to boycott all of Abbott's medicines by the French NGO AIDES. | Lopinavir
Lopinavir (ABT-378) is an antiretroviral of the protease inhibitor class. It is marketed by Abbott as Kaletra®, a co-formulation with a sub-therapeutic dose of ritonavir, as a component of combination therapy to treat HIV/AIDS.
As of 2006, lopinavir/ritonavir forms part of the preferred combination for first-line therapy recommended by the US DHHS.[1] It is available as capsules, tablets and oral solution.
# History
Lopinavir was developed by Abbott in an attempt to improve on the HIV resistance and serum protein-binding properties of the company's earlier protease inhibitor, ritonavir.[2] Administered alone, lopinavir has insufficient bioavailability; however, like several HIV protease inhibitors, its blood levels are greatly increased by low doses of ritonavir, a potent inhibitor of cytochrome P450 3A4.[2] Abbott therefore pursued a strategy of co-administering lopinavir with sub-therapeutic doses of ritonavir, and lopinavir is only marketed as a co-formulation with ritonavir. It is the first multi-drug capsule to contain a drug not available individually.
Lopinavir/ritonavir was approved by the US FDA on 15 September 2000, and in Europe in April 2001. Its patent will expire in the US on June 26, 2016.
# Pharmacology
Lopinavir is highly bound to plasma proteins (98-99%).[3]
There are contradictory reports regarding lopinavir penetration into the CSF. Anecdotal reports state that lopinavir cannot be detected in the CSF; however, a study of paired CSF-plasma samples from 26 patients receiving lopinavir/ritonavir found lopinavir CSF levels above the IC50 in 77% of samples.[4]
# Adverse effects
The most common adverse effects observed with lopinavir/ritonavir are diarrhea and nausea. In key clinical trials, moderate or severe diarrhea occurred in up to 27% of patients, and moderate/severe nausea in up to 16%.[3] Other common adverse effects include abdominal pain, asthenia, headache, vomiting and, particularly in children, rash.[3]
Raised liver enzymes and hyperlipidemia (both hypertriglyceridemia and hypercholesterolemia) are also commonly observed during lopinavir/ritonavir treatment.
# Access
As a result of high prices and the spread of HIV infection, the government of Thailand issued a compulsory license on 29 January 2007 to produce and/or import generic lopinavir/ritonavir.[5] In response, Abbott Laboratories pulled registration for lopinavir and seven of their other new drugs in Thailand, citing the Thai government's lack of respect for patents.[6]
Abbott's attitude has been denounced by several NGOs worldwide, including a netstrike initiated by Act Up-Paris and a public call to boycott all of Abbott's medicines by the French NGO AIDES.[7] | https://www.wikidoc.org/index.php/Kaletra | |
3e8bd324cb5d6a1e0b9f80e4790125f55dda000e | wikidoc | Kanamycin | Kanamycin
# 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
Kanamycin is an antibiotic that is FDA approved for the treatment of shortterm treatment of serious infections caused by susceptible strains of the designated microorganisms like E. coli, Proteus species (both indole-positive and indole-negative), Enterobacter aerogenes, Klebsiella pneumoniae, Serratia marcescens, Acinetobacter species. There is a Black Box Warning for this drug as shown here. Common adverse reactions include ototoxicity, nephrotoxicity and neuromuscular blockade.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of Kanamycin Injection and other antibacterial drugs, Kanamycin Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.
- In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- Kanamycin injection is indicated in the short term treatment of serious infections caused by susceptible strains of the designated microorganisms below. Bacteriological studies to identify the causative organisms and to determine their susceptibility to kanamycin should be performed. Therapy may be instituted prior to obtaining the results of susceptibility testing.
- Kanamycin may be considered as initial therapy in the treatment of infections where one or more of the following are the known or suspected pathogens: E. coli, Proteus species (both indole-positive and indole-negative), Enterobacter aerogenes, Klebsiella pneumoniae, Serratia marcescens, Acinetobacter species. The decision to continue therapy with the drug should be based on results of the susceptibility tests, the response of the infection to therapy.
- In serious infections when the causative organisms are unknown, kanamycin injection, may be administered as initial therapy in conjunction with a penicillin- or cephalosporin-type drug before obtaining results of susceptibility testing. If anaerobic organisms are suspected, consideration should be given to using other suitable antimicrobial therapy in conjunction with kanamycin.
- Although kanamycin is not the drug of choice for staphylococcal infections, it may be indicated under certain conditions for the treatment of known or suspected staphylococcal disease. These situations include the initial therapy of severe infections where the organism is thought to be either a Gram-negative bacterium or a staphylococcus, infections due to susceptible strains of staphylococci in patients allergic to other antibiotics, and mixed staphylococcal/Gram-negative infections.
- Kanamycin injection may be given intramuscularly or intravenously. The patient’s pretreatment body weight should be obtained for calculation of the correct dosage. The dosage of an aminoglycoside in obese patients should be based on an estimate of the lean body mass. The status of renal function should be determined by measurement of serum creatinine concentration or calculation of the endogenous creatinine clearance rate. The blood urea nitrogen (BUN) level is much less reliable for this purpose. Renal function should be reassessed frequently during therapy.
- It is desirable to measure both peak and trough serum concentrations intermittently during therapy since both concentrations are used to determine the adequacy and safety of the dose and to adjust the dosage during treatment. Peak serum concentrations (30 to 90 minutes after injection) above 35 mcg per mL and trough concentrations (just prior to the next dose) above 10 mcg per mL should be avoided.
- Inject deeply into the upper outer quadrant of the gluteal muscle. The recommended dose for adults or children is 15 mg/kg/day in two equally divided dosages administered at equally divided intervals; i.e., 7.5 mg/kg q12h. If continuously high blood levels are desired, the daily dose of 15 mg/kg may be given in equally divided doses every 6 or 8 hours. Treatment of patients in the heavier weight classes, i.e., 100 kg, should not exceed 1.5 g/day.
- In patients with impaired renal function, it is desirable to follow therapy by appropriate serum assays. If this is not feasible, a suggested method is to reduce the frequency of administration in patients with renal dysfunction. The interval between doses may be calculated with the following formula:
- Serum creatinine (mg/100 mL) x 9 = Dosage Interval (in hours); e.g., if the serum creatinine is 2 mg, the recommended dose (7.5 mg/kg) should be administered every 18 hours. Changes in creatinine concentration during therapy would, of course, necessitate changes in the dosage frequency.
- It is desirable to limit the duration of treatment with kanamycin to short-term. The usual duration of treatment is 7 to 10 days. Total daily dose by all routes of administration should not exceed 1.5 g/day. If longer therapy is required, measurement of kanamycin peak and trough serum concentrations is particularly important as a basis for determining the adequacy and safety of the dose. These patients should be carefully monitored for changes in renal, auditory, and vestibular function. Dosage should be adjusted as needed. The risks of toxicity multiply as the length of treatment increases.
- At the recommended dosage level, uncomplicated infections due to kanamycin-susceptible organisms should respond to therapy in 24 to 48 hours. If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked. Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage.
- The dose should not exceed 15 mg/kg per day and must be administered slowly. The solution for intravenous use is prepared by adding the contents of a 500 mg vial to 100 to 200 mL of sterile diluent such as Normal Saline or 5% Dextrose in Water, or the contents of a 1g vial to 200 to 400 mL of sterile diluent. The appropriate dose is administered over a 30- to 60-minute period. The total daily dose should be divided into 2 or 3 equally divided doses.
- Kanamycin Injection, USP should not be physically mixed with other antibacterial agents but each should be administered separately in accordance with its recommended route of administration and dosage schedule.
- (Following exploration for established peritonitis or after peritoneal contamination due to fecal spill during surgery.)
- 500 mg diluted in 20 mL sterile distilled water may be instilled through a polyethylene catheter sutured into the wound at closure. If possible, instillation should be postponed until the patient has fully recovered from the effects of anesthesia and muscle-relaxing drugs. Serum levels should be carefully monitored during treatment.
- NOTE: The pediatric dosage form “75 mg/2 mL” should be used for pediatric patients.
- 250 mg two to four times a day. Withdraw 250 mg (1mL) from a 500 mg vial and dilute it with 3 mL Physiological Saline and nebulize. Serum levels should be carefully monitored during treatment.
- Kanamycin injection in concentrations of 0.25 percent (2.5 mg/mL) has been used as an irrigating solution in abscess cavities, pleural space, peritoneal and ventricular cavities. Possible absorption of kanamycin by such routes must be taken into account and dosage adjustments should be arranged so that a maximum total dose of 1.5 g/day by all routes of administration is not exceeded. Serum levels should be carefully monitored during treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Kanamycin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Kanamycin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Kanamycin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Kanamycin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Kanamycin in pediatric patients.
# Contraindications
- A history of hypersensitivity or toxic reaction to one aminoglycoside may also contraindicate the use of any other aminoglycoside, because of the known cross-sensitivity and cumulative effects of drugs in this category.
- THIS DRUG IS NOT INDICATED IN LONG-TERM THERAPY (e.g., Tuberculosis) BECAUSE OF THE TOXIC HAZARD ASSOCIATED WITH EXTENDED ADMINISTRATION.
# Warnings
- Aminoglycosides can cause fetal harm when administered to pregnant women. Aminoglycoside antibiotics cross the placenta and there have been several reports of total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy.
- Although serious side effects to fetus or newborn have not been reported in treatment of pregnant women with other aminoglycosides, the potential for harm exists.
- Reproductive studies have been performed in rats and rabbits and have revealed no evidence of impaired fertility or teratogenic effects. Dosages of 200 mg/kg/day in pregnant rats and pregnant guinea pigs led to hearing impairment in the off-spring. There are no well-controlled studies in pregnant women but clinical experience does not include any positive evidence of adverse effects on the fetus. However, if the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard on the fetus.
- Contains sodium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Kanamycin in the drug label.
## Postmarketing Experience
- Kanamycin has the potential to induce auditory and sometimes vestibular toxicity, renal toxicity, and neuromuscular blockade.
- The risks are higher for patients with a present or past history of renal impairment (especially if hemodialysis is required): for those receiving concomitant or sequential treatment with other ototoxic or nephrotoxic drugs or rapid acting diuretic agents given intravenously (ethacrynic acid, furosemide, and mannitol), and for patients treated for longer periods and/or with higher doses than recommended.
- Toxic effects of kanamycin on the eighth cranial nerve can result in partially reversible or irreversible bilateral loss of hearing, loss of balance, or both.
- Tinnitus or vertigo may or may not be experienced. Cochlear damage is usually manifested initially by small changes in audiometric test results at the high frequencies and may not be associated with subjective hearing loss.
- Vestibular dysfunction is usually manifested by nystagmus, vertigo, nausea, vomiting, or acute Meniere’s syndrome.
- Albuminuria, presence of red and white cells, and granular casts; azotemia and oliguria have been reported.
- Renal function changes are usually reversible when the drug is discontinued. Renal impairment may be characterized by a rise in serum creatinine and may be accompanied by oliguria, presence of casts, cells, and protein in the urine, by rising levels of BUN or by decrease in creatinine clearance.
- Acute muscular paralysis and apnea can occur following treatment with aminoglycoside antibiotics.
- Neurotoxicity can occur after intrapleural and interperitoneal instillation of large doses of an aminoglycoside; however, the reaction has followed intravenous, intramuscular, and even the oral administration of these agents.
- Some local irritation or pain may follow the intramuscular injection of kanamycin. Other adverse reactions of the drug reported on rare occasions are skin rash, drug fever, headache, paresthesia, nausea, vomiting, and diarrhea.
- The “malabsorption syndrome” characterized by an increase in fecal fat, decrease in serum carotene, and fall in xylose absorption, reportedly has occurred with prolonged therapy.
# Drug Interactions
There is limited information regarding Kanamycin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Kanamycin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Kanamycin during labor and delivery.
### Nursing Mothers
- Kanamycin is excreted in minute amounts in human milk. Because of the potential for serious adverse reactions from aminoglycosides in nursing infants, 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
- Aminoglycosides should be used with caution in prematures and neonates because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs.
### Geriatic Use
There is no FDA guidance on the use of Kanamycin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Kanamycin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Kanamycin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Kanamycin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Kanamycin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Kanamycin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Kanamycin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular.
- Intraperitoneal.
- Intravenous.
- Aerosol.
- An irrigating solution in abscess cavities, pleural space, peritoneal and ventricular cavities.
### Monitoring
- Renal and eighth nerve function should be closely monitored, especially in patients with known or suspected reduced renal function at the onset of therapy, and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy.
- Serum concentrations of parenterally administered aminoglycosides should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels.
- Monitoring of renal function during treatment with kanamycin, as with other aminoglycosides, is particularly important in such patients.
- If longer therapy is required, measurement of kanamycin peak and trough serum concentrations is particularly important as a basis for determining the adequacy and safety of the dose. These patients should be carefully monitored for changes in renal, auditory, and vestibular function. Dosage should be adjusted as needed. The risks of toxicity multiply as the length of treatment increases.
# IV Compatibility
There is limited information regarding IV Compatibility of Kanamycin in the drug label.
# Overdosage
- In the event of overdosage or toxic reaction, hemodialysis or peritoneal dialysis will aid in the removal of kanamycin from the blood. In the newborn infant, exchange transfusion may also be considered.
# Pharmacology
## Mechanism of Action
- Kanamycin is a bactericidal antibiotic which acts by inhibiting the synthesis of protein in susceptible microorganisms.
- Kanamycin sulfate is active in vitro against many strains of Staphylococcus aureus (including penicillinase and non penicillinase-producing strains), Staphylococcus epidermidis, N. gonorrhoeae, H. influenzae, E. coli, Enterobactor aerogenes, Shigella and Salmonella species, K. pneumoniae, Serratia marcescens, Providencia species, Acinetobacter species and Citrobacter freundii and Citrobacter species, and many strains of both indole-positive and indole-negative Proteus strains that are frequently resistant to other antibiotics.
- Aminoglycosides have a low order of activity against most gram-positive organisms including Streptococcus pyogenes, Streptococcus pneumoniae and enterococci. In vitro studies have demonstrated that an aminoglycoside combined with an antibiotic which interferes with cell wall synthesis (i.e., Penicillin G or ampicillin) affects some Group D streptococcal strains synergistically.
- Bacteriological testing and tests for antibiotic synergism are necessary.
## Structure
- Kanamycin sulfate is an aminoglycoside antibiotic produced by Streptomyces kanamyceticus. It is D-Streptamine, 0-3-amino-3-deoxy-α-D-glucopyranosyl - (1→6)-0- -2-deoxy, sulfate 1:1 (salt). It consists of two amino sugars glycosidically linked to deoxystreptamine.
- Kanamycin Injection, USP, sterile solution for parenteral administration, contains respectively; kanamycin sulfate equivalent to 500 mg and 1g kanamycin; sodium bisulfite, an antioxidant, 0.66% and 0.45%; and sodium citrate, 2.2% and 2.2% with pH of each dosage form adjusted to 4.5 with sulfuric acid.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Kanamycin in the drug label.
## Pharmacokinetics
- The drug is rapidly absorbed after intramuscular injection and peak serum levels are generally reached within approximately one hour.
- Doses of 7.5 mg/kg give mean peak levels of 22 mcg/mL. At 8 hours following a 7.5 mg/kg dose, mean serum levels are 3.2 mcg/mL. The serum half-life is 2 1/2 hours.
- Intravenous administration of kanamycin over a period of one hour resulted in serum concentrations similar to those obtained by intramuscular administration.
- Kanamycin diffuses rapidly into most body fluids including synovial and peritoneal fluids and bile. Significant levels of the drug appear in cord blood and amniotic fluid following intramuscular administration to pregnant patients. Spinal fluid concentrations in normal infants are approximately 10 to 20 percent of serum levels and may reach 50 percent when the meninges are inflamed.
- Studies in normal adult patients have shown only trace levels of kanamycin in spinal fluid. No data are available on adults with meningitis.
- The drug is excreted almost entirely by glomerular filtration and is not reabsorbed by the renal tubules. Hence, high concentrations are attained in the nephron, and the urine may contain levels 10 to 20 times higher than those in serum. Little, if any, metabolic transformation occurs.
- Renal excretion is extremely rapid. In patients with normal renal function, approximately one-half of the administered dose is cleared within 4 hours and excretion is complete within 24 to 48 hours.
- Patients with impaired renal function or with diminished glomerular filtration pressure excrete kanamycin more slowly. Such patients may build up excessively high blood levels which greatly increase the risk of ototoxic reactions.
- In severely burned patients the half-life may be significantly decreased and resulting serum concentrations may be lower than anticipated from the mg per kg dose.
## Nonclinical Toxicology
- Quantitative methods for susceptibility testing that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility.
- One such procedure has been recommended for use with discs to test susceptibility to kanamycin. Interpretation involves correlation of the diameters obtained in the disc test with minimal inhibitory concentration (MIC) values for kanamycin.
- Reports from the laboratory give results of the standardized single disc susceptibility test (Bauer, et al., Am J Clin Path 1966;45:493 and Federal Register 37:20525-20529, 1972), using a 30 mcg kanamycin disc should be interpreted according to the following criteria:
- Organisms producing zones of 18 mm or greater, or MIC’s of 16 mcg or less are considered susceptible, indicating that the test organism is likely to respond to therapy.
- Resistant organisms produce zones of 14 mm or less or MIC’s of 16 mcg or greater. A report of “resistant” from the laboratory indicates that the infecting organism is not likely to respond to therapy.
- Zones greater than 14 mm and less than 18 mm, or MIC’s of greater than 16 mcg and less than 65 mcg, indicate intermediate susceptibility. A report of “intermediate” susceptibility suggests that the organism would be susceptible if the infection is confined to tissues and fluids (e.g., urine), in which high antibiotic levels are attained.
- Control organisms are recommended for susceptibility testing. Each time the test is performed one or more of the following organisms should be included: Escherichia coli ATCC 15922, Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. The control organisms should produce zones of inhibition within the following ranges:
# Clinical Studies
There is limited information regarding Clinical Studies of Kanamycin in the drug label.
# How Supplied
- Kanamycin Injection, USP, is supplied in packages of 10 vials.
- Vial stoppers do not contain natural rubber latex.
## Storage
- Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Kanamycin in the drug label.
# Precautions with Alcohol
- Alcohol-Kanamycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- KANAMYCIN ®
# Look-Alike Drug Names
There is limited information regarding Kanamycin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Kanamycin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Kanamycin is an antibiotic that is FDA approved for the treatment of shortterm treatment of serious infections caused by susceptible strains of the designated microorganisms like E. coli, Proteus species (both indole-positive and indole-negative), Enterobacter aerogenes, Klebsiella pneumoniae, Serratia marcescens, Acinetobacter species. There is a Black Box Warning for this drug as shown here. Common adverse reactions include ototoxicity, nephrotoxicity and neuromuscular blockade.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of Kanamycin Injection and other antibacterial drugs, Kanamycin Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.
- In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- Kanamycin injection is indicated in the short term treatment of serious infections caused by susceptible strains of the designated microorganisms below. Bacteriological studies to identify the causative organisms and to determine their susceptibility to kanamycin should be performed. Therapy may be instituted prior to obtaining the results of susceptibility testing.
- Kanamycin may be considered as initial therapy in the treatment of infections where one or more of the following are the known or suspected pathogens: E. coli, Proteus species (both indole-positive and indole-negative), Enterobacter aerogenes, Klebsiella pneumoniae, Serratia marcescens, Acinetobacter species. The decision to continue therapy with the drug should be based on results of the susceptibility tests, the response of the infection to therapy.
- In serious infections when the causative organisms are unknown, kanamycin injection, may be administered as initial therapy in conjunction with a penicillin- or cephalosporin-type drug before obtaining results of susceptibility testing. If anaerobic organisms are suspected, consideration should be given to using other suitable antimicrobial therapy in conjunction with kanamycin.
- Although kanamycin is not the drug of choice for staphylococcal infections, it may be indicated under certain conditions for the treatment of known or suspected staphylococcal disease. These situations include the initial therapy of severe infections where the organism is thought to be either a Gram-negative bacterium or a staphylococcus, infections due to susceptible strains of staphylococci in patients allergic to other antibiotics, and mixed staphylococcal/Gram-negative infections.
- Kanamycin injection may be given intramuscularly or intravenously. The patient’s pretreatment body weight should be obtained for calculation of the correct dosage. The dosage of an aminoglycoside in obese patients should be based on an estimate of the lean body mass. The status of renal function should be determined by measurement of serum creatinine concentration or calculation of the endogenous creatinine clearance rate. The blood urea nitrogen (BUN) level is much less reliable for this purpose. Renal function should be reassessed frequently during therapy.
- It is desirable to measure both peak and trough serum concentrations intermittently during therapy since both concentrations are used to determine the adequacy and safety of the dose and to adjust the dosage during treatment. Peak serum concentrations (30 to 90 minutes after injection) above 35 mcg per mL and trough concentrations (just prior to the next dose) above 10 mcg per mL should be avoided.
- Inject deeply into the upper outer quadrant of the gluteal muscle. The recommended dose for adults or children is 15 mg/kg/day in two equally divided dosages administered at equally divided intervals; i.e., 7.5 mg/kg q12h. If continuously high blood levels are desired, the daily dose of 15 mg/kg may be given in equally divided doses every 6 or 8 hours. Treatment of patients in the heavier weight classes, i.e., 100 kg, should not exceed 1.5 g/day.
- In patients with impaired renal function, it is desirable to follow therapy by appropriate serum assays. If this is not feasible, a suggested method is to reduce the frequency of administration in patients with renal dysfunction. The interval between doses may be calculated with the following formula:
- Serum creatinine (mg/100 mL) x 9 = Dosage Interval (in hours); e.g., if the serum creatinine is 2 mg, the recommended dose (7.5 mg/kg) should be administered every 18 hours. Changes in creatinine concentration during therapy would, of course, necessitate changes in the dosage frequency.
- It is desirable to limit the duration of treatment with kanamycin to short-term. The usual duration of treatment is 7 to 10 days. Total daily dose by all routes of administration should not exceed 1.5 g/day. If longer therapy is required, measurement of kanamycin peak and trough serum concentrations is particularly important as a basis for determining the adequacy and safety of the dose. These patients should be carefully monitored for changes in renal, auditory, and vestibular function. Dosage should be adjusted as needed. The risks of toxicity multiply as the length of treatment increases.
- At the recommended dosage level, uncomplicated infections due to kanamycin-susceptible organisms should respond to therapy in 24 to 48 hours. If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked. Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage.
- The dose should not exceed 15 mg/kg per day and must be administered slowly. The solution for intravenous use is prepared by adding the contents of a 500 mg vial to 100 to 200 mL of sterile diluent such as Normal Saline or 5% Dextrose in Water, or the contents of a 1g vial to 200 to 400 mL of sterile diluent. The appropriate dose is administered over a 30- to 60-minute period. The total daily dose should be divided into 2 or 3 equally divided doses.
- Kanamycin Injection, USP should not be physically mixed with other antibacterial agents but each should be administered separately in accordance with its recommended route of administration and dosage schedule.
- (Following exploration for established peritonitis or after peritoneal contamination due to fecal spill during surgery.)
- 500 mg diluted in 20 mL sterile distilled water may be instilled through a polyethylene catheter sutured into the wound at closure. If possible, instillation should be postponed until the patient has fully recovered from the effects of anesthesia and muscle-relaxing drugs. Serum levels should be carefully monitored during treatment.
- NOTE: The pediatric dosage form “75 mg/2 mL” should be used for pediatric patients.
- 250 mg two to four times a day. Withdraw 250 mg (1mL) from a 500 mg vial and dilute it with 3 mL Physiological Saline and nebulize. Serum levels should be carefully monitored during treatment.
- Kanamycin injection in concentrations of 0.25 percent (2.5 mg/mL) has been used as an irrigating solution in abscess cavities, pleural space, peritoneal and ventricular cavities. Possible absorption of kanamycin by such routes must be taken into account and dosage adjustments should be arranged so that a maximum total dose of 1.5 g/day by all routes of administration is not exceeded. Serum levels should be carefully monitored during treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Kanamycin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Kanamycin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Kanamycin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Kanamycin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Kanamycin in pediatric patients.
# Contraindications
- A history of hypersensitivity or toxic reaction to one aminoglycoside may also contraindicate the use of any other aminoglycoside, because of the known cross-sensitivity and cumulative effects of drugs in this category.
- THIS DRUG IS NOT INDICATED IN LONG-TERM THERAPY (e.g., Tuberculosis) BECAUSE OF THE TOXIC HAZARD ASSOCIATED WITH EXTENDED ADMINISTRATION.
# Warnings
- Aminoglycosides can cause fetal harm when administered to pregnant women. Aminoglycoside antibiotics cross the placenta and there have been several reports of total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy.
- Although serious side effects to fetus or newborn have not been reported in treatment of pregnant women with other aminoglycosides, the potential for harm exists.
- Reproductive studies have been performed in rats and rabbits and have revealed no evidence of impaired fertility or teratogenic effects. Dosages of 200 mg/kg/day in pregnant rats and pregnant guinea pigs led to hearing impairment in the off-spring. There are no well-controlled studies in pregnant women but clinical experience does not include any positive evidence of adverse effects on the fetus. However, if the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard on the fetus.
- Contains sodium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Kanamycin in the drug label.
## Postmarketing Experience
- Kanamycin has the potential to induce auditory and sometimes vestibular toxicity, renal toxicity, and neuromuscular blockade.
- The risks are higher for patients with a present or past history of renal impairment (especially if hemodialysis is required): for those receiving concomitant or sequential treatment with other ototoxic or nephrotoxic drugs or rapid acting diuretic agents given intravenously (ethacrynic acid, furosemide, and mannitol), and for patients treated for longer periods and/or with higher doses than recommended.
- Toxic effects of kanamycin on the eighth cranial nerve can result in partially reversible or irreversible bilateral loss of hearing, loss of balance, or both.
- Tinnitus or vertigo may or may not be experienced. Cochlear damage is usually manifested initially by small changes in audiometric test results at the high frequencies and may not be associated with subjective hearing loss.
- Vestibular dysfunction is usually manifested by nystagmus, vertigo, nausea, vomiting, or acute Meniere’s syndrome.
- Albuminuria, presence of red and white cells, and granular casts; azotemia and oliguria have been reported.
- Renal function changes are usually reversible when the drug is discontinued. Renal impairment may be characterized by a rise in serum creatinine and may be accompanied by oliguria, presence of casts, cells, and protein in the urine, by rising levels of BUN or by decrease in creatinine clearance.
- Acute muscular paralysis and apnea can occur following treatment with aminoglycoside antibiotics.
- Neurotoxicity can occur after intrapleural and interperitoneal instillation of large doses of an aminoglycoside; however, the reaction has followed intravenous, intramuscular, and even the oral administration of these agents.
- Some local irritation or pain may follow the intramuscular injection of kanamycin. Other adverse reactions of the drug reported on rare occasions are skin rash, drug fever, headache, paresthesia, nausea, vomiting, and diarrhea.
- The “malabsorption syndrome” characterized by an increase in fecal fat, decrease in serum carotene, and fall in xylose absorption, reportedly has occurred with prolonged therapy.
# Drug Interactions
There is limited information regarding Kanamycin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Kanamycin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Kanamycin during labor and delivery.
### Nursing Mothers
- Kanamycin is excreted in minute amounts in human milk. Because of the potential for serious adverse reactions from aminoglycosides in nursing infants, 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
- Aminoglycosides should be used with caution in prematures and neonates because of the renal immaturity of these patients and the resulting prolongation of serum half-life of these drugs.
### Geriatic Use
There is no FDA guidance on the use of Kanamycin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Kanamycin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Kanamycin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Kanamycin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Kanamycin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Kanamycin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Kanamycin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular.
- Intraperitoneal.
- Intravenous.
- Aerosol.
- An irrigating solution in abscess cavities, pleural space, peritoneal and ventricular cavities.
### Monitoring
- Renal and eighth nerve function should be closely monitored, especially in patients with known or suspected reduced renal function at the onset of therapy, and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy.
- Serum concentrations of parenterally administered aminoglycosides should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels.
- Monitoring of renal function during treatment with kanamycin, as with other aminoglycosides, is particularly important in such patients.
- If longer therapy is required, measurement of kanamycin peak and trough serum concentrations is particularly important as a basis for determining the adequacy and safety of the dose. These patients should be carefully monitored for changes in renal, auditory, and vestibular function. Dosage should be adjusted as needed. The risks of toxicity multiply as the length of treatment increases.
# IV Compatibility
There is limited information regarding IV Compatibility of Kanamycin in the drug label.
# Overdosage
- In the event of overdosage or toxic reaction, hemodialysis or peritoneal dialysis will aid in the removal of kanamycin from the blood. In the newborn infant, exchange transfusion may also be considered.
# Pharmacology
## Mechanism of Action
- Kanamycin is a bactericidal antibiotic which acts by inhibiting the synthesis of protein in susceptible microorganisms.
- Kanamycin sulfate is active in vitro against many strains of Staphylococcus aureus (including penicillinase and non penicillinase-producing strains), Staphylococcus epidermidis, N. gonorrhoeae, H. influenzae, E. coli, Enterobactor aerogenes, Shigella and Salmonella species, K. pneumoniae, Serratia marcescens, Providencia species, Acinetobacter species and Citrobacter freundii and Citrobacter species, and many strains of both indole-positive and indole-negative Proteus strains that are frequently resistant to other antibiotics.
- Aminoglycosides have a low order of activity against most gram-positive organisms including Streptococcus pyogenes, Streptococcus pneumoniae and enterococci. In vitro studies have demonstrated that an aminoglycoside combined with an antibiotic which interferes with cell wall synthesis (i.e., Penicillin G or ampicillin) affects some Group D streptococcal strains synergistically.
- Bacteriological testing and tests for antibiotic synergism are necessary.
## Structure
- Kanamycin sulfate is an aminoglycoside antibiotic produced by Streptomyces kanamyceticus. It is D-Streptamine, 0-3-amino-3-deoxy-α-D-glucopyranosyl - (1→6)-0- [6-amino-6-deoxy-α-D-glucopyranosyl - (1→4)]-2-deoxy, sulfate 1:1 (salt). It consists of two amino sugars glycosidically linked to deoxystreptamine.
- Kanamycin Injection, USP, sterile solution for parenteral administration, contains respectively; kanamycin sulfate equivalent to 500 mg and 1g kanamycin; sodium bisulfite, an antioxidant, 0.66% and 0.45%; and sodium citrate, 2.2% and 2.2% with pH of each dosage form adjusted to 4.5 with sulfuric acid.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Kanamycin in the drug label.
## Pharmacokinetics
- The drug is rapidly absorbed after intramuscular injection and peak serum levels are generally reached within approximately one hour.
- Doses of 7.5 mg/kg give mean peak levels of 22 mcg/mL. At 8 hours following a 7.5 mg/kg dose, mean serum levels are 3.2 mcg/mL. The serum half-life is 2 1/2 hours.
- Intravenous administration of kanamycin over a period of one hour resulted in serum concentrations similar to those obtained by intramuscular administration.
- Kanamycin diffuses rapidly into most body fluids including synovial and peritoneal fluids and bile. Significant levels of the drug appear in cord blood and amniotic fluid following intramuscular administration to pregnant patients. Spinal fluid concentrations in normal infants are approximately 10 to 20 percent of serum levels and may reach 50 percent when the meninges are inflamed.
- Studies in normal adult patients have shown only trace levels of kanamycin in spinal fluid. No data are available on adults with meningitis.
- The drug is excreted almost entirely by glomerular filtration and is not reabsorbed by the renal tubules. Hence, high concentrations are attained in the nephron, and the urine may contain levels 10 to 20 times higher than those in serum. Little, if any, metabolic transformation occurs.
- Renal excretion is extremely rapid. In patients with normal renal function, approximately one-half of the administered dose is cleared within 4 hours and excretion is complete within 24 to 48 hours.
- Patients with impaired renal function or with diminished glomerular filtration pressure excrete kanamycin more slowly. Such patients may build up excessively high blood levels which greatly increase the risk of ototoxic reactions.
- In severely burned patients the half-life may be significantly decreased and resulting serum concentrations may be lower than anticipated from the mg per kg dose.
## Nonclinical Toxicology
- Quantitative methods for susceptibility testing that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility.
- One such procedure has been recommended for use with discs to test susceptibility to kanamycin. Interpretation involves correlation of the diameters obtained in the disc test with minimal inhibitory concentration (MIC) values for kanamycin.
- Reports from the laboratory give results of the standardized single disc susceptibility test (Bauer, et al., Am J Clin Path 1966;45:493 and Federal Register 37:20525-20529, 1972), using a 30 mcg kanamycin disc should be interpreted according to the following criteria:
- Organisms producing zones of 18 mm or greater, or MIC’s of 16 mcg or less are considered susceptible, indicating that the test organism is likely to respond to therapy.
- Resistant organisms produce zones of 14 mm or less or MIC’s of 16 mcg or greater. A report of “resistant” from the laboratory indicates that the infecting organism is not likely to respond to therapy.
- Zones greater than 14 mm and less than 18 mm, or MIC’s of greater than 16 mcg and less than 65 mcg, indicate intermediate susceptibility. A report of “intermediate” susceptibility suggests that the organism would be susceptible if the infection is confined to tissues and fluids (e.g., urine), in which high antibiotic levels are attained.
- Control organisms are recommended for susceptibility testing. Each time the test is performed one or more of the following organisms should be included: Escherichia coli ATCC 15922, Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. The control organisms should produce zones of inhibition within the following ranges:
# Clinical Studies
There is limited information regarding Clinical Studies of Kanamycin in the drug label.
# How Supplied
- Kanamycin Injection, USP, is supplied in packages of 10 vials.
- Vial stoppers do not contain natural rubber latex.
## Storage
- Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Kanamycin in the drug label.
# Precautions with Alcohol
- Alcohol-Kanamycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- KANAMYCIN ®[1]
# Look-Alike Drug Names
There is limited information regarding Kanamycin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Kanamycin | |
faae3543727f680fbbf6c08f81e60cf132f9c728 | wikidoc | Kaolinite | Kaolinite
# Overview
Kaolinite (/ˈkeɪlˌnaɪt/) is a clay mineral, part of the group of industrial minerals, with the chemical composition Al2Si2O5(OH)4. It is a layered silicate mineral, with one tetrahedral sheet linked through oxygen atoms to one octahedral sheet of alumina octahedra. Rocks that are rich in kaolinite are known as kaolin or china clay.
The name is derived from Chinese Kao-Ling (高岭/高嶺, pinyin Gāolǐng), a village near Jingdezhen, Jiangxi province, China. The name entered English in 1727 from the French version of the word: kaolin, following Francois Xavier d'Entrecolles's reports from Jingdezhen. In Africa, kaolin is sometimes known as kalaba (in Gabon and Cameroon), calaba, and calabachop (in Equatorial Guinea).
Kaolinite has a low shrink–swell capacity and a low cation-exchange capacity (1–15 meq/100 g). It is a soft, earthy, usually white mineral (dioctahedral phyllosilicate clay), produced by the chemical weathering of aluminium silicate minerals like feldspar. In many parts of the world, it is colored pink-orange-red by iron oxide, giving it a distinct rust hue. Lighter concentrations yield white, yellow or light orange colors. Alternating layers are sometimes found, as at Providence Canyon State Park in Georgia, United States. Commercial grades of kaolin are supplied and transported as dry powder, semi-dry noodle or as liquid slurry.
# Chemistry
## Notation
The chemical formula for kaolinite as used in mineralogy is Al2Si2O5(OH)4, however, in ceramics applications the formula is typically written in terms of oxides, thus the formula for kaolinite is Al2O3·2SiO2·2H2O. Cement chemist notation is even more terse: AS2H2, with the oxides represented as A = Al2O3, S = SiO2, H = H2O.
## Structural transformations
Kaolinite group clays undergo a series of phase transformations upon thermal treatment in air at atmospheric pressure.
### Drying
Below 100 °C, exposure to dry air will slowly remove liquid water from the kaolin. The end-state for this transformation is referred to as "leather dry". Between 100 °C and about 550 °C, any remaining liquid water is expelled from kaolinite. The end state for this transformation is referred to as "bone dry". Through this state, the expulsion of water is reversible: if the kaolin is exposed to liquid water, it will be reabsorbed and disintegrate into its fine particulate form. Subsequent transformations are not reversible, and represent permanent chemical changes.
### Metakaolin
Endothermic dehydration of kaolinite begins at 550–600 °C producing disordered metakaolin, but continuous hydroxyl loss is observed up to 900 °C. Although historically there was much disagreement concerning the nature of the metakaolin phase, extensive research has led to a general consensus that metakaolin is not a simple mixture of amorphous silica (SiO2) and alumina (Al2O3), but rather a complex amorphous structure that retains some longer-range order (but not strictly crystalline) due to stacking of its hexagonal layers.
### Spinel
Further heating to 925–950 °C converts metakaolin to an aluminium-silicon spinel which is sometimes also referred to as a gamma-alumina type structure:
### Platelet mullite
Upon calcination above 1050 °C, the spinel phase nucleates and transforms to platelet mullite and highly crystalline cristobalite:
### Needle mullite
Finally, at 1400 °C the "needle" form of mullite appears, offering substantial increases in structural strength and heat resistance. This is a structural but not chemical transformation. See stoneware for more information on this form.
# Occurrence
Kaolinite is one of the most common minerals; it is mined, as kaolin, in Pakistan, Vietnam, Brazil, Bulgaria, France, United Kingdom, Iran, Germany, India, Australia, Korea, the People's Republic of China, the Czech Republic, Spain and the United States.
Kaolinite clay occurs in abundance in soils that have formed from the chemical weathering of rocks in hot, moist climates—for example in tropical rainforest areas. Comparing soils along a gradient towards progressively cooler or drier climates, the proportion of kaolinite decreases, while the proportion of other clay minerals such as illite (in cooler climates) or smectite (in drier climates) increases. Such climatically-related differences in clay mineral content are often used to infer changes in climates in the geological past, where ancient soils have been buried and preserved.
In the Institut National pour l'Etude Agronomique au Congo Belge (INEAC) classification system, soils in which the clay fraction is predominantly kaolinite are called kaolisol (from kaolin and soil).
In the US the main kaolin deposits are found in central Georgia, on a stretch of the Atlantic Seaboard fall line between Augusta and Macon. The deposits were formed between the late Cretaceous and early Paleogene, about 100 million to 45 million years ago, in sediments derived from weathered igneous and metakaolin rocks. Kaolin production in the US during 2011 was 5.5 million tonnes.
# Synthesis and genesis
Syntheses of kaolinite at high temperatures (more than 100o C) are relatively well known. There are for example the syntheses of Van Nieuwenberg and Pieters (1928); Noll (1934); Noll (1936); Norton (1939); Roy and Osborn (1954); Roy (1961); Tomura et al. (1985); Satokawa et al. (1994) and Huertas et al. (1999).
Relatively few low-temperature syntheses have become known (cf. Brindley and DeKimpe (1961); DeKimpe (1969); Bogatyrev et al. (1997) ). At high temperatures, equilibrium thermodynamic models appear to be satisfactory for the description of kaolinite dissolution and nucleation, because the thermal energy suffices to overcome the energy barriers involved in the nucleation process. The importance of syntheses at ambient temperature and atmospheric pressure towards the understanding of the mechanism involved in the nucleation of clay minerals lies in overcoming these energy barriers. As indicated by Caillère and Hénin (1962) the processes involved will have to be studied in well-defined experiments, because it is virtually impossible to isolate the factors involved by mere deduction from complex natural physico-chemical systems such as the soil environment.
Fripiat and Herbillon (1971), in a review on the formation of kaolinite, raised the fundamental question how a disordered material (i.e., the amorphous fraction of tropical soils) could ever be transformed into a corresponding ordered structure. This transformation seems to take place in soils without major changes in the environment, in a relatively short period of time and at ambient temperature (and pressure). Difficulties are encountered when trying to explain kaolinite formation under atmospheric conditions by extrapolation of thermodynamic data from the more successful high-temperature syntheses (as for example Meijer and Van der Plas, 1980 have pointed out). La Iglesia and Van Oosterwijk-Gastuche (1978) thought that the conditions under which kaolinite will nucleate can be deduced from stability diagrams based as these are on dissolution data. Based on the lack of convincing results in their own experiments, La Iglesia and Van Oosterwijk-Gastuche (1978) had to conclude, however, that there were other, still unknown, factors involved in the low-temperature nucleation of kaolinite. Because of the observed very slow crystallization rates of kaolinite from solution at room temperature Fripiat and Herbillon (1971) postulated the existence of high activation energies in the low-temperature nucleation of kaolinite.
Low-temperature synthesis of clay minerals (with kaolinite as an example) has several aspects. In the first place the silicic acid to be supplied to the growing crystal must be in a monomeric form, i.e., silica should be present in very dilute solution (Caillère et al., 1957; Caillère and Hénin, 1962; Wey and Siffert, 1962; Millot, 1970 ). In order to prevent the formation of amorphous silica gels precipitating from supersaturated solutions without reacting with the aluminium or magnesium cations to form crystalline silicates, the silicic acid must be present in concentrations below the maximum solubility of amorphous silica. The principle behind this prerequisite can be found in structural chemistry: “Since the polysilicate ions are not of uniform size, they cannot arrange themselves along with the metal ions into a regular crystal lattice” (Iler, 1955, p. 182 ).
The second aspect of the low-temperature synthesis of kaolinite is that the aluminium cations must be hexacoordinated with respect to oxygen (Caillère and Hénin, 1947; Caillère et al., 1953; Hénin and Robichet, 1955). Gastuche et al. (1962), as well as Caillère and Hénin (1962) have concluded, that only in those instances when the aluminium hydroxide is in the form of gibbsite, kaolinite can ever be formed. If not, the precipitate formed will be a “mixed alumino-silicic gel” (as Millot, 1970, p. 343 put it). If this would be the only requirement, large amounts of kaolinite could be harvested simply by adding gibbsite powder to a silica solution. Undoubtedly a marked degree of sorption of the silica in solution by the gibbsite surfaces will take place, but, as stated before, mere adsorption does not create the layer lattice typical of kaolinite crystals.
The third aspect is that these two initial components must be incorporated into one and the same mixed crystal with a layer structure. From the following equation (as given by Gastuche and DeKimpe, 1962) for kaolinite formation
it can be seen, that five molecules of water must be removed from the reaction for every molecule of kaolinite formed. Field evidence illustrating the importance of the removal of water from the kaolinite reaction has been supplied by Gastuche and DeKimpe (1962). While studying soil formation on a basaltic rock in Kivu (Zaïre), Gastuche and DeKimpe (1962) noted how the occurrence of kaolinite depended on the ‘’degrée de drainage’’ of the area involved. A clear distinction was found between areas with good drainage (i.e., areas with a marked difference between wet and dry seasons) and those areas with poor drainage (i.e., perennially swampy areas). Only in the areas with distinct seasonal alternations between wet and dry conditions kaolinite was found. The possible significance of alternating wet and dry conditions on the transition of allophane into kaolinite has been stressed by Tamura and Jackson (1953). The role of alternations between wetting and drying on the formation of kaolinite has also been noted by Moore (1964).
Laboratory syntheses of kaolinite at room temperature and atmospheric pressure have been described by DeKimpe et al. (1961). From those tests the role of periodicity becomes convincingly clear. For DeKimpe et al. (1961) had used daily additions of alumina (as AlCl3.6 H2O) and silica (in the form of ethyl silicate) during at least two months. In addition adjustments of the pH took place every day by way of adding either hydrochloric acid or sodium hydroxide. Such daily additions of Si and Al to the solution in combination with the daily titrations with hydrochloric acid or sodium hydroxide during at least 60 days will have introduced the necessary element of periodicity.
Only now the actual role of what has been described as the “aging” (Alterung) of amorphous alumino-silicates (as for example Harder, 1978 had noted) can be fully understood. For time as such is not bringing about any change in a closed system at equilibrium, but a series of alternations, of periodically changing conditions (by definition taking place in an open system), will bring about the low-temperature formation of more and more of the stable phase kaolinite instead of (ill-defined) amorphous alumino-silicates.
# Uses
The largest use is in the production of paper, including ensuring the gloss on some grades of coated paper.
In April 2008, the US Naval Medical Research Institute announced the successful use of a kaolinite-derived aluminosilicate nanoparticle infusion in traditional gauze, known commercially as QuikClot Combat Gauze.
Kaolin is used (or was used in the past):
- in ceramics (it is generally the main component in porcelain)
- in toothpaste
- as a light diffusing material in white incandescent light bulbs
- in cosmetics
- as paint to extend titanium dioxide (TiO2) and modify gloss levels
- for its semi-reinforcing properties in rubber
- in adhesives to modify rheology
- in the production of common smoking pipes in Europe and Asia
- in organic farming, as a spray applied to crops to deter insect damage, and in the case of apples, to prevent sun scald
- as whitewash in traditional stone masonry homes in Nepal (the most common method is to paint the upper part with white kaolin clay and the middle with red clay; the red clay may extend to the bottom, or the bottom may be painted black)
- as a filler in Edison Diamond Discs
- as an indicator in radiological dating since kaolinite can contain very small traces of uranium and thorium
- to soothe an upset stomach, similar to the way parrots (and later, humans) in South America originally used it (more recently, industrially-produced kaolinite preparations were common for treatment of diarrhea; the most common of these was kaopectate, which abandoned the use of kaolin in favor of attapulgite and then (in the United States) bismuth subsalicylate (the active ingredient in Pepto-Bismol))
- for facial masks or soap
- as adsorbents in water and wastewater treatment
- to induce blood clotting in diagnostic procedures, e.g. Kaolin clotting time
- In its altered metakaolin form, as a pozzolan; when added to a concrete mix, metakaolin accelerates the hydration of Portland cement and takes part in the pozzolanic reaction with the portlandite formed in the hydration of the main cement minerals (e.g. alite).
- In its altered metakaolin form, as a base component for geopolymer compounds
## Geophagy
Kaolin is eaten for health or to suppress hunger, a practice known as geophagy. Consumption is greater among women, especially during pregnancy. This practice has also been observed within a small population of African-American women in the Southern United States, especially Georgia. There, the kaolin is called white dirt, chalk or white clay. | Kaolinite
Template:Infobox mineral
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Kaolinite (/ˈkeɪ[invalid input: 'ɵ']l[invalid input: 'ɨ']ˌnaɪt/) is a clay mineral, part of the group of industrial minerals, with the chemical composition Al2Si2O5(OH)4. It is a layered silicate mineral, with one tetrahedral sheet linked through oxygen atoms to one octahedral sheet of alumina octahedra.[1] Rocks that are rich in kaolinite are known as kaolin or china clay.[2]
The name is derived from Chinese Kao-Ling (高岭/高嶺, pinyin Gāolǐng), a village near Jingdezhen, Jiangxi province, China.[3] The name entered English in 1727 from the French version of the word: kaolin, following Francois Xavier d'Entrecolles's reports from Jingdezhen.[4] In Africa, kaolin is sometimes known as kalaba (in Gabon[5] and Cameroon[6]), calaba, and calabachop (in Equatorial Guinea).
Kaolinite has a low shrink–swell capacity and a low cation-exchange capacity (1–15 meq/100 g). It is a soft, earthy, usually white mineral (dioctahedral phyllosilicate clay), produced by the chemical weathering of aluminium silicate minerals like feldspar. In many parts of the world, it is colored pink-orange-red by iron oxide, giving it a distinct rust hue. Lighter concentrations yield white, yellow or light orange colors. Alternating layers are sometimes found, as at Providence Canyon State Park in Georgia, United States. Commercial grades of kaolin are supplied and transported as dry powder, semi-dry noodle or as liquid slurry.
# Chemistry
## Notation
The chemical formula for kaolinite as used in mineralogy is Al2Si2O5(OH)4,[7] however, in ceramics applications the formula is typically written in terms of oxides, thus the formula for kaolinite is Al2O3·2SiO2·2H2O.[8] Cement chemist notation is even more terse: AS2H2, with the oxides represented as A = Al2O3, S = SiO2, H = H2O.[citation needed]
## Structural transformations
Kaolinite group clays undergo a series of phase transformations upon thermal treatment in air at atmospheric pressure.
### Drying
Below 100 °C, exposure to dry air will slowly remove liquid water from the kaolin. The end-state for this transformation is referred to as "leather dry". Between 100 °C and about 550 °C, any remaining liquid water is expelled from kaolinite. The end state for this transformation is referred to as "bone dry". Through this state, the expulsion of water is reversible: if the kaolin is exposed to liquid water, it will be reabsorbed and disintegrate into its fine particulate form. Subsequent transformations are not reversible, and represent permanent chemical changes.
### Metakaolin
Endothermic dehydration of kaolinite begins at 550–600 °C producing disordered metakaolin, but continuous hydroxyl loss is observed up to 900 °C.[9] Although historically there was much disagreement concerning the nature of the metakaolin phase, extensive research has led to a general consensus that metakaolin is not a simple mixture of amorphous silica (SiO2) and alumina (Al2O3), but rather a complex amorphous structure that retains some longer-range order (but not strictly crystalline) due to stacking of its hexagonal layers.[9]
### Spinel
Further heating to 925–950 °C converts metakaolin to an aluminium-silicon spinel which is sometimes also referred to as a gamma-alumina type structure:
### Platelet mullite
Upon calcination above 1050 °C, the spinel phase nucleates and transforms to platelet mullite and highly crystalline cristobalite:
### Needle mullite
Finally, at 1400 °C the "needle" form of mullite appears, offering substantial increases in structural strength and heat resistance. This is a structural but not chemical transformation. See stoneware for more information on this form.
# Occurrence
Kaolinite is one of the most common minerals; it is mined, as kaolin, in Pakistan, Vietnam, Brazil, Bulgaria, France, United Kingdom, Iran, Germany, India, Australia, Korea, the People's Republic of China, the Czech Republic, Spain and the United States.[10]
Kaolinite clay occurs in abundance in soils that have formed from the chemical weathering of rocks in hot, moist climates—for example in tropical rainforest areas. Comparing soils along a gradient towards progressively cooler or drier climates, the proportion of kaolinite decreases, while the proportion of other clay minerals such as illite (in cooler climates) or smectite (in drier climates) increases. Such climatically-related differences in clay mineral content are often used to infer changes in climates in the geological past, where ancient soils have been buried and preserved.
In the Institut National pour l'Etude Agronomique au Congo Belge (INEAC) classification system, soils in which the clay fraction is predominantly kaolinite are called kaolisol (from kaolin and soil).[11]
In the US the main kaolin deposits are found in central Georgia, on a stretch of the Atlantic Seaboard fall line between Augusta and Macon. The deposits were formed between the late Cretaceous and early Paleogene, about 100 million to 45 million years ago, in sediments derived from weathered igneous and metakaolin rocks.[12] Kaolin production in the US during 2011 was 5.5 million tonnes.[13]
# Synthesis and genesis
Syntheses of kaolinite at high temperatures (more than 100o C) are relatively well known. There are for example the syntheses of Van Nieuwenberg and Pieters (1928);[14] Noll (1934);[15] Noll (1936);[16] Norton (1939);[17] Roy and Osborn (1954);[18] Roy (1961);[19] Tomura et al. (1985);[20] Satokawa et al. (1994) [21] and Huertas et al. (1999).[22]
Relatively few low-temperature syntheses have become known (cf. Brindley and DeKimpe (1961);[23] DeKimpe (1969);[24] Bogatyrev et al. (1997) [25]). At high temperatures, equilibrium thermodynamic models appear to be satisfactory for the description of kaolinite dissolution and nucleation, because the thermal energy suffices to overcome the energy barriers involved in the nucleation process. The importance of syntheses at ambient temperature and atmospheric pressure towards the understanding of the mechanism involved in the nucleation of clay minerals lies in overcoming these energy barriers. As indicated by Caillère and Hénin (1962) [26] the processes involved will have to be studied in well-defined experiments, because it is virtually impossible to isolate the factors involved by mere deduction from complex natural physico-chemical systems such as the soil environment.
Fripiat and Herbillon (1971),[27] in a review on the formation of kaolinite, raised the fundamental question how a disordered material (i.e., the amorphous fraction of tropical soils) could ever be transformed into a corresponding ordered structure. This transformation seems to take place in soils without major changes in the environment, in a relatively short period of time and at ambient temperature (and pressure). Difficulties are encountered when trying to explain kaolinite formation under atmospheric conditions by extrapolation of thermodynamic data from the more successful high-temperature syntheses (as for example Meijer and Van der Plas, 1980 [28] have pointed out). La Iglesia and Van Oosterwijk-Gastuche (1978) [29] thought that the conditions under which kaolinite will nucleate can be deduced from stability diagrams based as these are on dissolution data. Based on the lack of convincing results in their own experiments, La Iglesia and Van Oosterwijk-Gastuche (1978) had to conclude, however, that there were other, still unknown, factors involved in the low-temperature nucleation of kaolinite. Because of the observed very slow crystallization rates of kaolinite from solution at room temperature Fripiat and Herbillon (1971) postulated the existence of high activation energies in the low-temperature nucleation of kaolinite.
Low-temperature synthesis of clay minerals (with kaolinite as an example) has several aspects. In the first place the silicic acid to be supplied to the growing crystal must be in a monomeric form, i.e., silica should be present in very dilute solution (Caillère et al., 1957;[30] Caillère and Hénin, 1962; Wey and Siffert, 1962;[31] Millot, 1970 [32]). In order to prevent the formation of amorphous silica gels precipitating from supersaturated solutions without reacting with the aluminium or magnesium cations to form crystalline silicates, the silicic acid must be present in concentrations below the maximum solubility of amorphous silica. The principle behind this prerequisite can be found in structural chemistry: “Since the polysilicate ions are not of uniform size, they cannot arrange themselves along with the metal ions into a regular crystal lattice” (Iler, 1955, p. 182 [33]).
The second aspect of the low-temperature synthesis of kaolinite is that the aluminium cations must be hexacoordinated with respect to oxygen (Caillère and Hénin, 1947;[34] Caillère et al., 1953;[35] Hénin and Robichet, 1955[36]). Gastuche et al. (1962),[37] as well as Caillère and Hénin (1962) have concluded, that only in those instances when the aluminium hydroxide is in the form of gibbsite, kaolinite can ever be formed. If not, the precipitate formed will be a “mixed alumino-silicic gel” (as Millot, 1970, p. 343 put it). If this would be the only requirement, large amounts of kaolinite could be harvested simply by adding gibbsite powder to a silica solution. Undoubtedly a marked degree of sorption of the silica in solution by the gibbsite surfaces will take place, but, as stated before, mere adsorption does not create the layer lattice typical of kaolinite crystals.
The third aspect is that these two initial components must be incorporated into one and the same mixed crystal with a layer structure. From the following equation (as given by Gastuche and DeKimpe, 1962) [38] for kaolinite formation
it can be seen, that five molecules of water must be removed from the reaction for every molecule of kaolinite formed. Field evidence illustrating the importance of the removal of water from the kaolinite reaction has been supplied by Gastuche and DeKimpe (1962). While studying soil formation on a basaltic rock in Kivu (Zaïre), Gastuche and DeKimpe (1962) [39] noted how the occurrence of kaolinite depended on the ‘’degrée de drainage’’ of the area involved. A clear distinction was found between areas with good drainage (i.e., areas with a marked difference between wet and dry seasons) and those areas with poor drainage (i.e., perennially swampy areas). Only in the areas with distinct seasonal alternations between wet and dry conditions kaolinite was found. The possible significance of alternating wet and dry conditions on the transition of allophane into kaolinite has been stressed by Tamura and Jackson (1953).[40] The role of alternations between wetting and drying on the formation of kaolinite has also been noted by Moore (1964).[41]
Laboratory syntheses of kaolinite at room temperature and atmospheric pressure have been described by DeKimpe et al. (1961).[42] From those tests the role of periodicity becomes convincingly clear. For DeKimpe et al. (1961) had used daily additions of alumina (as AlCl3.6 H2O) and silica (in the form of ethyl silicate) during at least two months. In addition adjustments of the pH took place every day by way of adding either hydrochloric acid or sodium hydroxide. Such daily additions of Si and Al to the solution in combination with the daily titrations with hydrochloric acid or sodium hydroxide during at least 60 days will have introduced the necessary element of periodicity.
Only now the actual role of what has been described as the “aging” (Alterung) of amorphous alumino-silicates (as for example Harder, 1978 [43] had noted) can be fully understood. For time as such is not bringing about any change in a closed system at equilibrium, but a series of alternations, of periodically changing conditions (by definition taking place in an open system), will bring about the low-temperature formation of more and more of the stable phase kaolinite instead of (ill-defined) amorphous alumino-silicates.
# Uses
The largest use is in the production of paper, including ensuring the gloss on some grades of coated paper.
In April 2008, the US Naval Medical Research Institute announced the successful use of a kaolinite-derived aluminosilicate nanoparticle infusion in traditional gauze, known commercially as QuikClot Combat Gauze.[44]
Kaolin is used (or was used in the past):
- in ceramics (it is generally the main component in porcelain)
- in toothpaste
- as a light diffusing material in white incandescent light bulbs
- in cosmetics
- as paint to extend titanium dioxide (TiO2) and modify gloss levels
- for its semi-reinforcing properties in rubber
- in adhesives to modify rheology[45]
- in the production of common smoking pipes in Europe and Asia
- in organic farming, as a spray applied to crops to deter insect damage, and in the case of apples, to prevent sun scald
- as whitewash in traditional stone masonry homes in Nepal (the most common method is to paint the upper part with white kaolin clay and the middle with red clay; the red clay may extend to the bottom, or the bottom may be painted black)
- as a filler in Edison Diamond Discs[46]
- as an indicator in radiological dating since kaolinite can contain very small traces of uranium and thorium
- to soothe an upset stomach, similar to the way parrots (and later, humans) in South America originally used it[47] (more recently, industrially-produced kaolinite preparations were common for treatment of diarrhea; the most common of these was kaopectate, which abandoned the use of kaolin in favor of attapulgite and then (in the United States) bismuth subsalicylate (the active ingredient in Pepto-Bismol))
- for facial masks or soap[48]
- as adsorbents in water and wastewater treatment[49]
- to induce blood clotting in diagnostic procedures, e.g. Kaolin clotting time
- In its altered metakaolin form, as a pozzolan; when added to a concrete mix, metakaolin accelerates the hydration of Portland cement and takes part in the pozzolanic reaction with the portlandite formed in the hydration of the main cement minerals (e.g. alite).
- In its altered metakaolin form, as a base component for geopolymer compounds
## Geophagy
Kaolin is eaten for health or to suppress hunger,[6] a practice known as geophagy. Consumption is greater among women, especially during pregnancy.[50] This practice has also been observed within a small population of African-American women in the Southern United States, especially Georgia.[51][52] There, the kaolin is called white dirt, chalk or white clay.[51] | https://www.wikidoc.org/index.php/Kaolin | |
231466c5679ceccd0b842d516f28a483da406b62 | wikidoc | Ken Jeong | Ken Jeong
Ken Jeong, a.k.a. "Dr. Ken", is an American comedian, actor, and physician. He is known for incorporating his medical knowledge into his comedy.
Jeong is of Korean descent. He completed his undergraduate studies at Duke University and attained his medical degree at the University of North Carolina at Chapel Hill. He then completed his Internal Medicine residency in New Orleans while developing his stand-up comedy. His big break then came when he won the Big Easy Laff-Off where NBC president Brandon Tartikoff and Improv founder Budd Friedman were judges. They both urged Jeong to move to Los Angeles and he began performing regularly at the Improv and Laugh Factory comedy clubs.
Jeong's background in theater and improv has led to several television appearances which include NBC's The Office, HBO's Entourage and Curb Your Enthusiasm, and the Jon Stewart-produced Three Strikes pilot. Jeong made his feature film debut in Knocked Up in 2007 and will reteam with Judd Apatow and Seth Rogen in The Pineapple Express. He is currently filming All About Steve, starring Sandra Bullock, Thomas Haden Church, and Bradley Cooper.
# Filmography
- All About Steve (2008)
- The Pineapple Express (2008)
- Knocked Up (2007)
# Television
- Boston Legal (2007)
- Curb Your Enthusiasm (2007)
- The Shield (2007)
- Three Strikes (TV series) (2006)
- Entourage (TV series) (2006)
- The Office (2005)
- Two and a Half Men (2005)
- Crossing Jordan (2004) | Ken Jeong
Template:Infobox Comedian
Ken Jeong, a.k.a. "Dr. Ken", is an American comedian, actor, and physician. He is known for incorporating his medical knowledge into his comedy.
Jeong is of Korean descent. He completed his undergraduate studies at Duke University and attained his medical degree at the University of North Carolina at Chapel Hill. He then completed his Internal Medicine residency in New Orleans while developing his stand-up comedy.[1] His big break then came when he won the Big Easy Laff-Off where NBC president Brandon Tartikoff and Improv founder Budd Friedman were judges. They both urged Jeong to move to Los Angeles and he began performing regularly at the Improv and Laugh Factory comedy clubs.
Jeong's background in theater and improv has led to several television appearances which include NBC's The Office, HBO's Entourage and Curb Your Enthusiasm, and the Jon Stewart-produced Three Strikes pilot. Jeong made his feature film debut in Knocked Up in 2007 and will reteam with Judd Apatow and Seth Rogen in The Pineapple Express. He is currently filming All About Steve, starring Sandra Bullock, Thomas Haden Church, and Bradley Cooper.
# Filmography
- All About Steve (2008)
- The Pineapple Express (2008)
- Knocked Up (2007)
# Television
- Boston Legal (2007)
- Curb Your Enthusiasm (2007)
- The Shield (2007)
- Three Strikes (TV series) (2006)
- Entourage (TV series) (2006)
- The Office (2005)
- Two and a Half Men (2005)
- Crossing Jordan (2004) | https://www.wikidoc.org/index.php/Ken_Jeong | |
96197cc3f58c79a1eccb27db7527c386fd434a20 | wikidoc | Keratin 7 | Keratin 7
Keratin, type II cytoskeletal 7 also known as cytokeratin-7 (CK-7) or keratin-7 (K7) or sarcolectin (SCL) is a protein that in humans is encoded by the KRT7 gene. Keratin 7 is a type II keratin. It is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels.
# Function
Keratin-7 is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels. The genes encoding the type II cytokeratins are clustered in a region of chromosome 12q12-q13. Alternative splicing may result in several transcript variants; however, not all variants have been fully described.
Keratin-7 is found in simple glandular epithelia, and in transitional epithelium. Epithelial cells of the lung and breast both contain keratin-7, but some other glandular epithelia, such as those of the colon and prostate, do not. Because the keratin-7 antigen is found in both healthy and neoplastic cells, antibodies to CK7 can be used in immunohistochemistry to distinguish ovarian and transitional cell carcinomas from colonic and prostate cancers, respectively. It is commonly used together with CK20 when making such diagnoses.
# Model organisms
Model organisms have been used in the study of KRT7 function. A conditional knockout mouse line called Krt7tm1b(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | Keratin 7
Keratin, type II cytoskeletal 7 also known as cytokeratin-7 (CK-7) or keratin-7 (K7) or sarcolectin (SCL) is a protein that in humans is encoded by the KRT7 gene.[1][2][3] Keratin 7 is a type II keratin. It is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels.
# Function
Keratin-7 is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels. The genes encoding the type II cytokeratins are clustered in a region of chromosome 12q12-q13. Alternative splicing may result in several transcript variants; however, not all variants have been fully described.[3]
Keratin-7 is found in simple glandular epithelia, and in transitional epithelium. Epithelial cells of the lung and breast both contain keratin-7, but some other glandular epithelia, such as those of the colon and prostate, do not. Because the keratin-7 antigen is found in both healthy and neoplastic cells, antibodies to CK7 can be used in immunohistochemistry to distinguish ovarian and transitional cell carcinomas from colonic and prostate cancers, respectively. It is commonly used together with CK20 when making such diagnoses.[4]
# Model organisms
Model organisms have been used in the study of KRT7 function. A conditional knockout mouse line called Krt7tm1b(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[5] Male and female animals underwent a standardized phenotypic screen[6] to determine the effects of deletion.[7][8][9][10] Additional screens performed: - In-depth immunological phenotyping[11] | https://www.wikidoc.org/index.php/Keratin_7 | |
11dcb6c0d16f51d6357780e15ce98cb1d1f317e2 | wikidoc | Keratin 8 | Keratin 8
Keratin, type II cytoskeletal 8 also known as cytokeratin-8 (CK-8) or keratin-8 (K8) is a keratin protein that is encoded in humans by the KRT8 gene. It is often paired with keratin 18.
# Utility as an immunohistochemical stain
Antibodies to CK8 (e.g. CAM 5.2) can be used to differentiate lobular carcinoma of the breast from ductal carcinoma of the breast. CAM 5.2, an antibody that reacts with an epitope found on both CK8 and CK18, is used in immunohistochemistry to demonstrate certain forms of cancer. In normal tissue, it reacts mainly with secretory epithelia, but not with squamous epithelium, such as that found in the skin, cervix, and esophagus. However, it also reacts with a range of malignant cells, including those derived from secretory epithelia, but also some squamous carcinomata, such as spindle cell carcinoma. It is considered useful in identifying microscopic metastases of breast carcinoma in lymph nodes, and in distinguishing Paget's disease from malignant melanoma. It also reacts with neuroendocrine tumors.
Keratin 8 is often used together with keratin 18 and keratin 19 to differentiate cells of epithelial origin from hematopoietic cells in tests that enumerate circulating tumor cells in blood.
# Interactions
Keratin 8 has been shown to interact with MAPK14, Pinin and PPL. | Keratin 8
Keratin, type II cytoskeletal 8 also known as cytokeratin-8 (CK-8) or keratin-8 (K8) is a keratin protein that is encoded in humans by the KRT8 gene. It is often paired with keratin 18.
# Utility as an immunohistochemical stain
Antibodies to CK8 (e.g. CAM 5.2) can be used to differentiate lobular carcinoma of the breast from ductal carcinoma of the breast.[1] CAM 5.2, an antibody that reacts with an epitope found on both CK8 and CK18, is used in immunohistochemistry to demonstrate certain forms of cancer. In normal tissue, it reacts mainly with secretory epithelia, but not with squamous epithelium, such as that found in the skin, cervix, and esophagus. However, it also reacts with a range of malignant cells, including those derived from secretory epithelia, but also some squamous carcinomata, such as spindle cell carcinoma. It is considered useful in identifying microscopic metastases of breast carcinoma in lymph nodes, and in distinguishing Paget's disease from malignant melanoma. It also reacts with neuroendocrine tumors.[2]
Keratin 8 is often used together with keratin 18 and keratin 19 to differentiate cells of epithelial origin from hematopoietic cells in tests that enumerate circulating tumor cells in blood.[3]
# Interactions
Keratin 8 has been shown to interact with MAPK14,[4] Pinin[5] and PPL.[6] | https://www.wikidoc.org/index.php/Keratin_8 | |
1f15e5e2413cb4c20856af5e6c27e1a35a6c59a3 | wikidoc | Ketazolam | Ketazolam
# Overview
Ketazolam (marketed under the brand names Anseren, Ansieten, Ansietil, Marcen, Sedatival, Sedotime, Solatran and Unakalm) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.
# Therapeutic uses
It is used for the treatment of anxiety and has similar effectiveness compared to diazepam. Ketazolam also appears to produce a reduced level of side effects such as sedation compared with diazepam and the side effects when they occur tend to be milder. Ketazolam is also an effective antispasmodic drug and is used for the treatment of spasticity.
# Availability
Ketazolam is not approved for sale in Australia, United Kingdom or the United States. In South Africa, GlaxoSmithKline markets ketazolam under its Solatran brand name. In Canada, ketazolam is listed in schedule IV of the Controlled Drugs and Substances Act, along with other benzodiazepines.
# Tolerance and physical dependence
Chronic use of ketazolam as with other benzodiazepines can lead to physical dependence and the appearance of the benzodiazepine withdrawal syndrome upon cessation of use or decrease in dose. Tolerance to ketazolam's therapeutic effects occurs over a period of 15 days.
# Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.
# Pharmacokinetics
Ketazolam breaks down in the blood to diazepam which breaks down to demoxepam which breaks down to desmethyldiazepam.
# Warnings
The U.S. Food and Drug Administration warns that in Spain, ketazolam marketed as Marcen may sometimes be mistakenly confused with Narcan.
# Legal status
Ketazolam is a List 3 drug under the Betäubungsmittelgesetz, like almost all benzodiazepines in Germany. Ketazolam is a List II drugs of the Opium Law in the Netherlands. Ketazolam is a Schedule IV drug under the Controlled Substances Act in the US. | Ketazolam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ketazolam (marketed under the brand names Anseren, Ansieten, Ansietil, Marcen, Sedatival, Sedotime, Solatran and Unakalm) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties.
# Therapeutic uses
It is used for the treatment of anxiety and has similar effectiveness compared to diazepam. Ketazolam also appears to produce a reduced level of side effects such as sedation compared with diazepam and the side effects when they occur tend to be milder.[2][3][4][5] Ketazolam is also an effective antispasmodic drug and is used for the treatment of spasticity.[6][7][8]
# Availability
Ketazolam is not approved for sale in Australia, United Kingdom or the United States.[9] In South Africa, GlaxoSmithKline markets ketazolam under its Solatran brand name.[10] In Canada, ketazolam is listed in schedule IV of the Controlled Drugs and Substances Act, along with other benzodiazepines.[11]
# Tolerance and physical dependence
Chronic use of ketazolam as with other benzodiazepines can lead to physical dependence and the appearance of the benzodiazepine withdrawal syndrome upon cessation of use or decrease in dose. Tolerance to ketazolam's therapeutic effects occurs over a period of 15 days.[12]
# Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[13]
# Pharmacokinetics
Ketazolam breaks down in the blood to diazepam which breaks down to demoxepam which breaks down to desmethyldiazepam.[14]
# Warnings
The U.S. Food and Drug Administration warns that in Spain, ketazolam marketed as Marcen may sometimes be mistakenly confused with Narcan.[15]
# Legal status
Ketazolam is a List 3 drug under the Betäubungsmittelgesetz, like almost all benzodiazepines in Germany. Ketazolam is a List II drugs of the Opium Law in the Netherlands. Ketazolam is a Schedule IV drug under the Controlled Substances Act in the US.[16] | https://www.wikidoc.org/index.php/Ketazolam | |
954bf213df88c66bc892321343efb18d11951ad4 | wikidoc | Keto acid | Keto acid
File:Pyruvic-acid-2D-skeletal.png
Keto acids are organic acids containing a ketone functional group and a carboxylic acid group.
Common types of keto acids include:
- Alpha-keto acids, or 2-oxo acids, such as pyruvic acid have the keto group adjacent to the carboxylic acid
- Beta-keto acids, or 3-oxo acids, such as acetoacetic acid have the ketone group at the second carbon from the carboxylic acid
- Gamma-keto acids, or 4-oxo acids, such as levulinic acid have the ketone group at the third carbon from the carboxylic acid | Keto acid
File:Pyruvic-acid-2D-skeletal.png
Keto acids are organic acids containing a ketone functional group and a carboxylic acid group.
Common types of keto acids include:
- Alpha-keto acids, or 2-oxo acids, such as pyruvic acid have the keto group adjacent to the carboxylic acid
- Beta-keto acids, or 3-oxo acids, such as acetoacetic acid have the ketone group at the second carbon from the carboxylic acid
- Gamma-keto acids, or 4-oxo acids, such as levulinic acid have the ketone group at the third carbon from the carboxylic acid
# External links
- Keto+Acids at the US National Library of Medicine Medical Subject Headings (MeSH)
cs:Oxokyseliny
de:Ketosäuren
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Keto-acid | |
1714212ea12c3d821cea794109353aff451d9073 | wikidoc | Kilometer | Kilometer
A kilometre (American spelling: kilometer, symbol km) is a unit of length in the metric system, equal to one thousand metres, the current SI base unit of length. It can be written in scientific notations as 1×10³ m (engineering notation) or 1 E+3 m (exponential notation) — both meaning 1,000 × 1 m.
A corresponding unit of area is the square kilometre and a corresponding unit of volume is the cubic kilometre.
Although, in English, metric units of measurement are usually pronounced with the stress on the first syllable, as in /ˈkɪl.əˌmiː.tə(r)/, pronunciation of the word "kilometre" with the stress on the second syllable /kɪˈlɒm.ə.tə(r)/ is in common usage (see List of words of disputed pronunciation). The latter pronunciation follows the stress pattern used for the names of measuring instruments, such as barometer, thermometer, tachometer and speedometer. This stress pattern is not commonly used for other metric measurements such as millimetre or centimetre.
Slang terms for kilometre include "click" (sometimes spelled "klick" or "klik") and "kay" (or "k"). These non-standard terms can also refer to kilometres per hour, which itself is abbreviated as km/h, km h-1, km·h-1 or, informally, kph.
"Kilometrage" may be used in the same way as "mileage".
# Equivalence to other units of length
1 kilometre is equal to:
- 1,000 metres (1 metre is equal to 0.001 kilometres)
- about 0.621 statute miles (1 statute mile is equal to 1.609344 kilometres)
the formula "multiply by 5 and divide by 8" gives a conversion of 0.625, accurate to 0.6%, which is a useful approximation
- the formula "multiply by 5 and divide by 8" gives a conversion of 0.625, accurate to 0.6%, which is a useful approximation
- about 1,094 international yards (1 international yard is equal to 0.0009144 kilometres)
- about 3,281 feet (1 foot is equal to 0.0003048 kilometres)
- exactly 0.00000000000010570008340246153 Light Years (1 light year is equal to about 9.5 trillion kilometers)
# International usage
The United Kingdom and the United States are the only two developed countries that have not changed their road signs from miles to kilometres.
Although the UK has officially adopted the metric system, there is no intention to replace the mile on road signs in the near future, owing to the British public's attachment to traditional imperial units of distance, i.e., miles, yards and inches, and the cost of changing speed signs (which could not be replaced during general maintenance, like distance signs, for safety reasons). As of 11 September 2007, the EU has allowed Britain to continue using the imperial systems. EU commissioner Günter Verheugen said: "There is not now and never will be any requirement to drop imperial measurements."
In the US, the National Highway System Designation Act of 1995 prohibits the use of federal-aid highway funds to convert existing signs or purchase new signs with metric units. However, the Manual on Uniform Traffic Control Devices since 2000 published in both metric and American Customary Units. (See also Metrication in the United States.)
# Unicode symbols
For the purposes of compatibility with Chinese, Japanese and Korean (CJK) characters, Unicode has symbols for:
- kilometre (㎞) - code 339E
- square kilometre (㎢) - code 33A2
- cubic kilometre (㎦) - code 33A6 | Kilometer
Template:Unit of length
A kilometre (American spelling: kilometer, symbol km) is a unit of length in the metric system, equal to one thousand metres, the current SI base unit of length. It can be written in scientific notations as 1×10³ m (engineering notation) or 1 E+3 m (exponential notation) — both meaning 1,000 × 1 m.
A corresponding unit of area is the square kilometre and a corresponding unit of volume is the cubic kilometre.
Although, in English, metric units of measurement are usually pronounced with the stress on the first syllable, as in /ˈkɪl.əˌmiː.tə(r)/, pronunciation of the word "kilometre" with the stress on the second syllable /kɪˈlɒm.ə.tə(r)/ is in common usage (see List of words of disputed pronunciation). The latter pronunciation follows the stress pattern used for the names of measuring instruments, such as barometer, thermometer, tachometer and speedometer. This stress pattern is not commonly used for other metric measurements such as millimetre or centimetre.
Slang terms for kilometre include "click" (sometimes spelled "klick" or "klik") and "kay" (or "k"). These non-standard terms can also refer to kilometres per hour, which itself is abbreviated as km/h, km h-1, km·h-1 or, informally, kph.
"Kilometrage" may be used in the same way as "mileage".
# Equivalence to other units of length
1 kilometre is equal to:
- 1,000 metres (1 metre is equal to 0.001 kilometres)
- about 0.621 statute miles (1 statute mile is equal to 1.609344 kilometres)
the formula "multiply by 5 and divide by 8" gives a conversion of 0.625, accurate to 0.6%, which is a useful approximation
- the formula "multiply by 5 and divide by 8" gives a conversion of 0.625, accurate to 0.6%, which is a useful approximation
- about 1,094 international yards (1 international yard is equal to 0.0009144 kilometres)
- about 3,281 feet (1 foot is equal to 0.0003048 kilometres)
- exactly 0.00000000000010570008340246153 Light Years (1 light year is equal to about 9.5 trillion kilometers)
# International usage
The United Kingdom and the United States are the only two developed countries that have not changed their road signs from miles to kilometres.
Although the UK has officially adopted the metric system, there is no intention to replace the mile on road signs in the near future, owing to the British public's attachment to traditional imperial units of distance, i.e., miles, yards and inches, and the cost of changing speed signs (which could not be replaced during general maintenance, like distance signs, for safety reasons).[1][2] As of 11 September 2007, the EU has allowed Britain to continue using the imperial systems. EU commissioner Günter Verheugen said: "There is not now and never will be any requirement to drop imperial measurements."[3]
In the US, the National Highway System Designation Act of 1995 prohibits the use of federal-aid highway funds to convert existing signs or purchase new signs with metric units.[4] However, the Manual on Uniform Traffic Control Devices since 2000 published in both metric and American Customary Units. (See also Metrication in the United States.)
# Unicode symbols
For the purposes of compatibility with Chinese, Japanese and Korean (CJK) characters, Unicode has symbols for:
- kilometre (㎞) - code 339E
- square kilometre (㎢) - code 33A2
- cubic kilometre (㎦) - code 33A6 | https://www.wikidoc.org/index.php/Kilometer | |
5f4c002a54b9997c042fd3559c51eebd9a744e29 | wikidoc | Kiwifruit | Kiwifruit
The kiwifruit (or kiwi) is the edible berry of a cultivar group of the woody vine Actinidia deliciosa and hybrids between this and other species in the genus Actinidia. The Actinidia is native to Shaanxi, China.
The most common cultivars of kiwifruit are oval, about the size of a large hen's egg (5–8 cm / 2–3 in long and 4.5–5.5 cm / 1¾–2 in diameter). It has a fibrous, dull green-brown skin and bright green or golden flesh with rows of small, black, edible seeds. The fruit has a soft texture and a unique flavour.
Originally known as the Chinese Gooseberry, the fruit was renamed for marketing reasons in the mid-20th century, first to melonette, and then to kiwifruit. The latter name was chosen for the indigenous New Zealand bird, kiwi, which is one of the country's national symbols. The first renaming was done in order to avoid a tariff on melons imported into the US. It is not uncommon outside New Zealand and Australia for the fruit to be referred to simply as "kiwi". Today, kiwifruit is a commercial crop in several countries.
# History
Actinidia deliciosa is native to southern China, where it is declared as the "National Fruit" of the People's Republic of China. Other species of Actinidia are also found in India and range east to Japan and north into southeastern Siberia. Cultivation spread from India in the early 20th century, when seeds were introduced to New Zealand by Mary Isabel Fraser, the principal of Wanganui Girls' College, who had been visiting mission schools in India. The seeds were planted in 1906 by a Wanganui nurseryman, Alexander Allison, with the vines first fruiting in 1910.
The familiar cultivar Actinidia deliciosa 'Hayward' was developed by Hayward Wright in Avondale, New Zealand around 1924. It was initially grown in domestic gardens, but commercial planting began in the 1940s. Italy is now the leading producer of kiwifruit in the world, followed by China, New Zealand, Chile, France, Greece, Japan and the United States. In China, kiwifruit was traditionally collected from the wild, but until recently China was not a major producing country. In China, it is grown mainly in the mountainous area upstream of the Yangtze River. It is also grown in other areas of China, including Sichuan.
# Names
This fruit had a long history before it was commercialised as kiwifruit and therefore had many other older names.
In Chinese:
- Macaque peach (獼猴桃 míhóu táo): the most common name
- Macaque pear (猕猴梨 míhóu lí)
- Vine pear (藤梨 téng lí)
- Sunny peach (阳桃 yáng táo)
- Wood berry (木子 mù zi)
- Hairy bush fruit (毛木果 máo mù guǒ)
- Unusual fruit or wonder fruit (奇異果 qíyì guǒ): the most common name in Taiwan and Hong Kong (奇異果 kay yee goh). A quasi-transliteration of "kiwifruit", literally "strange fruit".
When introduced to New Zealand by Isabel Fraser it was called yáng táo in China. People in New Zealand thought it had a gooseberry flavour and began to call it the Chinese gooseberry, although it is not related to the Grossulariaceae (gooseberry) family.
New Zealand exported the fruit to the US in the 1950s. Among the exporters was the prominent produce company Turners and Growers, who were calling the berries melonettes, because the name Chinese gooseberry had political connotations due to the Cold War. An American importer, Norman Sondag of San Francisco, complained that melonettes was as bad as Chinese gooseberry because melons and berries were both subject to high import tariffs. In June 1959, during a meeting of Turners and Growers management in Auckland, Jack Turner suggested the name kiwifruit which was adopted and later became the industry-wide name.
Most New Zealand kiwifruit is now marketed under the brand-name label Zespri which is trademarked by a marketing company domiciled in New Zealand, ZESPRI International. The branding move also served to distinguish New Zealand kiwifruit from fruit produced by other countries who could cash in on the "Kiwi" name, as it was not trademarked. From 2005, Zespri launched a new promotional campaign worldwide featuring Japanese superstar Ayumi Hamasaki as their spokeswoman.
# Cultivars
Almost all kiwifruit in commerce belong to a few cultivars of Actinidia deliciosa: 'Hayward', 'Chico', and 'Saanichton 12'. The fruit of these cultivars are practically indistinguishable from each other and match the description of a standard kiwifruit given at the head of this article.
A new Cultivar Group of Actinidia chinensis known as Gold Kiwifruit or "Hinabelle", with yellow flesh and sweeter, less acidic flavour resembling a tropical fruit salad, was produced by the New Zealand Crown Research Institute, HortResearch and is being marketed worldwide in increasing volumes. Some wild vines in India have yellow fruit but are small and not commercially viable. Seeds from these plants were imported to New Zealand in 1987 and the company took 11 years to develop the new fruit through cross-pollination and grafting with green kiwi vines. Gold Kiwifruit have a smooth, bronze skin, a pointed cap at one end and distinctive golden yellow flesh with a less tart and more tropical flavour than green kiwifruit. It has a higher market price than green kiwifruit. Unlike the green cultivars, it is less hairy, so it can be eaten whole after rubbing off the thin, fluffy coat.
# Food value
Kiwifruit is a rich source of vitamin C, 1.5 times the DRI scale in the US. Its potassium content by weight is slightly less than that of a banana. It also contains vitamins A and E. The skin is a good source of flavonoid antioxidants. The kiwifruit seed oil contains on average 62% alpha-linolenic acid, an omega-3 fatty acid. Usually a medium size kiwifruit contains about 46 kilocalories, 0.3-gram fats, 1 gm proteins, 11 gm carbohydrates, 75 mg vitamins and 2.6 grams dietary fiber.
Kiwifruit is often reported to have mild laxative effects, possibly because of the high level of dietary fibre.
Raw kiwifruit is also rich in the protein-dissolving enzyme actinidin, (in the same family of thiol proteases as papain), which is commercially useful as a meat tenderizer but can be an allergen for some individuals. Specifically, people allergic to latex, papayas or pineapples are likely to be allergic to kiwifruit also. Reactions include tingling and sore mouth; swelling of the lips, tongue and face; rash; vomiting and abdominal pain; and, in the most severe cases, breathing difficulties, wheezing and collapse. The most common symptoms are unpleasant itching and soreness of the mouth, with the most common severe symptom being wheezing. Severe symptoms are most likely to occur in young children.
This enzyme makes raw kiwifruit unsuitable for use in desserts containing milk or any other dairy products which are not going to be served within hours, because it soon begins to digest milk proteins. This applies to gelatin-based desserts as well, as the actinidin will dissolve the collagen proteins in gelatin very quickly, either liquifying the dessert, or preventing it from solidifying. However, the U.S. Department of Agriculture suggests that cooking the fruit for a few minutes before adding it to the gelatin will overcome this effect.
Sliced kiwifruit has long been regularly used as a garnish atop whipped cream on one of New Zealand and Australia's favourite desserts, the pavlova.
# Cultivation
Kiwifruit can be grown in most temperate climates with adequate summer heat. Where Actinidia deliciosa is not hardy, other species can be grown as substitutes.
Kiwifruit is commercially grown on sturdy support structures, as it can produce several tonnes per hectare, more than the rather weak vines can support. These are generally equipped with a watering system for irrigation and frost protection in the spring.
Kiwifruit vines require vigorous pruning, similar to that of grapevines. Fruit is borne on one-year-old and older canes, but production declines as each cane ages. Canes should be pruned off and replaced after their third year.
Kiwifruit plants are normally dioecious, meaning that individual plants are male or female. Only female plants bear fruit, and only when pollenized by a male plant. One male pollenizer is required for each three to eight female vines. An exception is the cultivar 'Issai', a hybrid (Actinidia arguta x polygama) from Japan, which produces perfect flowers and can self-pollinate; unfortunately it lacks vigour, is less hardy than most A. arguta forms and is not a large producer.
Kiwifruit is notoriously difficult to pollinate because the flowers are not very attractive to bees. Some producers blow collected pollen over the female flowers. But generally the most successful approach is saturation pollination, where the bee populations are made so large (by placing hives in the orchards) that bees are forced to use this flower because of intense competition for all flowers within flight distance. The kiwifruit tree is actually a vine.
- Female flower
Female flower
- Male flowers
Male flowers
# Preparation and consumption
Kiwifruit can be eaten whole, like an apple (and, rarely, even including the skin, which increases the tartness), cut in half and eaten like a passion fruit or peeled and sliced, like a pineapple. For people who prefer not to eat the skin, the fruit can be cut in half and then the flesh scooped out with a spoon. Kiwifruit is sometimes sold with a spife, a plastic tool designed for this purpose with a spoon at one end and a knife at the other. Another method is to slice the fruit into several rounds about 5 mm (¼ in) thick, possibly cutting each round into quarters, and serving it, skin-on, as a platter or with plain yogurt.
Kiwifruit can be peeled using a potato peeler, drawing up from the bottom towards the thicker, harder end where the fruit was attached to its branch. Cutting "against the grain" releases juice which lubricates the blade and a swifter, cleaner cut results.
# Notes
- ↑ Zespri kiwifruit history and time line
- ↑ National Symbols of China
- ↑ Kiwifruit planting and production in China
- ↑ Kiwifruit in China
- ↑ 李, 时珍. "本草纲目·果部". Retrieved 2007-05-07..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}
- ↑ Zespri site, "How Kiwifruit Got Its Name" Retrieved on July 9 2007.
- ↑ Seed Oil Fatty Acids - SOFA Database Retrieval
- ↑ Rush; et al. (2002-06). "Kiwifruit promotes laxation in the elderly". Asia Pacific Journal of Clinical Nutrition. Retrieved 2007-06-11. Check date values in: |date= (help)CS1 maint: Explicit use of et al. (link)
- ↑ USDA Agricultural Marketing Service (1994-01). "How To Buy Fresh Fruits" (PDF). United States Department of Agriculture . Retrieved 2006-12-02. Check date values in: |date= (help); External link in |publisher= (help)
# Further reading
- How to grow kiwifruit vines and nutritional data
- Zespri's international website
- Purdue University NewCROP
- Kiwifruits in Australia
- NCBI's taxonomy browser
- Photos of kiwifruit and alfalfa pollination in California
- Seeka Kiwifruit Industries website
ar:كيوي (فاكهة)
zh-min-nan:Kiwi
bs:Kivi (voće)
bg:Киви (плод)
cs:Kiwi
da:Kiwi (frugt)
de:Kiwifrucht
eo:Kivo
fa:کیوی
ko:참다래
hr:Kiwi
he:קיווי (פרי)
nl:Kiwi (fruit)
no:Kiwi (frukt)
nn:Kiwifrukt
simple:Kiwifruit
fi:Kiivi (hedelmä)
sv:Kiwi | Kiwifruit
Template:Nutritionalvalue
The kiwifruit (or kiwi) is the edible berry of a cultivar group of the woody vine Actinidia deliciosa and hybrids between this and other species in the genus Actinidia. The Actinidia is native to Shaanxi, China.
The most common cultivars of kiwifruit are oval, about the size of a large hen's egg (5–8 cm / 2–3 in long and 4.5–5.5 cm / 1¾–2 in diameter). It has a fibrous, dull green-brown skin and bright green or golden flesh with rows of small, black, edible seeds. The fruit has a soft texture and a unique flavour.
Originally known as the Chinese Gooseberry, the fruit was renamed for marketing reasons in the mid-20th century, first to melonette, and then to kiwifruit. The latter name was chosen for the indigenous New Zealand bird, kiwi, which is one of the country's national symbols. The first renaming was done in order to avoid a tariff on melons imported into the US.[1] It is not uncommon outside New Zealand and Australia for the fruit to be referred to simply as "kiwi". Today, kiwifruit is a commercial crop in several countries.
# History
Actinidia deliciosa is native to southern China, where it is declared as the "National Fruit" of the People's Republic of China.[2] Other species of Actinidia are also found in India and range east to Japan and north into southeastern Siberia. Cultivation spread from India in the early 20th century, when seeds were introduced to New Zealand by Mary Isabel Fraser, the principal of Wanganui Girls' College, who had been visiting mission schools in India. The seeds were planted in 1906 by a Wanganui nurseryman, Alexander Allison, with the vines first fruiting in 1910.
The familiar cultivar Actinidia deliciosa 'Hayward' was developed by Hayward Wright in Avondale, New Zealand around 1924. It was initially grown in domestic gardens, but commercial planting began in the 1940s. Italy is now the leading producer of kiwifruit in the world, followed by China, New Zealand, Chile, France, Greece, Japan and the United States. In China, kiwifruit was traditionally collected from the wild, but until recently China was not a major producing country.[3] In China, it is grown mainly in the mountainous area upstream of the Yangtze River. It is also grown in other areas of China, including Sichuan.[4]
# Names
This fruit had a long history before it was commercialised as kiwifruit and therefore had many other older names.
In Chinese:[5]
- Macaque peach (獼猴桃 míhóu táo): the most common name
- Macaque pear (猕猴梨 míhóu lí)
- Vine pear (藤梨 téng lí)
- Sunny peach (阳桃 yáng táo)
- Wood berry (木子 mù zi)
- Hairy bush fruit (毛木果 máo mù guǒ)
- Unusual fruit or wonder fruit (奇異果 qíyì guǒ): the most common name in Taiwan and Hong Kong (奇異果 kay yee goh). A quasi-transliteration of "kiwifruit", literally "strange fruit".
When introduced to New Zealand by Isabel Fraser it was called yáng táo in China. People in New Zealand thought it had a gooseberry flavour and began to call it the Chinese gooseberry, although it is not related to the Grossulariaceae (gooseberry) family.
New Zealand exported the fruit to the US in the 1950s. Among the exporters was the prominent produce company Turners and Growers, who were calling the berries melonettes, because the name Chinese gooseberry had political connotations due to the Cold War. An American importer, Norman Sondag of San Francisco, complained that melonettes was as bad as Chinese gooseberry because melons and berries were both subject to high import tariffs. In June 1959, during a meeting of Turners and Growers management in Auckland, Jack Turner suggested the name kiwifruit which was adopted and later became the industry-wide name.[6]
Most New Zealand kiwifruit is now marketed under the brand-name label Zespri which is trademarked by a marketing company domiciled in New Zealand, ZESPRI International. The branding move also served to distinguish New Zealand kiwifruit from fruit produced by other countries who could cash in on the "Kiwi" name, as it was not trademarked. From 2005, Zespri launched a new promotional campaign worldwide featuring Japanese superstar Ayumi Hamasaki as their spokeswoman.
# Cultivars
Almost all kiwifruit in commerce belong to a few cultivars of Actinidia deliciosa: 'Hayward', 'Chico', and 'Saanichton 12'. The fruit of these cultivars are practically indistinguishable from each other and match the description of a standard kiwifruit given at the head of this article.
A new Cultivar Group of Actinidia chinensis known as Gold Kiwifruit or "Hinabelle", with yellow flesh and sweeter, less acidic flavour resembling a tropical fruit salad, was produced by the New Zealand Crown Research Institute, HortResearch and is being marketed worldwide in increasing volumes. Some wild vines in India have yellow fruit but are small and not commercially viable. Seeds from these plants were imported to New Zealand in 1987 and the company took 11 years to develop the new fruit through cross-pollination and grafting with green kiwi vines. Gold Kiwifruit have a smooth, bronze skin, a pointed cap at one end and distinctive golden yellow flesh with a less tart and more tropical flavour than green kiwifruit. It has a higher market price than green kiwifruit. Unlike the green cultivars, it is less hairy, so it can be eaten whole after rubbing off the thin, fluffy coat.
# Food value
Kiwifruit is a rich source of vitamin C, 1.5 times the DRI scale in the US. Its potassium content by weight is slightly less than that of a banana. It also contains vitamins A and E. The skin is a good source of flavonoid antioxidants. The kiwifruit seed oil contains on average 62% alpha-linolenic acid, an omega-3 fatty acid.[7] Usually a medium size kiwifruit contains about 46 kilocalories, 0.3-gram fats, 1 gm proteins, 11 gm carbohydrates, 75 mg vitamins and 2.6 grams dietary fiber.
Kiwifruit is often reported to have mild laxative effects, possibly because of the high level of dietary fibre.[8]
Raw kiwifruit is also rich in the protein-dissolving enzyme actinidin, (in the same family of thiol proteases as papain), which is commercially useful as a meat tenderizer but can be an allergen for some individuals. Specifically, people allergic to latex, papayas or pineapples are likely to be allergic to kiwifruit also. Reactions include tingling and sore mouth; swelling of the lips, tongue and face; rash; vomiting and abdominal pain; and, in the most severe cases, breathing difficulties, wheezing and collapse. The most common symptoms are unpleasant itching and soreness of the mouth, with the most common severe symptom being wheezing. Severe symptoms are most likely to occur in young children.
This enzyme makes raw kiwifruit unsuitable for use in desserts containing milk or any other dairy products which are not going to be served within hours, because it soon begins to digest milk proteins. This applies to gelatin-based desserts as well, as the actinidin will dissolve the collagen proteins in gelatin very quickly, either liquifying the dessert, or preventing it from solidifying. However, the U.S. Department of Agriculture suggests that cooking the fruit for a few minutes before adding it to the gelatin will overcome this effect.[9]
Sliced kiwifruit has long been regularly used as a garnish atop whipped cream on one of New Zealand and Australia's favourite desserts, the pavlova.
# Cultivation
Kiwifruit can be grown in most temperate climates with adequate summer heat. Where Actinidia deliciosa is not hardy, other species can be grown as substitutes.
Kiwifruit is commercially grown on sturdy support structures, as it can produce several tonnes per hectare, more than the rather weak vines can support. These are generally equipped with a watering system for irrigation and frost protection in the spring.
Kiwifruit vines require vigorous pruning, similar to that of grapevines. Fruit is borne on one-year-old and older canes, but production declines as each cane ages. Canes should be pruned off and replaced after their third year.
Kiwifruit plants are normally dioecious, meaning that individual plants are male or female. Only female plants bear fruit, and only when pollenized by a male plant. One male pollenizer is required for each three to eight female vines. An exception is the cultivar 'Issai', a hybrid (Actinidia arguta x polygama) from Japan, which produces perfect flowers and can self-pollinate; unfortunately it lacks vigour, is less hardy than most A. arguta forms and is not a large producer.
Kiwifruit is notoriously difficult to pollinate because the flowers are not very attractive to bees. Some producers blow collected pollen over the female flowers. But generally the most successful approach is saturation pollination, where the bee populations are made so large (by placing hives in the orchards) that bees are forced to use this flower because of intense competition for all flowers within flight distance. The kiwifruit tree is actually a vine.
- Female flower
Female flower
- Male flowers
Male flowers
# Preparation and consumption
Kiwifruit can be eaten whole, like an apple (and, rarely, even including the skin, which increases the tartness), cut in half and eaten like a passion fruit or peeled and sliced, like a pineapple. For people who prefer not to eat the skin, the fruit can be cut in half and then the flesh scooped out with a spoon. Kiwifruit is sometimes sold with a spife, a plastic tool designed for this purpose with a spoon at one end and a knife at the other. Another method is to slice the fruit into several rounds about 5 mm (¼ in) thick, possibly cutting each round into quarters, and serving it, skin-on, as a platter or with plain yogurt.
Kiwifruit can be peeled using a potato peeler, drawing up from the bottom towards the thicker, harder end where the fruit was attached to its branch. Cutting "against the grain" releases juice which lubricates the blade and a swifter, cleaner cut results.
# Notes
Template:Wikispecies
- ↑ Zespri kiwifruit history and time line
- ↑ National Symbols of China
- ↑ Kiwifruit planting and production in China
- ↑ Kiwifruit in China
- ↑ 李, 时珍. "本草纲目·果部". Retrieved 2007-05-07..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}
- ↑ Zespri site, "How Kiwifruit Got Its Name" Retrieved on July 9 2007.
- ↑ Seed Oil Fatty Acids - SOFA Database Retrieval
- ↑ Rush; et al. (2002-06). "Kiwifruit promotes laxation in the elderly". Asia Pacific Journal of Clinical Nutrition. Retrieved 2007-06-11. Check date values in: |date= (help)CS1 maint: Explicit use of et al. (link)
- ↑ USDA Agricultural Marketing Service (1994-01). "How To Buy Fresh Fruits" (PDF). United States Department of Agriculture . Retrieved 2006-12-02. Check date values in: |date= (help); External link in |publisher= (help)
# Further reading
- How to grow kiwifruit vines and nutritional data
- Zespri's international website
- Purdue University NewCROP
- Kiwifruits in Australia
- NCBI's taxonomy browser
- Photos of kiwifruit and alfalfa pollination in California
- Seeka Kiwifruit Industries website
ar:كيوي (فاكهة)
zh-min-nan:Kiwi
bs:Kivi (voće)
bg:Киви (плод)
cs:Kiwi
da:Kiwi (frugt)
de:Kiwifrucht
eo:Kivo
fa:کیوی
ko:참다래
hr:Kiwi
he:קיווי (פרי)
nl:Kiwi (fruit)
no:Kiwi (frukt)
nn:Kiwifrukt
simple:Kiwifruit
fi:Kiivi (hedelmä)
sv:Kiwi
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Kiwifruit | |
728d6536915ac15e7eee96507a88ec0d096b2b31 | wikidoc | L-838,417 | L-838,417
L-838,417 is an anxiolytic drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.
L-838,417 is a subtype-selective GABAA agonist, acting as a partial agonist at α2, α3 and α5 subtypes, but as an antagonist at the α1 subtype, and has little affinity for the α4 or α6 subtypes. This gives it selective anxiolytic effects, which are mediated mainly by α2 and α3 subtypes, but with little sedative or amnestic effects as these effects are mediated by α1. Some sedation might still be expected due to its activity at the α5 subtype, which can also cause sedation, however no sedative effects were seen in animal studies even at high doses, suggesting that L-838,417 is primarily acting at α2 and α3 subtypes with the α5 subtype of lesser importance.
As might be predicted from its binding profile, L-838,417 substitutes for the anxiolytic benzodiazepine chlordiazepoxide in animals, but not for the hypnotic imidazopyridine drug zolpidem. | L-838,417
L-838,417 is an anxiolytic drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.
L-838,417 is a subtype-selective GABAA agonist, acting as a partial agonist at α2, α3 and α5 subtypes, but as an antagonist at the α1 subtype, and has little affinity for the α4 or α6 subtypes.[1] This gives it selective anxiolytic effects, which are mediated mainly by α2 and α3 subtypes, but with little sedative or amnestic effects as these effects are mediated by α1.[2][3] Some sedation might still be expected due to its activity at the α5 subtype, which can also cause sedation, however no sedative effects were seen in animal studies even at high doses, suggesting that L-838,417 is primarily acting at α2 and α3 subtypes with the α5 subtype of lesser importance.[4][5]
As might be predicted from its binding profile, L-838,417 substitutes for the anxiolytic benzodiazepine chlordiazepoxide in animals, but not for the hypnotic imidazopyridine drug zolpidem.[6][7]
Template:Pharmacology-stub | https://www.wikidoc.org/index.php/L-838,417 | |
ec18b6862bf52b7cad718dff825ff2a90ee9cf94 | wikidoc | L1 family | L1 family
# Overview
The L1 family is a family of cell adhesion molecules that includes several different L1-like proteins, found in the nervous system and other tissues of many animal species. They are a found on radial glial cells and, as such, are important for neural cell migration during development.
The members of the L1-family in humans are called L1, CHL1 (close homolog of L1), Neurofascin and NrCAM (NgCAM related cell adhesion molecule).
The family is characterised by its ability to bind to a family of proteins called ankrins.
NrCAM and neurofascin both have class 1 PDZ domain binding motifs at their COOH termini. NrCAM can bind to SAP102 and other members of the MAGUK family. | L1 family
# Overview
The L1 family is a family of cell adhesion molecules that includes several different L1-like proteins, found in the nervous system and other tissues of many animal species. They are a found on radial glial cells and, as such, are important for neural cell migration during development.
The members of the L1-family in humans are called L1, CHL1 (close homolog of L1), Neurofascin and NrCAM (NgCAM related cell adhesion molecule).
The family is characterised by its ability to bind to a family of proteins called ankrins.
NrCAM and neurofascin both have class 1 PDZ domain binding motifs at their COOH termini. NrCAM can bind to SAP102 and other members of the MAGUK family.
# External links
- http://zygote.swarthmore.edu/cell9.html
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/L1_family | |
0d0f39119655cac036e210edc178d05d356a7c17 | wikidoc | Labetalol | Labetalol
- Dosage must be individualized.
- The recommended initial dosage is 100 mg twice daily whether used alone or added to a diuretic regimen. After 2 or 3 days, using standing blood pressure as an indicator, dosage may be titrated in increments of 100 mg b.i.d. every 2 or 3 days. The usual maintenance dosage of labetalol HCl is between 200 and 400 mg twice daily.
- Since the full antihypertensive effect of labetalol HCl is usually seen within the first 1 to 3 hours of the initial dose or dose increment, the assurance of a lack of an exaggerated hypotensive response can be clinically established in the office setting. The antihypertensive effects of continued dosing can be measured at subsequent visits, approximately 12 hours after a dose, to determine whether further titration is necessary.
- Patients with severe hypertension may require from 1,200 to 2,400 mg per day, with or without thiazide diuretics. - Should side effects (principally nausea or dizziness) occur with these doses administered twice daily, the same total daily dose administered three times daily may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg twice daily.
- When a diuretic is added, an additive antihypertensive effect can be expected. In some cases this may necessitate a labetalol HCl dosage adjustment. As with most antihypertensive drugs, optimal dosages of labetalol hydrochloride tablets are usually lower in patients also receiving a diuretic.
- When transferring patients from other antihypertensive drugs, labetalol hydrochloride tablets should be introduced as recommended and the dosage of the existing therapy progressively decreased.
As in the general patient population, labetalol therapy may be initiated at 100 mg twice daily and titrated upwards in increments of 100 mg b.i.d. as required for control of blood pressure. Since some elderly patients eliminate labetalol more slowly, however, adequate control of blood pressure may be achieved at a lower maintenance dosage compared to the general population. The majority of elderly patients will require between 100 and 200 mg b.i.d.
Labetalol hydrochloride injection is intended for intravenous use in hospitalized patients. Dosage must be individualized depending upon the severity of hypertension and the response of the patient during dosing.
Patients should always be kept in a supine position during the period of intravenous drug administration. A substantial fall in blood pressure on standing should be expected in these patients. The patient’s ability to tolerate an upright position should be established before permitting any ambulation, such as using toilet facilities.
Either of two methods of administration of labetalol hydrochloride injection may be used:
- Repeated intravenous injections.
- Slow continuous infusion.
Initially, labetalol hydrochloride injection should be given in a dose of 20 mg labetalol HCl (which corresponds to 0.25 mg/kg for an 80 kg patient) by slow intravenous injection over a 2-minute period.
Immediately before the injection and at 5 and 10 minutes after injection, supine blood pressure should be measured to evaluate response. Additional injections of 40 mg or 80 mg can be given at 10 minute intervals until a desired supine blood pressure is achieved or a total of 300 mg labetalol HCl has been injected. The maximum effect usually occurs within 5 minutes of each injection.
Labetalol hydrochloride injection is prepared for continuous intravenous infusion by diluting the contents with commonly used intravenous fluids (see below). Examples of methods of preparing the infusion solution are:
The contents of either two 20 mL vials (40 mL), or one 40 mL vial, are added to 160 mL of a commonly used intravenous fluid such that the resultant 200 mL of solution contains 200 mg of labetalol hydrochloride, 1 mg/mL. The diluted solution should be administered at a rate of 2 mL/min to deliver 2 mg/min.
Alternatively, the contents of either two 20 mL vials (40 mL), or one 40 mL vial, of labetalol hydrochloride injection are added to 250 mL of a commonly used intravenous fluid. The resultant solution will contain 200 mg of labetalol hydrochloride, approximately 2 mg/3 mL. The diluted solution should be administered at a rate of 3 mL/min to deliver approximately 2 mg/min.
The rate of infusion of the diluted solution may be adjusted according to the blood pressure response, at the discretion of the physician. To facilitate a desired rate of infusion, the diluted solution can be infused using a controlled administration mechanism, e.g., graduated burette or mechanically driven infusion pump.
Since the half-life of labetalol is 5 to 8 hours, steady-state blood levels (in the face of a constant rate of infusion) would not be reached during the usual infusion time period. The infusion should be continued until a satisfactory response is obtained and should then be stopped and oral labetalol hydrochloride started. The effective intravenous dose is usually in the range of 50 to 200 mg. A total dose of up to 300 mg may be required in some patients.
Subsequent oral dosing with labetalol hydrochloride tablets should begin when it has been established that the supine diastolic blood pressure has begun to rise. The recommended initial dose is 200 mg, followed in 6 to 12 hours by an additional dose of 200 or 400 mg, depending on the blood pressure response. Thereafter, inpatient titration with labetalol hydrochloride tablets may proceed as follows:
While in the hospital, the dosage of labetalol hydrochloride tablets may be increased at 1 day intervals to achieve the desired blood pressure reduction.
- Developed by: ACC/AHA
- Class of Recommendation: Class IIb
- Strength of Evidence: Level of Evidence C
- Dosing Information/Recommendation
- 200 to 600 mg bid for the treatment of cocaine induced ACS.
- Dosing Information
- 100 mg bid.
- Dosing Information
- Oral: 800 mg/day (hypertension + premature ventricular beats)
- IV: 1 mg/min (sinus rhythm restoration in patients resenting: sinus tachycardia, paroxysmal SVT, paroxysmal AFib, chronic AFib or VT
- Dosing Information
- 5 mg/mL (treatment of hypertension and arrhythmias).
- Dosing Information
- Initial dose of 10 mg IV over 2 minutes, 10 to 20 mg doses every 10 minutes to a maximum of 300 mg/day may be administered if required.
- Dosing Information
- 200 mg PO.
- Dosing Information
- 1 to 2 mg/kg IV bolus.
- Dosing Information
- Initial dose of 0.3 mg/kg IV, then 0.05 to 0.07 mg/kg administered every 30 minutes.
- Dosing Information
- Continuous infusion 0.05 to 0.75 mg/kg/hour or 10 to 20 mg IV boluses with 60 to 120 minute intervals.
- Dosing Information
- 75 mg PO q12h.
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Overt cardiac failure
- Second degree heart block
- Third degree heart block
- Cardiogenic shock
- Severe bradycardia
- Hypotension
- Hypersensitivity
Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.
Severe hepatocellular injury, confirmed by rechallenge in at least one case, occurs rarely with labetalol therapy. The hepatic injury is usually reversible, but hepatic necrosis and death have been reported. Injury has occurred after both short- and long-term treatment and may be slowly progressive despite minimal symptomatology. Similar hepatic events have been reported with a related compound, dilevalol HCl, including two deaths. Dilevalol HCl is one of the four isomers of labetalol. Thus, for patients taking labetalol, periodic determination of suitable hepatic laboratory tests would be appropriate. Laboratory testing should also be done at the very first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness, or unexplained “flu-like” symptoms). If the patient has jaundice or laboratory evidence of liver injury, labetalol should be stopped and not restarted.
Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure. Beta-blockade carries a potential hazard of further depressing myocardial contractility and precipitating more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, labetalol can be used with caution in patients with a history of heart failure, who are well compensated. Congestive heart failure has been observed in patients receiving labetalol. Labetalol does not abolish the inotropic action of digitalis on heart muscle.
In patients with latent cardiac insufficiency, continued depression of the myocardium with beta-blocking agents over a period of time can lead, in some cases, to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic, labetalol therapy should be withdrawn (gradually if possible).
Angina pectoris has not been reported upon labetalol discontinuation. However, following abrupt cessation of therapy with some beta-blocking agents in patients with coronary artery disease, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported. Therefore, such patients should be cautioned against interruption of therapy without the physician’s advice. Even in the absence of overt angina pectoris, when discontinuation of labetalol is planned, the patient should be carefully observed and should be advised to limit physical activity. If angina markedly worsens or acute coronary insufficiency develops, labetalol administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken.
Since labetalol injection at the usual intravenous therapeutic doses has not been studied in patients with nonallergic bronchospastic disease, it should not be used in such patients.
Intravenous labetalol has been shown to be effective in lowering the blood pressure and relieving symptoms in patients with pheochromocytoma; higher than usual doses may be required. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol to patients with pheochromocytoma.
Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; it may therefore be necessary to adjust the dose of antidiabetic drugs.
Do not routinely withdraw chronic beta-blocker therapy prior to surgery. The effect of labetalol’s alpha adrenergic activity has not been evaluated in this setting.
Several deaths have occurred when labetalol injection was used during surgery (including when used in cases to control bleeding).
A synergism between labetalol and halothane anesthesia has been shown.
Caution must be observed when reducing severely elevated blood pressure. A number of adverse reactions, including cerebral infarction, optic nerve infarction, angina, and ischemic changes in the electrocardiogram, have been reported with other agents when severely elevated blood pressure was reduced over time courses of several hours to as long as 1 or 2 days. The desired blood pressure lowering should therefore be achieved over as long a period of time as is compatible with the patient's status.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrineused to treat allergic reaction.
due to one or more adverse effects was required in 7% of all patients. In these same trials, other agents with solely beta-blocking activity used in the control groups led to discontinuation in 8% to 10% of patients, and a centrally acting alpha-agonist led to discontinuation in 30% of patients.
The incidence rates of adverse reactions listed in the following table were derived from multicenter, controlled clinical trials comparing labetalol HCl, placebo, metoprolol, and propranolol over treatment periods of 3 and 4 months. Where the frequency of adverse effects for labetalol HCl and placebo is similar, causal relationship is uncertain. The rates are based on adverse reactions considered probably drug related by the investigator. If all reports are considered, the rates are somewhat higher (e.g., dizziness, 20%; nausea, 14%; fatigue, 11%), but the overall conclusions are unchanged.
The adverse effects were reported spontaneously and are representative of the incidence of adverse effects that may be observed in a properly selected hypertensive patient population, i.e., a group excluding patients with bronchospastic disease, overt congestive heart failure, or other contraindications to beta-blocker therapy.
Clinical trials also included studies utilizing daily doses up to 2,400 mg in more severely hypertensive patients. Certain of the side effects increased with increasing dose, as shown in the following table that depicts the entire U.S. therapeutic trials data base for adverse reactions that are clearly or possibly dose related.
In addition, a number of other less common adverse events have been reported:
- Body as a Whole: Fever.
- Cardiovascular: Hypotension, and rarely, syncope, bradycardia, heart block.
- Central and Peripheral Nervous Systems: Paresthesia, most frequently described as scalp tingling. In most cases, it was mild and transient and usually occurred at the beginning of treatment.
- Collagen Disorders: Systemic lupus erythematosus, positive antinuclear factor.
- Eyes: Dry eyes.
- Immunological System: Antimitochondrial antibodies.
- Liver and Biliary System: Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests.
- Musculoskeletal System: Muscle cramps, toxic myopathy.
- Respiratory System: Bronchospasm.
- Skin and Appendages: Rashes of various types, such as generalized maculopapular, lichenoid, urticarial, bullous lichen planus, psoriaform, and facial erythema; Peyronie's disease; reversible alopecia.
- Urinary System: Difficulty in micturition, including acute urinary bladder retention.
- Hypersensitivity: Rare reports of hypersensitivity (e.g., rash, urticaria, pruritus, angioedema, dyspnea andanaphylactoidreactions.
- Following approval for marketing in the United Kingdom, a monitored release survey involving approximately 6,900 patients was conducted for further safety and efficacy evaluation of this product. Results of this survey indicate that the type, severity, and incidence of adverse effects were comparable to those cited above.
- Potential Adverse Effects: In addition, other adverse effects not listed above have been reported with other beta-adrenergic blocking agents.
- Central Nervous System: Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientationfor time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on psychometrics.
- Cardiovascular: Intensification of A-V block (see CONTRAINDICATIONS).
- Allergic: Fever combined with aching and sore throat, laryngospasm, respiratory distress.
- Hematologic: Agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura.
- Gastrointestinal: Mesenteric artery thrombosis, ischemic colitis.
- The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with labetalol HCl.
- Clinical Laboratory Tests: There have been reversible increases of serum transaminases in 4% of patients treated with labetalol HCl and tested and, more rarely, reversible increases in blood urea.
- Beta-Blockers: Drugs possessing beta-blocking properties can blunt the bronchodilator effect of beta-receptor agonist drugs in patients with bronchospasm; therefore, doses greater than the normal antiasthmatic dose of beta-agonist bronchodilator drugs may be required.
- Cimetidine: Has been shown to increase the bioavailability of labetalol HCl. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol HCl, special care should be used in establishing the dose required for blood pressure control in such patients.
- Halothane: Synergism has been shown between halothane anesthesia and intravenously administered labetalol HCl. During controlled hypotensive anesthesia using labetalol HCl in association with halothane, high concentrations (3% or above) of halothane should not be used because the degree of hypotension will be increased and because of the possibility of a large reduction in cardiac output and an increase in central venous pressure. The anesthesiologist should be informed when a patient is receiving labetalol HCl.
- Nitroglycerin: Labetalol HCl blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol HCl is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur.
- Calcium channel blockers: Care should be taken if labetalol is used concomitantly with calcium channel blockers of the verapamil type.
- Digitalis glycosides: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
# Drug & OR Laboratory Test Interactions
The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine, normetanephrine, and vanillylmandelic acid when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with labetalol HCl, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J Chromatogr 385:241,1987) should be employed in determining levels of catecholamines.
Labetalol HCl has also been reported to produce a false-positive test for amphetamine when screening urine for the presence of drugs using the commercially available assay methods Toxi-Lab A®(thin-layer chromatographic assay) and Emit-d.a.u ®(radioenzymatic assay). When patients being treated with labetalol have a positive urine test for amphetamine using these techniques, confirmation should be made by using more specific methods, such as a gas chromatographic-mass spectrometer technique.
Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD. A teratology study performed with labetalol in rabbits at IV doses up to 1.7 times the MRHD revealed no evidence of drug related harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol HCl for hypertension during pregnancy. Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.
The blood pressure should be monitored during and after completion of the infusion or intravenous injections. Rapid or excessive falls in either systolic blood pressure or diastolic blood pressure during intravenous treatment should be avoided. In patients with excessive systolic hypertension, the decrease in systolic pressure should be used as indicator of effectiveness in addition to the response of the diastolic pressure.
- Ringer's Injection, USP
- Lactated Ringer's Injection, USP
- 5% Dextrose and Ringer's Injection
- 5% Lactated Ringer's and 5% Dextrose Injection
- 5% Dextrose Injection, USP
- 0.9% Sodium Chloride Injection, USP
- 5% Dextrose and 0.2% Sodium Chloride Injection, USP
- 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP
- 5% Dextrose and 0.9% Sodium Chloride Injection, USP
- 5% Dextrose and 0.33% Sodium Chloride Injection, USP.
- Labetalol hydrochloride injection was NOT compatible with 5% sodium bicarbonate injection, USP.
Care should be taken when administering alkaline drugs, including furosemide, in combination with labetalol. Compatibility should be assured prior to administering these drugs together.
- Excessive ]—administer atropine or epinephrine.
- Cardiac failure—administer a digitalis glycoside and a diuretic.
- Dopamine or dobutamine may also be useful.hypotension—administer vasopressors, e.g., norepinephrine. There is pharmacologic evidence that norepinephrine may be the drug of choice.
- Bronchospasm—administer epinephrine and/or an aerosolized beta2-agonist.
- Seizures—administer diazepam.
In severe beta-blocker overdose resulting in hypotension and/or bradycardia, glucagon has been shown to be effective when administered in large doses (5 to 10 mg rapidly over 30 seconds, followed by continuous infusion of 5 mg per hour that can be reduced as the patient improves).
Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol HCl from the general circulation (<1%).
The oral LD50 value of labetalol HCl in the mouse is approximately 600 mg/kg and in the rat is >2 g/kg. The IV LD50 in these species is 50 to 60 mg/kg.
Labetalol hydrochloride (HCl) is a racemate chemically designated as 2-hydroxy-5- ethyl] benzamide monohydrochloride, and it has the following structure:
Labetalol HCl has the molecular formula C19H24N2O3HCl and a molecular weight of 364.9. It has two asymmetric centers and therefore exists as a molecular complex of two diastereoisomeric pairs. Dilevalol, the R, R´stereoisomer, makes up 25% of racemic labetalol.
Labetalol HCl is a white or off-white crystalline powder, soluble in water.
Labetalol hydrochloride tablets contain 100, 200, or 300 mg of labetalol HCl and are taken orally. The tablets also contain the inactive ingredients lactose monohydrate, corn starch, crospovidone, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc.
Single oral doses of Labetalol administered to patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The atrioventricular (A-V) conduction time was modestly prolonged in two of seven patients. In another study, IV Labetalol slightly prolonged A-V nodal conduction time and atrial effective refractory period with only small changes in heart rate. The effects on A-V nodal refractoriness were inconsistent.
Labetalol produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha- and beta-blocking effects. Hemodynamic effects are variable, with small, nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma renins are reduced.
Doses of Labetalol that controlled hypertension did not affect renal function in mildly to severely hypertensive patients with normal renal function.
Due to the alpha1-receptor blocking activity of Labetalol , blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (2%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the recommended starting dose and titration increments are closely followed. Symptomatic postural hypotension is most likely to occur 2 to 4 hours after a dose, especially following the use of large initial doses or upon large changes in dose.
The peak effects of single oral doses of Labetalol occur within 2 to 4 hours. The duration of effect depends upon dose, lasting at least 8 hours following single oral doses of 100 mg and more than 12 hours following single oral doses of 300 mg. The maximum, steady-state blood pressure response upon oral, twice-a-day dosing occurs within 24 to 72 hours.
The antihypertensive effect of labetalol has a linear correlation with the logarithm of labetalol plasma concentration, and there is also a linear correlation between the reduction in exercise-induced tachycardia occurring at 2 hours after oral administration of Labetalol and the logarithm of the plasma concentration.
About 70% of the maximum beta-blocking effect is present for 5 hours after the administration of a single oral dose of 400 mg with suggestion that about 40% remains at 8 hours.
The antianginal efficacy of Labetalol has not been studied. In 37 patients with hypertension and coronary artery disease, Labetalol did not increase the incidence or severity of angina attacks.
Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.
Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen A-V block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm, and it may also interfere with exogenous bronchodilators in such patients.
The plasma half-life of labetalol following oral administration is about 6 to 8 hours. Steady-state plasma levels of labetalol during repetitive dosing are reached by about the third day of dosing. In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased "first-pass" metabolism.
The metabolism of labetalol is mainly through conjugation to glucuronide metabolites. These metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing.
Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier in animal studies. Labetalol is approximately 50% protein bound. Neither hemodialysis nor peritoneal dialysis removes a significant amount of Labetalol from the general circulation (<1%).
Some pharmacokinetic studies indicate that the elimination of labetalol is reduced in elderly patients. Therefore, although elderly patients may initiate therapy at the currently recommended dosage of 100 mg b.i.d., elderly patients will generally require lower maintenance dosages than nonelderly patients.
- Labetalol hydrochloride tablets, USP 100 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "041" on the other side of the tablet, bottles of 100 (NDC 49884-122-01), 500 (NDC 49884-122-05) and 1000(NDC 49884-122-10).
- Labetalol hydrochloride tablets, USP 200 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "042" on the other side of the tablet, bottles of 100 (NDC 49884-123-01), 500 (NDC 49884-123-05), and 1000(NDC 49884-123-10).
- Labetalol hydrochloride tablets, USP 300 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "043" on the other side of the tablet, bottles of 100 (NDC 49884-124-01), 500 (NDC 49884-124-05), and 1000(NDC 49884-124-10).
NDC Labetalol Hydrochloride Injection, USP (5 mg per mL):
- 100 mg per 20 mL Multi-Dose Vial (25021-300-20)
- 200 mg per 40 mL Multi-Dose Vial (25021-300-40)
- Labetalol hydrochloride tablets, USP should be stored at 20° to 25°C (68° to 77°F).
- Store at 20° to 25°C (68° to 77°F).
- Do not freeze.
- Protect from light. Retain in carton until time of use.
- Trandate
- ↑ Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE; et al. (2007). "ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine". Circulation. 116 (7): e148–304. doi:10.1161/CIRCULATIONAHA.107.181940. PMID 17679616.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Condorelli M, Brevetti G, Chiariello M, Miceli D, Lavecchia G, Paudice G; et al. (1982). "Effects of combined alpha- and beta-blockade by labetalol in patients with coronary artery disease". Br J Clin Pharmacol. 13 (1 Suppl): 101S–110S. PMC 1401826. PMID 7093092.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Stoudemire A, Knos G, Gladson M, Markwalter H, Sung YF, Morris R; et al. (1990). "Labetalol in the control of cardiovascular responses to electroconvulsive therapy in high-risk depressed medical patients". J Clin Psychiatry. 51 (12): 508–12. PMID 2258364.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Orlowski JP, Vidt DG, Walker S, Haluska JF (1989). "The hemodynamic effects of intravenous labetalol for postoperative hypertension". Cleve Clin J Med. 56 (1): 29–34. PMID 2731325.CS1 maint: Multiple names: authors list (link)
- ↑ Davies AB, Bala Subramanian V, Gould B, Raftery EB (1982). "Rapid reduction of blood pressure with acute oral labetalol". Br J Clin Pharmacol. 13 (5): 705–10. PMC 1402081. PMID 7082539.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Smith WB, Clifton GG, O'Neill WM, Wallin JD (1983). "Antihypertensive effectiveness of intravenous labetalol in accelerated hypertension". Hypertension. 5 (4): 579–83. PMID 6862581.CS1 maint: Multiple names: authors list (link)
- ↑ Saarnivaara L, Klemola UM, Lindgren L (1987). "Labetalol as a hypotensive agent for middle ear microsurgery". Acta Anaesthesiol Scand. 31 (3): 196–201. PMID 3577641.CS1 maint: Multiple names: authors list (link)
- ↑ Orlowski JP, Shiesley D, Vidt DG, Barnett GH, Little JR (1988). "Labetalol to control blood pressure after cerebrovascular surgery". Crit Care Med. 16 (8): 765–8. PMID 3396371.CS1 maint: Multiple names: authors list (link)
- ↑ Grubb BP (1991). "The use of oral labetalol in the treatment of arrhythmias associated with the long QT syndrome". Chest. 100 (6): 1724–5. PMID 1959422. | Labetalol
- Dosage must be individualized.
- The recommended initial dosage is 100 mg twice daily whether used alone or added to a diuretic regimen. After 2 or 3 days, using standing blood pressure as an indicator, dosage may be titrated in increments of 100 mg b.i.d. every 2 or 3 days. The usual maintenance dosage of labetalol HCl is between 200 and 400 mg twice daily.
- Since the full antihypertensive effect of labetalol HCl is usually seen within the first 1 to 3 hours of the initial dose or dose increment, the assurance of a lack of an exaggerated hypotensive response can be clinically established in the office setting. The antihypertensive effects of continued dosing can be measured at subsequent visits, approximately 12 hours after a dose, to determine whether further titration is necessary.
- Patients with severe hypertension may require from 1,200 to 2,400 mg per day, with or without thiazide diuretics. * Should side effects (principally nausea or dizziness) occur with these doses administered twice daily, the same total daily dose administered three times daily may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg twice daily.
- When a diuretic is added, an additive antihypertensive effect can be expected. In some cases this may necessitate a labetalol HCl dosage adjustment. As with most antihypertensive drugs, optimal dosages of labetalol hydrochloride tablets are usually lower in patients also receiving a diuretic.
- When transferring patients from other antihypertensive drugs, labetalol hydrochloride tablets should be introduced as recommended and the dosage of the existing therapy progressively decreased.
As in the general patient population, labetalol therapy may be initiated at 100 mg twice daily and titrated upwards in increments of 100 mg b.i.d. as required for control of blood pressure. Since some elderly patients eliminate labetalol more slowly, however, adequate control of blood pressure may be achieved at a lower maintenance dosage compared to the general population. The majority of elderly patients will require between 100 and 200 mg b.i.d.
Labetalol hydrochloride injection is intended for intravenous use in hospitalized patients. Dosage must be individualized depending upon the severity of hypertension and the response of the patient during dosing.
Patients should always be kept in a supine position during the period of intravenous drug administration. A substantial fall in blood pressure on standing should be expected in these patients. The patient’s ability to tolerate an upright position should be established before permitting any ambulation, such as using toilet facilities.
Either of two methods of administration of labetalol hydrochloride injection may be used:
- Repeated intravenous injections.
- Slow continuous infusion.
Initially, labetalol hydrochloride injection should be given in a dose of 20 mg labetalol HCl (which corresponds to 0.25 mg/kg for an 80 kg patient) by slow intravenous injection over a 2-minute period.
Immediately before the injection and at 5 and 10 minutes after injection, supine blood pressure should be measured to evaluate response. Additional injections of 40 mg or 80 mg can be given at 10 minute intervals until a desired supine blood pressure is achieved or a total of 300 mg labetalol HCl has been injected. The maximum effect usually occurs within 5 minutes of each injection.
Labetalol hydrochloride injection is prepared for continuous intravenous infusion by diluting the contents with commonly used intravenous fluids (see below). Examples of methods of preparing the infusion solution are:
The contents of either two 20 mL vials (40 mL), or one 40 mL vial, are added to 160 mL of a commonly used intravenous fluid such that the resultant 200 mL of solution contains 200 mg of labetalol hydrochloride, 1 mg/mL. The diluted solution should be administered at a rate of 2 mL/min to deliver 2 mg/min.
Alternatively, the contents of either two 20 mL vials (40 mL), or one 40 mL vial, of labetalol hydrochloride injection are added to 250 mL of a commonly used intravenous fluid. The resultant solution will contain 200 mg of labetalol hydrochloride, approximately 2 mg/3 mL. The diluted solution should be administered at a rate of 3 mL/min to deliver approximately 2 mg/min.
The rate of infusion of the diluted solution may be adjusted according to the blood pressure response, at the discretion of the physician. To facilitate a desired rate of infusion, the diluted solution can be infused using a controlled administration mechanism, e.g., graduated burette or mechanically driven infusion pump.
Since the half-life of labetalol is 5 to 8 hours, steady-state blood levels (in the face of a constant rate of infusion) would not be reached during the usual infusion time period. The infusion should be continued until a satisfactory response is obtained and should then be stopped and oral labetalol hydrochloride started. The effective intravenous dose is usually in the range of 50 to 200 mg. A total dose of up to 300 mg may be required in some patients.
Subsequent oral dosing with labetalol hydrochloride tablets should begin when it has been established that the supine diastolic blood pressure has begun to rise. The recommended initial dose is 200 mg, followed in 6 to 12 hours by an additional dose of 200 or 400 mg, depending on the blood pressure response. Thereafter, inpatient titration with labetalol hydrochloride tablets may proceed as follows:
While in the hospital, the dosage of labetalol hydrochloride tablets may be increased at 1 day intervals to achieve the desired blood pressure reduction.
- Developed by: ACC/AHA
- Class of Recommendation: Class IIb
- Strength of Evidence: Level of Evidence C
- Dosing Information/Recommendation
- 200 to 600 mg bid for the treatment of cocaine induced ACS.[1]
- Dosing Information
- 100 mg bid.[2]
- Dosing Information
- Oral: 800 mg/day (hypertension + premature ventricular beats)
- IV: 1 mg/min (sinus rhythm restoration in patients resenting: sinus tachycardia, paroxysmal SVT, paroxysmal AFib, chronic AFib or VT
- Dosing Information
- 5 mg/mL (treatment of hypertension and arrhythmias).[3]
- Dosing Information
- Initial dose of 10 mg IV over 2 minutes, 10 to 20 mg doses every 10 minutes to a maximum of 300 mg/day may be administered if required.[4]
- Dosing Information
- 200 mg PO.[5]
- Dosing Information
- 1 to 2 mg/kg IV bolus.[6]
- Dosing Information
- Initial dose of 0.3 mg/kg IV, then 0.05 to 0.07 mg/kg administered every 30 minutes.[7]
- Dosing Information
- Continuous infusion 0.05 to 0.75 mg/kg/hour or 10 to 20 mg IV boluses with 60 to 120 minute intervals.[8]
- Dosing Information
- 75 mg PO q12h.[9]
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Overt cardiac failure
- Second degree heart block
- Third degree heart block
- Cardiogenic shock
- Severe bradycardia
- Hypotension
- Hypersensitivity
Beta-blockers, even those with apparent cardioselectivity, should not be used in patients with a history of obstructive airway disease, including asthma.
Severe hepatocellular injury, confirmed by rechallenge in at least one case, occurs rarely with labetalol therapy. The hepatic injury is usually reversible, but hepatic necrosis and death have been reported. Injury has occurred after both short- and long-term treatment and may be slowly progressive despite minimal symptomatology. Similar hepatic events have been reported with a related compound, dilevalol HCl, including two deaths. Dilevalol HCl is one of the four isomers of labetalol. Thus, for patients taking labetalol, periodic determination of suitable hepatic laboratory tests would be appropriate. Laboratory testing should also be done at the very first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness, or unexplained “flu-like” symptoms). If the patient has jaundice or laboratory evidence of liver injury, labetalol should be stopped and not restarted.
Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure. Beta-blockade carries a potential hazard of further depressing myocardial contractility and precipitating more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, labetalol can be used with caution in patients with a history of heart failure, who are well compensated. Congestive heart failure has been observed in patients receiving labetalol. Labetalol does not abolish the inotropic action of digitalis on heart muscle.
In patients with latent cardiac insufficiency, continued depression of the myocardium with beta-blocking agents over a period of time can lead, in some cases, to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic, labetalol therapy should be withdrawn (gradually if possible).
Angina pectoris has not been reported upon labetalol discontinuation. However, following abrupt cessation of therapy with some beta-blocking agents in patients with coronary artery disease, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported. Therefore, such patients should be cautioned against interruption of therapy without the physician’s advice. Even in the absence of overt angina pectoris, when discontinuation of labetalol is planned, the patient should be carefully observed and should be advised to limit physical activity. If angina markedly worsens or acute coronary insufficiency develops, labetalol administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken.
Since labetalol injection at the usual intravenous therapeutic doses has not been studied in patients with nonallergic bronchospastic disease, it should not be used in such patients.
Intravenous labetalol has been shown to be effective in lowering the blood pressure and relieving symptoms in patients with pheochromocytoma; higher than usual doses may be required. However, paradoxical hypertensive responses have been reported in a few patients with this tumor; therefore, use caution when administering labetalol to patients with pheochromocytoma.
Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; it may therefore be necessary to adjust the dose of antidiabetic drugs.
Do not routinely withdraw chronic beta-blocker therapy prior to surgery. The effect of labetalol’s alpha adrenergic activity has not been evaluated in this setting.
Several deaths have occurred when labetalol injection was used during surgery (including when used in cases to control bleeding).
A synergism between labetalol and halothane anesthesia has been shown.
Caution must be observed when reducing severely elevated blood pressure. A number of adverse reactions, including cerebral infarction, optic nerve infarction, angina, and ischemic changes in the electrocardiogram, have been reported with other agents when severely elevated blood pressure was reduced over time courses of several hours to as long as 1 or 2 days. The desired blood pressure lowering should therefore be achieved over as long a period of time as is compatible with the patient's status.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrineused to treat allergic reaction.
due to one or more adverse effects was required in 7% of all patients. In these same trials, other agents with solely beta-blocking activity used in the control groups led to discontinuation in 8% to 10% of patients, and a centrally acting alpha-agonist led to discontinuation in 30% of patients.
The incidence rates of adverse reactions listed in the following table were derived from multicenter, controlled clinical trials comparing labetalol HCl, placebo, metoprolol, and propranolol over treatment periods of 3 and 4 months. Where the frequency of adverse effects for labetalol HCl and placebo is similar, causal relationship is uncertain. The rates are based on adverse reactions considered probably drug related by the investigator. If all reports are considered, the rates are somewhat higher (e.g., dizziness, 20%; nausea, 14%; fatigue, 11%), but the overall conclusions are unchanged.
The adverse effects were reported spontaneously and are representative of the incidence of adverse effects that may be observed in a properly selected hypertensive patient population, i.e., a group excluding patients with bronchospastic disease, overt congestive heart failure, or other contraindications to beta-blocker therapy.
Clinical trials also included studies utilizing daily doses up to 2,400 mg in more severely hypertensive patients. Certain of the side effects increased with increasing dose, as shown in the following table that depicts the entire U.S. therapeutic trials data base for adverse reactions that are clearly or possibly dose related.
In addition, a number of other less common adverse events have been reported:
- Body as a Whole: Fever.
- Cardiovascular: Hypotension, and rarely, syncope, bradycardia, heart block.
- Central and Peripheral Nervous Systems: Paresthesia, most frequently described as scalp tingling. In most cases, it was mild and transient and usually occurred at the beginning of treatment.
- Collagen Disorders: Systemic lupus erythematosus, positive antinuclear factor.
- Eyes: Dry eyes.
- Immunological System: Antimitochondrial antibodies.
- Liver and Biliary System: Hepatic necrosis, hepatitis, cholestatic jaundice, elevated liver function tests.
- Musculoskeletal System: Muscle cramps, toxic myopathy.
- Respiratory System: Bronchospasm.
- Skin and Appendages: Rashes of various types, such as generalized maculopapular, lichenoid, urticarial, bullous lichen planus, psoriaform, and facial erythema; Peyronie's disease; reversible alopecia.
- Urinary System: Difficulty in micturition, including acute urinary bladder retention.
- Hypersensitivity: Rare reports of hypersensitivity (e.g., rash, urticaria, pruritus, angioedema, dyspnea andanaphylactoidreactions.
- Following approval for marketing in the United Kingdom, a monitored release survey involving approximately 6,900 patients was conducted for further safety and efficacy evaluation of this product. Results of this survey indicate that the type, severity, and incidence of adverse effects were comparable to those cited above.
- Potential Adverse Effects: In addition, other adverse effects not listed above have been reported with other beta-adrenergic blocking agents.
- Central Nervous System: Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientationfor time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on psychometrics.
- Cardiovascular: Intensification of A-V block (see CONTRAINDICATIONS).
- Allergic: Fever combined with aching and sore throat, laryngospasm, respiratory distress.
- Hematologic: Agranulocytosis, thrombocytopenic or nonthrombocytopenic purpura.
- Gastrointestinal: Mesenteric artery thrombosis, ischemic colitis.
- The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with labetalol HCl.
- Clinical Laboratory Tests: There have been reversible increases of serum transaminases in 4% of patients treated with labetalol HCl and tested and, more rarely, reversible increases in blood urea.
- Beta-Blockers: Drugs possessing beta-blocking properties can blunt the bronchodilator effect of beta-receptor agonist drugs in patients with bronchospasm; therefore, doses greater than the normal antiasthmatic dose of beta-agonist bronchodilator drugs may be required.
- Cimetidine: Has been shown to increase the bioavailability of labetalol HCl. Since this could be explained either by enhanced absorption or by an alteration of hepatic metabolism of labetalol HCl, special care should be used in establishing the dose required for blood pressure control in such patients.
- Halothane: Synergism has been shown between halothane anesthesia and intravenously administered labetalol HCl. During controlled hypotensive anesthesia using labetalol HCl in association with halothane, high concentrations (3% or above) of halothane should not be used because the degree of hypotension will be increased and because of the possibility of a large reduction in cardiac output and an increase in central venous pressure. The anesthesiologist should be informed when a patient is receiving labetalol HCl.
- Nitroglycerin: Labetalol HCl blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effect. If labetalol HCl is used with nitroglycerin in patients with angina pectoris, additional antihypertensive effects may occur.
- Calcium channel blockers: Care should be taken if labetalol is used concomitantly with calcium channel blockers of the verapamil type.
- Digitalis glycosides: Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
## Drug & OR Laboratory Test Interactions
The presence of labetalol metabolites in the urine may result in falsely elevated levels of urinary catecholamines, metanephrine, normetanephrine, and vanillylmandelic acid when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with labetalol HCl, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J Chromatogr 385:241,1987) should be employed in determining levels of catecholamines.
Labetalol HCl has also been reported to produce a false-positive test for amphetamine when screening urine for the presence of drugs using the commercially available assay methods Toxi-Lab A®(thin-layer chromatographic assay) and Emit-d.a.u ®(radioenzymatic assay). When patients being treated with labetalol have a positive urine test for amphetamine using these techniques, confirmation should be made by using more specific methods, such as a gas chromatographic-mass spectrometer technique.
Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD. A teratology study performed with labetalol in rabbits at IV doses up to 1.7 times the MRHD revealed no evidence of drug related harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Labetalol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol HCl for hypertension during pregnancy. Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.
The blood pressure should be monitored during and after completion of the infusion or intravenous injections. Rapid or excessive falls in either systolic blood pressure or diastolic blood pressure during intravenous treatment should be avoided. In patients with excessive systolic hypertension, the decrease in systolic pressure should be used as indicator of effectiveness in addition to the response of the diastolic pressure.
- Ringer's Injection, USP
- Lactated Ringer's Injection, USP
- 5% Dextrose and Ringer's Injection
- 5% Lactated Ringer's and 5% Dextrose Injection
- 5% Dextrose Injection, USP
- 0.9% Sodium Chloride Injection, USP
- 5% Dextrose and 0.2% Sodium Chloride Injection, USP
- 2.5% Dextrose and 0.45% Sodium Chloride Injection, USP
- 5% Dextrose and 0.9% Sodium Chloride Injection, USP
- 5% Dextrose and 0.33% Sodium Chloride Injection, USP.
- Labetalol hydrochloride injection was NOT compatible with 5% sodium bicarbonate injection, USP.
Care should be taken when administering alkaline drugs, including furosemide, in combination with labetalol. Compatibility should be assured prior to administering these drugs together.
- Excessive [[bradycardia]]—administer atropine or epinephrine.
- Cardiac failure—administer a digitalis glycoside and a diuretic.
- Dopamine or dobutamine may also be useful.hypotension—administer vasopressors, e.g., norepinephrine. There is pharmacologic evidence that norepinephrine may be the drug of choice.
- Bronchospasm—administer epinephrine and/or an aerosolized beta2-agonist.
- Seizures—administer diazepam.
In severe beta-blocker overdose resulting in hypotension and/or bradycardia, glucagon has been shown to be effective when administered in large doses (5 to 10 mg rapidly over 30 seconds, followed by continuous infusion of 5 mg per hour that can be reduced as the patient improves).
Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol HCl from the general circulation (<1%).
The oral LD50 value of labetalol HCl in the mouse is approximately 600 mg/kg and in the rat is >2 g/kg. The IV LD50 in these species is 50 to 60 mg/kg.
Labetalol hydrochloride (HCl) is a racemate chemically designated as 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl) amino] ethyl] benzamide monohydrochloride, and it has the following structure:
Labetalol HCl has the molecular formula C19H24N2O3•HCl and a molecular weight of 364.9. It has two asymmetric centers and therefore exists as a molecular complex of two diastereoisomeric pairs. Dilevalol, the R, R´stereoisomer, makes up 25% of racemic labetalol.
Labetalol HCl is a white or off-white crystalline powder, soluble in water.
Labetalol hydrochloride tablets contain 100, 200, or 300 mg of labetalol HCl and are taken orally. The tablets also contain the inactive ingredients lactose monohydrate, corn starch, crospovidone, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, polyethylene glycol, titanium dioxide and talc.
Single oral doses of Labetalol administered to patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The atrioventricular (A-V) conduction time was modestly prolonged in two of seven patients. In another study, IV Labetalol slightly prolonged A-V nodal conduction time and atrial effective refractory period with only small changes in heart rate. The effects on A-V nodal refractoriness were inconsistent.
Labetalol produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha- and beta-blocking effects. Hemodynamic effects are variable, with small, nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma renins are reduced.
Doses of Labetalol that controlled hypertension did not affect renal function in mildly to severely hypertensive patients with normal renal function.
Due to the alpha1-receptor blocking activity of Labetalol , blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (2%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the recommended starting dose and titration increments are closely followed. Symptomatic postural hypotension is most likely to occur 2 to 4 hours after a dose, especially following the use of large initial doses or upon large changes in dose.
The peak effects of single oral doses of Labetalol occur within 2 to 4 hours. The duration of effect depends upon dose, lasting at least 8 hours following single oral doses of 100 mg and more than 12 hours following single oral doses of 300 mg. The maximum, steady-state blood pressure response upon oral, twice-a-day dosing occurs within 24 to 72 hours.
The antihypertensive effect of labetalol has a linear correlation with the logarithm of labetalol plasma concentration, and there is also a linear correlation between the reduction in exercise-induced tachycardia occurring at 2 hours after oral administration of Labetalol and the logarithm of the plasma concentration.
About 70% of the maximum beta-blocking effect is present for 5 hours after the administration of a single oral dose of 400 mg with suggestion that about 40% remains at 8 hours.
The antianginal efficacy of Labetalol has not been studied. In 37 patients with hypertension and coronary artery disease, Labetalol did not increase the incidence or severity of angina attacks.
Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.
Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen A-V block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm, and it may also interfere with exogenous bronchodilators in such patients.
The plasma half-life of labetalol following oral administration is about 6 to 8 hours. Steady-state plasma levels of labetalol during repetitive dosing are reached by about the third day of dosing. In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased "first-pass" metabolism.
The metabolism of labetalol is mainly through conjugation to glucuronide metabolites. These metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing.
Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier in animal studies. Labetalol is approximately 50% protein bound. Neither hemodialysis nor peritoneal dialysis removes a significant amount of Labetalol from the general circulation (<1%).
Some pharmacokinetic studies indicate that the elimination of labetalol is reduced in elderly patients. Therefore, although elderly patients may initiate therapy at the currently recommended dosage of 100 mg b.i.d., elderly patients will generally require lower maintenance dosages than nonelderly patients.
- Labetalol hydrochloride tablets, USP 100 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "041" on the other side of the tablet, bottles of 100 (NDC 49884-122-01), 500 (NDC 49884-122-05) and 1000(NDC 49884-122-10).
- Labetalol hydrochloride tablets, USP 200 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "042" on the other side of the tablet, bottles of 100 (NDC 49884-123-01), 500 (NDC 49884-123-05), and 1000(NDC 49884-123-10).
- Labetalol hydrochloride tablets, USP 300 mg, white, round, film-coated tablets with bisect, debossed “N” on top and “T” on bottom of the bisect on one side and "043" on the other side of the tablet, bottles of 100 (NDC 49884-124-01), 500 (NDC 49884-124-05), and 1000(NDC 49884-124-10).
NDC Labetalol Hydrochloride Injection, USP (5 mg per mL):
- 100 mg per 20 mL Multi-Dose Vial (25021-300-20)
- 200 mg per 40 mL Multi-Dose Vial (25021-300-40)
- Labetalol hydrochloride tablets, USP should be stored at 20° to 25°C (68° to 77°F).
- Store at 20° to 25°C (68° to 77°F).
- Do not freeze.
- Protect from light. Retain in carton until time of use.
- Trandate
- ↑ Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE; et al. (2007). "ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine". Circulation. 116 (7): e148–304. doi:10.1161/CIRCULATIONAHA.107.181940. PMID 17679616.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Condorelli M, Brevetti G, Chiariello M, Miceli D, Lavecchia G, Paudice G; et al. (1982). "Effects of combined alpha- and beta-blockade by labetalol in patients with coronary artery disease". Br J Clin Pharmacol. 13 (1 Suppl): 101S–110S. PMC 1401826. PMID 7093092.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Stoudemire A, Knos G, Gladson M, Markwalter H, Sung YF, Morris R; et al. (1990). "Labetalol in the control of cardiovascular responses to electroconvulsive therapy in high-risk depressed medical patients". J Clin Psychiatry. 51 (12): 508–12. PMID 2258364.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Orlowski JP, Vidt DG, Walker S, Haluska JF (1989). "The hemodynamic effects of intravenous labetalol for postoperative hypertension". Cleve Clin J Med. 56 (1): 29–34. PMID 2731325.CS1 maint: Multiple names: authors list (link)
- ↑ Davies AB, Bala Subramanian V, Gould B, Raftery EB (1982). "Rapid reduction of blood pressure with acute oral labetalol". Br J Clin Pharmacol. 13 (5): 705–10. PMC 1402081. PMID 7082539.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Smith WB, Clifton GG, O'Neill WM, Wallin JD (1983). "Antihypertensive effectiveness of intravenous labetalol in accelerated hypertension". Hypertension. 5 (4): 579–83. PMID 6862581.CS1 maint: Multiple names: authors list (link)
- ↑ Saarnivaara L, Klemola UM, Lindgren L (1987). "Labetalol as a hypotensive agent for middle ear microsurgery". Acta Anaesthesiol Scand. 31 (3): 196–201. PMID 3577641.CS1 maint: Multiple names: authors list (link)
- ↑ Orlowski JP, Shiesley D, Vidt DG, Barnett GH, Little JR (1988). "Labetalol to control blood pressure after cerebrovascular surgery". Crit Care Med. 16 (8): 765–8. PMID 3396371.CS1 maint: Multiple names: authors list (link)
- ↑ Grubb BP (1991). "The use of oral labetalol in the treatment of arrhythmias associated with the long QT syndrome". Chest. 100 (6): 1724–5. PMID 1959422. | https://www.wikidoc.org/index.php/Labetalol | |
1f192f48f1b3074ea6b40ac7ab4335b428e19ebb | wikidoc | Lactation | Lactation
# Overview
Lactation describes the secretion of milk from the mammary glands, the process of providing that milk to the young, and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, and in humans it is commonly referred to as breastfeeding or nursing. In most species milk comes out of the mother's nipples; however, the platypus (a non-placental mammal) releases milk through ducts in its abdomen. In only one species of mammal, the Dayak fruit bat, is milk production a normal male function. In some other mammals, the male may produce milk as the result of a hormone imbalance. This phenomenon may also be observed in newborn infants as well (for instance witch's milk).
# Purpose
The chief function of lactation is to provide nutrition to the young after birth. In almost all mammals lactation, or more correctly the suckling stimulus, induces a period of infertility, usually by the suppression of ovulation, which serves to provide the optimal birth spacing for survival of the offspring.
# Human lactation
## Hormonal influences
From the fourth month of pregnancy (the second and third trimesters), a woman's body produces hormones that stimulate the growth of the milk duct system in the breasts:
- Progesterone — influences the growth in size of alveoli and lobes. Progesterone levels drop after birth. This triggers the onset of copious milk production.
- Oestrogen — stimulates the milk duct system to grow and become specific. Oestrogen levels also drop at delivery and remain low for the first several months of breastfeeding. It is recommended that breastfeeding mothers avoid oestrogen-based birth control methods, as a spike in estrogen levels may reduce a mother's milk supply.
- Follicle stimulating hormone (FSH)
- Luteinizing hormone (LH)
- Prolactin — contributes to the increased growth of the alveoli during pregnancy.
- Oxytocin — contracts the smooth muscle of the uterus during and after birth, and during orgasm. After birth, oxytocin contracts the smooth muscle layer of band-like cells surrounding the alveoli to squeeze the newly-produced milk into the duct system. Oxytocin is necessary for the milk ejection reflex, or let-down to occur.
- Human placental lactogen (HPL) — From the second month of pregnancy, the placenta releases large amounts of HPL. This hormone appears to be instrumental in breast, nipple, and areola growth before birth.
By the fifth or sixth month of pregnancy, the breasts are ready to produce milk. It is also possible to induce lactation without pregnancy.
### Lactogenesis I
During the latter part of pregnancy, the woman's breasts enter into the Lactogenesis I stage. This is when the breasts make colostrum (see below), a thick, sometimes yellowish fluid. At this stage, high levels of progesterone inhibit most milk production. It is not a medical concern if a pregnant woman leaks any colostrum before her baby's birth, nor is it an indication of future milk production.
### Lactogenesis II
At birth, prolactin levels remain high, while the delivery of the placenta results in a sudden drop in progesterone, estrogen, and HPL levels. This abrupt withdrawal of progesterone in the presence of high prolactin levels stimulates the copious milk production of Lactogenesis II.
When the breast is stimulated, prolactin levels in the blood rise, peak in about 45 minutes, and return to the pre-breastfeeding state about three hours later. The release of prolactin triggers the cells in the alveoli to make milk. Prolactin also transfers to the breast milk. Some research indicates that prolactin in milk is higher at times of higher milk production, and lower when breasts are fuller, and that the highest levels tend to occur between 2 a.m. and 6 a.m.
Other hormones—notably insulin, thyroxine, and cortisol—are also involved, but their roles are not yet well understood. Although biochemical markers indicate that Lactogenesis II begins about 30–40 hours after birth, mothers do not typically begin feeling increased breast fullness (the sensation of milk "coming in") until 50–73 hours (2–3 days) after birth.
Colostrum is the first milk a breastfed baby receives. It contains higher amounts of white blood cells and antibodies than mature milk, and is especially high in immunoglobulin A (IgA), which coats the lining of the baby's immature intestines, and helps to prevent germs from invading the baby's system. Secretory IgA also helps prevent food allergies. Over the first two weeks after the birth, colostrum production slowly gives way to mature breast milk.
### Lactogenesis III
The hormonal endocrine control system drives milk production during pregnancy and the first few days after the birth. When the milk supply is more firmly established, autocrine (or local) control system begins. This stage is called Lactogenesis III
During this stage, the more that milk is removed from the breasts, the more the breast will produce milk. Research also suggests that draining the breasts more fully also increases the rate of milk production. Thus the milk supply is strongly influenced by how often the baby feeds and how well it is able to transfer milk from the breast. Low supply can often be traced to:
- Not feeding or pumping often enough
- Inability of the infant to transfer milk effectively caused by, among other things:
Jaw or mouth structure deficits
Poor latching technique
- Jaw or mouth structure deficits
- Poor latching technique
- Rare maternal endocrine disorders
- Hypoplastic breast tissue
- A metabolic or digestive inability in the infant, making it unable to digest the milk it receives
- Inadequate calorie intake or malnutrition of the mother
## Milk ejection reflex
The release of the hormone oxytocin leads to the milk ejection or let-down reflex. Oxytocin stimulates the muscles surrounding the breast to squeeze out the milk. Breastfeeding mothers describe the sensation differently. Some feel a slight tingling, others feel immense amounts of pressure or slight pain/discomfort, and still others do not feel anything different.
The let-down reflex is not always consistent, especially at first. The thought of breastfeeding or the sound of any baby can stimulate this reflex, causing unwanted leakage, or both breasts may give out milk when an infant is feeding from one breast. However, this and other problems often settle after two weeks of feeding. Stress or anxiety can cause difficulties with breastfeeding.
A poor milk ejection reflex can be due to sore or cracked nipples, separation from the infant, a history of breast surgery, or tissue damage from prior breast trauma. If a mother has trouble breastfeeding, different methods of assisting the milk ejection reflex may help. These include feeding in a familiar and comfortable location, massage of the breast or back, or warming the breast with a cloth or shower.
## Afterpains
The surge of oxytocin that triggers the milk ejection reflex also causes the uterus to contract. During breastfeeding, mothers may feel these contractions as afterpains. These may range from period-like cramps to strong labour-like contractions and can be more severe with second and subsequent babies.
## Lactation without pregnancy
Women who have never been pregnant are sometimes able to induce enough lactation to breastfeed. This is called "induced lactation". A woman who has breastfed before and re-starts is said to "relactate". If the nipples are consistently stimulated by a breast pump or actual suckling, the breasts will eventually begin to produce enough milk to begin feeding a baby. Once established, lactation adjusts to demand. This is how some adoptive mothers, usually beginning with a supplemental nursing system or some other form of supplementation, can breastfeed. There is thought to be little or no difference in milk composition whether lactation is induced or a result of pregnancy. Rare accounts of male lactation (as distinct from galactorrhea) exist in the medical literature.
Some drugs, primarily atypical antipsychotics such as Risperdal, may cause lactation in both women and men. Also, some couples may use lactation for sexual purposes. | Lactation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]
# Overview
Lactation describes the secretion of milk from the mammary glands, the process of providing that milk to the young, and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, and in humans it is commonly referred to as breastfeeding or nursing. In most species milk comes out of the mother's nipples; however, the platypus (a non-placental mammal) releases milk through ducts in its abdomen. In only one species of mammal, the Dayak fruit bat, is milk production a normal male function. In some other mammals, the male may produce milk as the result of a hormone imbalance. This phenomenon may also be observed in newborn infants as well (for instance witch's milk).
# Purpose
The chief function of lactation is to provide nutrition to the young after birth. In almost all mammals lactation, or more correctly the suckling stimulus, induces a period of infertility, usually by the suppression of ovulation, which serves to provide the optimal birth spacing for survival of the offspring.[1]
# Human lactation
## Hormonal influences
From the fourth month of pregnancy (the second and third trimesters), a woman's body produces hormones that stimulate the growth of the milk duct system in the breasts:
- Progesterone — influences the growth in size of alveoli and lobes. Progesterone levels drop after birth. This triggers the onset of copious milk production.[2]
- Oestrogen — stimulates the milk duct system to grow and become specific. Oestrogen levels also drop at delivery and remain low for the first several months of breastfeeding.[2] It is recommended that breastfeeding mothers avoid oestrogen-based birth control methods, as a spike in estrogen levels may reduce a mother's milk supply.
- Follicle stimulating hormone (FSH)
- Luteinizing hormone (LH)
- Prolactin — contributes to the increased growth of the alveoli during pregnancy.
- Oxytocin — contracts the smooth muscle of the uterus during and after birth, and during orgasm. After birth, oxytocin contracts the smooth muscle layer of band-like cells surrounding the alveoli to squeeze the newly-produced milk into the duct system. Oxytocin is necessary for the milk ejection reflex, or let-down to occur.
- Human placental lactogen (HPL) — From the second month of pregnancy, the placenta releases large amounts of HPL. This hormone appears to be instrumental in breast, nipple, and areola growth before birth.
By the fifth or sixth month of pregnancy, the breasts are ready to produce milk. It is also possible to induce lactation without pregnancy.
### Lactogenesis I
During the latter part of pregnancy, the woman's breasts enter into the Lactogenesis I stage. This is when the breasts make colostrum (see below), a thick, sometimes yellowish fluid. At this stage, high levels of progesterone inhibit most milk production. It is not a medical concern if a pregnant woman leaks any colostrum before her baby's birth, nor is it an indication of future milk production.
### Lactogenesis II
At birth, prolactin levels remain high, while the delivery of the placenta results in a sudden drop in progesterone, estrogen, and HPL levels. This abrupt withdrawal of progesterone in the presence of high prolactin levels stimulates the copious milk production of Lactogenesis II.
When the breast is stimulated, prolactin levels in the blood rise, peak in about 45 minutes, and return to the pre-breastfeeding state about three hours later. The release of prolactin triggers the cells in the alveoli to make milk. Prolactin also transfers to the breast milk. Some research indicates that prolactin in milk is higher at times of higher milk production, and lower when breasts are fuller, and that the highest levels tend to occur between 2 a.m. and 6 a.m.[3]
Other hormones—notably insulin, thyroxine, and cortisol—are also involved, but their roles are not yet well understood. Although biochemical markers indicate that Lactogenesis II begins about 30–40 hours after birth, mothers do not typically begin feeling increased breast fullness (the sensation of milk "coming in") until 50–73 hours (2–3 days) after birth.
Colostrum is the first milk a breastfed baby receives. It contains higher amounts of white blood cells and antibodies than mature milk, and is especially high in immunoglobulin A (IgA), which coats the lining of the baby's immature intestines, and helps to prevent germs from invading the baby's system. Secretory IgA also helps prevent food allergies.[4] Over the first two weeks after the birth, colostrum production slowly gives way to mature breast milk.[2]
### Lactogenesis III
The hormonal endocrine control system drives milk production during pregnancy and the first few days after the birth. When the milk supply is more firmly established, autocrine (or local) control system begins. This stage is called Lactogenesis III
During this stage, the more that milk is removed from the breasts, the more the breast will produce milk.[5][6] Research also suggests that draining the breasts more fully also increases the rate of milk production.[7] Thus the milk supply is strongly influenced by how often the baby feeds and how well it is able to transfer milk from the breast. Low supply can often be traced to:
- Not feeding or pumping often enough
- Inability of the infant to transfer milk effectively caused by, among other things:
Jaw or mouth structure deficits
Poor latching technique
- Jaw or mouth structure deficits
- Poor latching technique
- Rare maternal endocrine disorders
- Hypoplastic breast tissue
- A metabolic or digestive inability in the infant, making it unable to digest the milk it receives
- Inadequate calorie intake or malnutrition of the mother
## Milk ejection reflex
The release of the hormone oxytocin leads to the milk ejection or let-down reflex. Oxytocin stimulates the muscles surrounding the breast to squeeze out the milk. Breastfeeding mothers describe the sensation differently. Some feel a slight tingling, others feel immense amounts of pressure or slight pain/discomfort, and still others do not feel anything different.
The let-down reflex is not always consistent, especially at first. The thought of breastfeeding or the sound of any baby can stimulate this reflex, causing unwanted leakage, or both breasts may give out milk when an infant is feeding from one breast. However, this and other problems often settle after two weeks of feeding. Stress or anxiety can cause difficulties with breastfeeding.
A poor milk ejection reflex can be due to sore or cracked nipples, separation from the infant, a history of breast surgery, or tissue damage from prior breast trauma. If a mother has trouble breastfeeding, different methods of assisting the milk ejection reflex may help. These include feeding in a familiar and comfortable location, massage of the breast or back, or warming the breast with a cloth or shower.
## Afterpains
The surge of oxytocin that triggers the milk ejection reflex also causes the uterus to contract. During breastfeeding, mothers may feel these contractions as afterpains. These may range from period-like cramps to strong labour-like contractions and can be more severe with second and subsequent babies.[8]
## Lactation without pregnancy
Women who have never been pregnant are sometimes able to induce enough lactation to breastfeed. This is called "induced lactation". A woman who has breastfed before and re-starts is said to "relactate". If the nipples are consistently stimulated by a breast pump or actual suckling, the breasts will eventually begin to produce enough milk to begin feeding a baby. Once established, lactation adjusts to demand. This is how some adoptive mothers, usually beginning with a supplemental nursing system or some other form of supplementation, can breastfeed.[9] There is thought to be little or no difference in milk composition whether lactation is induced or a result of pregnancy. Rare accounts of male lactation (as distinct from galactorrhea) exist in the medical literature.
Some drugs, primarily atypical antipsychotics such as Risperdal, may cause lactation in both women and men. Also, some couples may use lactation for sexual purposes. | https://www.wikidoc.org/index.php/Lactation | |
1e6b03240f30caba02ee2a452e938536c58a613e | wikidoc | Lactulose | Lactulose
# 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
Lactulose is a gastrointestinal, laxative and hyperosmotic agent that is FDA approved for the treatment of constipation. Common adverse reactions include bloating symptom, diarrhea, epigastric pain, flatulence, nausea, vomiting, muscular cramps, intestinal cramps..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For the treatment of constipation. In patients with a history of chronic constipation, lactulose solution therapy increases the number of bowel movements per day and the number of days on which bowel movements occur.
- The usual dose is 1 to 2 tablespoonfuls (15 to 30 mL, containing 10 g to 20 g of lactulose) daily. The dose may be increased to 60 mL daily if necessary. Twenty-four to 48 hours may be required to produce a normal bowel movement.
- Note: Some patients have found that lactulose solution may be more acceptable when mixed with fruit juice, water or milk.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lactulose in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lactulose in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lactulose in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lactulose in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lactulose in pediatric patients.
# Contraindications
- Since lactulose solution contains galactose (less than 1.6 g/15 mL), it is contraindicated in patients who require a low galactose diet.
# Warnings
- A theoretical hazard may exist for patients being treated with lactulose solution who may be required to undergo electrocautery procedures during proctoscopy or colonoscopy. Accumulation of H2 gas in significant concentration in the presence of an electrical spark may result in an explosive reaction. Although this complication has not been reported with lactulose, patients on lactulose therapy undergoing such procedures should have a thorough bowel cleansing with a non-fermentable solution. Insufflation of CO2 as an additional safeguard may be pursued but is considered to be a redundant measure.
# Adverse Reactions
## Clinical Trials Experience
- Precise frequency data are not available.
- Initial dosing may produce flatulence and intestinal cramps, which are usually transient. Excessive dosage can lead to diarrhea with potential complications such as loss of fluids, hypokalemia, and hypernatremia.
- Nausea and vomiting have been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Lactulose in the drug label.
# Drug Interactions
- Results of preliminary studies in humans and rats suggest that non-absorbable antacids given concurrently with lactulose may inhibit the desired lactulose-induced drop in colonic pH. Therefore, a possible lack of desired effect of treatment should be taken into consideration before such drugs are given concomitantly with lactulose solution.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in mice, rats, and rabbits at doses up to 3 or 6 times the usual human oral dose and have revealed no evidence of impaired fertility or harm to the fetus due to lactulose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lactulose in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lactulose 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 lactulose solution is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Lactulose with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Lactulose with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Lactulose with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lactulose with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Lactulose in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Lactulose in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lactulose in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lactulose in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lactulose in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lactulose in the drug label.
# Overdosage
- There have been no reports of accidental overdosage. In the event of overdosage, it is expected that diarrhea and abdominal cramps would be the major symptoms. Medication should be terminated.
- Oral LD50: The acute oral LD50 of the drug is 48.8 mL/kg in mice and greater than 30 mL/kg in rats.
- Dialysis: Dialysis data are not available for lactulose. Its molecular similarity to sucrose, however, would suggest that it should be dialyzable.
# Pharmacology
## Mechanism of Action
- Lactulose is poorly absorbed from the gastrointestinal tract and no enzyme capable of hydrolysis of this disaccharide is present in human gastrointestinal tissue. As a result, oral doses of lactulose reach the colon virtually unchanged. In the colon, lactulose is broken down primarily to lactic acid, and also to small amounts of formic and acetic acids, by the action of colonic bacteria, which results in an increase in osmotic pressure and slight acidification of the colonic contents. This in turn causes an increase in stool water content and softens the stool.
- Since lactulose does not exert its effect until it reaches the colon, and since transit time through the colon may be slow, 24 to 48 hours may be required to produce the desired bowel movement.
- Lactulose given orally to man and experimental animals resulted in only small amounts reaching the blood. Urinary excretion has been determined to be 3% or less and is essentially complete within 24 hours.
## Structure
- Lactulose is a synthetic disaccharide in solution form for oral administration. Each 15 mL of lactulose solution contains: 10 g lactulose (and less than 1.6 g galactose, less than 1.2 g lactose, and 0.1 g or less of fructose).
- Lactulose is a colonic acidifier which promotes laxation.
- The chemical name for lactulose is 4-O-β-D-galactopyranosyl-D-fructofuranose. It has the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Lactulose in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Lactulose in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Lactulose in the drug label.
# Clinical Studies
### Carcinogenesis, Mutagenesis, Impairment of Fertility=
- There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility.
- There are no known animal data on long-term potential for mutagenicity.
- Administration of lactulose solution in the diet of mice for 18 months in concentrations of 3 and 10 percent (v/w) did not produce any evidence of carcinogenicity.
- In studies of mice, rats, and rabbits, doses of lactulose solution up to 6 or 12 mL/kg/day produced no deleterious effects in breeding, conception, or parturition.
# How Supplied
- Lactulose Solution is a natural colored and an unflavored solution available in 8 fl oz (237 mL) and 1 quart (946 mL) bottles.
- Lactulose Solution contains lactulose 670 mg/mL (10 g/15 mL).
- Under recommended storage conditions, a normal darkening of color may occur. Such darkening is characteristic of sugar solutions and does not affect therapeutic action. Prolonged exposure to temperatures above 86°F (30°C) or to direct light may cause extreme darkening and turbidity which may be pharmaceutically objectionable. If this condition develops, do not use.
- Prolonged exposure to freezing temperatures may cause change to a semi-solid, too viscous to pour. Viscosity will return to normal upon warming to room temperature.
- Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure.
- Manufactured and packaged by:
- Fresenius Kabi Austria GmbH
- Estermannstraße 17
- 4020 Linz Austria
- Distributed by:
- Actavis Inc.
- 60 Columbia Rd., Bldg. B
- Morristown, NJ 07960 USA
- FORM NO. 1358
- Rev. January 2011
## Storage
- Store between 36°-86°F (2°-30°C). Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- In the event that an unusual diarrheal condition occurs, contact your physician.
# Precautions with Alcohol
- Alcohol-Lactulose interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Kristalose®
- Cholac®
- Constilac®
- Constulose®
- Generlac®
- Enulose
# Look-Alike Drug Names
There is limited information regarding Lactulose Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Lactulose
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Lactulose is a gastrointestinal, laxative and hyperosmotic agent that is FDA approved for the treatment of constipation. Common adverse reactions include bloating symptom, diarrhea, epigastric pain, flatulence, nausea, vomiting, muscular cramps, intestinal cramps..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For the treatment of constipation. In patients with a history of chronic constipation, lactulose solution therapy increases the number of bowel movements per day and the number of days on which bowel movements occur.
- The usual dose is 1 to 2 tablespoonfuls (15 to 30 mL, containing 10 g to 20 g of lactulose) daily. The dose may be increased to 60 mL daily if necessary. Twenty-four to 48 hours may be required to produce a normal bowel movement.
- Note: Some patients have found that lactulose solution may be more acceptable when mixed with fruit juice, water or milk.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lactulose in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lactulose in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lactulose in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lactulose in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lactulose in pediatric patients.
# Contraindications
- Since lactulose solution contains galactose (less than 1.6 g/15 mL), it is contraindicated in patients who require a low galactose diet.
# Warnings
- A theoretical hazard may exist for patients being treated with lactulose solution who may be required to undergo electrocautery procedures during proctoscopy or colonoscopy. Accumulation of H2 gas in significant concentration in the presence of an electrical spark may result in an explosive reaction. Although this complication has not been reported with lactulose, patients on lactulose therapy undergoing such procedures should have a thorough bowel cleansing with a non-fermentable solution. Insufflation of CO2 as an additional safeguard may be pursued but is considered to be a redundant measure.
# Adverse Reactions
## Clinical Trials Experience
- Precise frequency data are not available.
- Initial dosing may produce flatulence and intestinal cramps, which are usually transient. Excessive dosage can lead to diarrhea with potential complications such as loss of fluids, hypokalemia, and hypernatremia.
- Nausea and vomiting have been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Lactulose in the drug label.
# Drug Interactions
- Results of preliminary studies in humans and rats suggest that non-absorbable antacids given concurrently with lactulose may inhibit the desired lactulose-induced drop in colonic pH. Therefore, a possible lack of desired effect of treatment should be taken into consideration before such drugs are given concomitantly with lactulose solution.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in mice, rats, and rabbits at doses up to 3 or 6 times the usual human oral dose and have revealed no evidence of impaired fertility or harm to the fetus due to lactulose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lactulose in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lactulose 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 lactulose solution is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Lactulose with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Lactulose with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Lactulose with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lactulose with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Lactulose in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Lactulose in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lactulose in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lactulose in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lactulose in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lactulose in the drug label.
# Overdosage
- There have been no reports of accidental overdosage. In the event of overdosage, it is expected that diarrhea and abdominal cramps would be the major symptoms. Medication should be terminated.
- Oral LD50: The acute oral LD50 of the drug is 48.8 mL/kg in mice and greater than 30 mL/kg in rats.
- Dialysis: Dialysis data are not available for lactulose. Its molecular similarity to sucrose, however, would suggest that it should be dialyzable.
# Pharmacology
## Mechanism of Action
- Lactulose is poorly absorbed from the gastrointestinal tract and no enzyme capable of hydrolysis of this disaccharide is present in human gastrointestinal tissue. As a result, oral doses of lactulose reach the colon virtually unchanged. In the colon, lactulose is broken down primarily to lactic acid, and also to small amounts of formic and acetic acids, by the action of colonic bacteria, which results in an increase in osmotic pressure and slight acidification of the colonic contents. This in turn causes an increase in stool water content and softens the stool.
- Since lactulose does not exert its effect until it reaches the colon, and since transit time through the colon may be slow, 24 to 48 hours may be required to produce the desired bowel movement.
- Lactulose given orally to man and experimental animals resulted in only small amounts reaching the blood. Urinary excretion has been determined to be 3% or less and is essentially complete within 24 hours.
## Structure
- Lactulose is a synthetic disaccharide in solution form for oral administration. Each 15 mL of lactulose solution contains: 10 g lactulose (and less than 1.6 g galactose, less than 1.2 g lactose, and 0.1 g or less of fructose).
- Lactulose is a colonic acidifier which promotes laxation.
- The chemical name for lactulose is 4-O-β-D-galactopyranosyl-D-fructofuranose. It has the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Lactulose in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Lactulose in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Lactulose in the drug label.
# Clinical Studies
### Carcinogenesis, Mutagenesis, Impairment of Fertility=
- There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility.
- There are no known animal data on long-term potential for mutagenicity.
- Administration of lactulose solution in the diet of mice for 18 months in concentrations of 3 and 10 percent (v/w) did not produce any evidence of carcinogenicity.
- In studies of mice, rats, and rabbits, doses of lactulose solution up to 6 or 12 mL/kg/day produced no deleterious effects in breeding, conception, or parturition.
# How Supplied
- Lactulose Solution is a natural colored and an unflavored solution available in 8 fl oz (237 mL) and 1 quart (946 mL) bottles.
- Lactulose Solution contains lactulose 670 mg/mL (10 g/15 mL).
- Under recommended storage conditions, a normal darkening of color may occur. Such darkening is characteristic of sugar solutions and does not affect therapeutic action. Prolonged exposure to temperatures above 86°F (30°C) or to direct light may cause extreme darkening and turbidity which may be pharmaceutically objectionable. If this condition develops, do not use.
- Prolonged exposure to freezing temperatures may cause change to a semi-solid, too viscous to pour. Viscosity will return to normal upon warming to room temperature.
- Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure.
- Manufactured and packaged by:
- Fresenius Kabi Austria GmbH
- Estermannstraße 17
- 4020 Linz Austria
- Distributed by:
- Actavis Inc.
- 60 Columbia Rd., Bldg. B
- Morristown, NJ 07960 USA
- FORM NO. 1358
- Rev. January 2011
## Storage
- Store between 36°-86°F (2°-30°C). Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- In the event that an unusual diarrheal condition occurs, contact your physician.
# Precautions with Alcohol
- Alcohol-Lactulose interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Kristalose®
- Cholac®
- Constilac®
- Constulose®
- Generlac®
- Enulose
# Look-Alike Drug Names
There is limited information regarding Lactulose Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lactulose | |
24a7bd3a6ac37f5ce4ab44f8b2e745d0caf8b615 | wikidoc | Lamiaceae | Lamiaceae
Lamiaceae or Labiatae, also known as the Mint family, is a family of plants in about 210 genera and some 3,500 species. It has been considered closely related to Verbenaceae but several recent phylogenetic studies have shown that numererous genera classified in Verbenaceae belong instead in Lamiaceae, whereas the core genera of Verbenaceae are not closely related to Lamiaceae and are more closely related to other members of the Lamiales.
The plants are frequently aromatic in all parts and include many widely used culinary herbs, such as basil, mint, rosemary, sage, savory, marjoram, oregano, thyme, lavender, and perilla. Some are shrubs, but rarely trees or vines. Many members of the family are widely cultivated, owing not only to their aromatic qualities but also their ease of cultivation: these plants are among the easiest plants to propagate by stem cuttings. Besides those grown for their edible leaves, some are grown for decorative foliage, such as coleus. Others are grown for food purposes, but seeds are utilized instead of leaves, such as with chia.
The original family name is Labiatae, so given because the flowers typically have petals fused into an upper lip and a lower lip. Although this is still considered an acceptable alternate name, most botanists now use the name "Lamiaceae" in referring to this family.
The leaves emerge oppositely, each pair at right angles to the previous one (called decussate) or whorled.
The stems are frequently square in cross section, but this is not found in all members of the family, and is sometimes found in other plant families.
The flowers are bilaterally symmetrical with 5 united petals, 5 united sepals. They are usually bisexual and verticillastrate (a flower cluster that looks like a whorl of flowers but actually consists of two crowded clusters).
# Genera | Lamiaceae
Lamiaceae or Labiatae, also known as the Mint family, is a family of plants in about 210 genera and some 3,500 species. It has been considered closely related to Verbenaceae but several recent phylogenetic studies have shown that numererous genera classified in Verbenaceae belong instead in Lamiaceae, whereas the core genera of Verbenaceae are not closely related to Lamiaceae and are more closely related to other members of the Lamiales.
The plants are frequently aromatic in all parts and include many widely used culinary herbs, such as basil, mint, rosemary, sage, savory, marjoram, oregano, thyme, lavender, and perilla. Some are shrubs, but rarely trees or vines. Many members of the family are widely cultivated, owing not only to their aromatic qualities but also their ease of cultivation: these plants are among the easiest plants to propagate by stem cuttings. Besides those grown for their edible leaves, some are grown for decorative foliage, such as coleus. Others are grown for food purposes, but seeds are utilized instead of leaves, such as with chia.
The original family name is Labiatae, so given because the flowers typically have petals fused into an upper lip and a lower lip. Although this is still considered an acceptable alternate name, most botanists now use the name "Lamiaceae" in referring to this family.
The leaves emerge oppositely, each pair at right angles to the previous one (called decussate) or whorled.
The stems are frequently square in cross section, but this is not found in all members of the family, and is sometimes found in other plant families.
The flowers are bilaterally symmetrical with 5 united petals, 5 united sepals. They are usually bisexual and verticillastrate (a flower cluster that looks like a whorl of flowers but actually consists of two crowded clusters).
# Genera | https://www.wikidoc.org/index.php/Lamiaceae | |
59dc9e7296d738b9125999475cca2ffd164b1cd3 | wikidoc | Lapatinib | Lapatinib
- Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain
- capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.
- Limitation of Use: Patients should have disease progression on trastuzumab prior to initiation of treatment with Lapatinib in combination with capecitabine.
- Letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.
- Lapatinib in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.
- HER2-Positive Metastatic Breast Cancer: The recommended dose of Lapatinib is 1,250 mg given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21-day cycle. Lapatinib should be taken at least one hour before or one hour after a meal. The dose of Lapatinib should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended . Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.
- Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer: The recommended dose of Lapatinib is 1,500 mg given orally once daily continuously in combination with letrozole. When coadministered with Lapatinib, the recommended dose of letrozole is 2.5 mg once daily. Lapatinib should be taken at least one hour before or one hour after a meal. The dose of Lapatinib should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended.
- Cardiac Events: Lapatinib should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3) and in patients with an LVEF that drops below the institution’s lower limit of normal. Lapatinib in combination with capecitabine may be restarted at a reduced dose (1,000 mg/day) and in combination with letrozole may be restarted at a reduced dose of 1,250 mg/day after a minimum of 2 weeks if the LVEF recovers to normal and the patient is asymptomatic.
- Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh Class C) should have their dose of Lapatinib reduced. A dose reduction from 1,250 mg/day to 750 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day to 1,000 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered. However, there are no clinical data with this dose adjustment in patients with severe hepatic impairment.
- Diarrhea: Lapatinib should be interrupted in patients with diarrhea which is NCI CTCAE Grade 3 or Grade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomiting ≥NCI CTCAE Grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration). Lapatinib may be reintroduced at a lower dose (reduced from 1,250 mg/day to 1,000 mg/day or from 1,500 mg/day to 1,250 mg/day) when diarrhea resolves to Grade 1 or less. Lapatinib should be permanently discontinued in patients with diarrhea which is NCI CTCAE Grade 4
- Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit may also increase plasma concentrations of lapatinib and should be avoided. If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to 500 mg/day of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inhibitors and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose
- Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated gradually from 1,250 mg/day up to 4,500 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) based on tolerability. This dose of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inducers and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the lapatinib dose should be reduced to the indicated dose
- Other Toxicities: Discontinuation or interruption of dosing with Lapatinib may be considered when patients develop ≥Grade 2 NCI CTCAE toxicity and can be restarted at the standard dose of 1,250 or 1,500 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then Lapatinib in combination with capecitabine should be restarted at a lower dose (1,000 mg/day) and in combination with letrozole should be restarted at a lower dose of 1,250 mg/day.
- See manufacturer’s prescribing information for the coadministered product dosage adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.
- Paclitaxel 80 mg/m(2) IV once a week for 3 weeks every 4 weeks and either placebo or lapatinib 1500 mg once daily.
- Oral lapatinib 1500 mg daily
- Oral lapatinib 1500 mg/day
- Lapatinib has been reported to decrease LVEF . In clinical trials, the majority (>57%) of LVEF decreases occurred within the first 12 weeks of treatment; however, data on long-term exposure are limited. Caution should be taken if Lapatinib is to be administered to patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of treatment with Lapatinib to ensure that the patient has a baseline LVEF that is within the institution’s normal limits. LVEF should continue to be evaluated during treatment with Lapatinib to ensure that LVEF does not decline below the institution’s normal limits.
- Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with Lapatinib should be discontinued and patients should not be retreated with Lapatinib.
- Diarrhea has been reported during treatment with Lapatinib. The diarrhea may be severe, and deaths have been reported. Diarrhea generally occurs early during treatment with Lapatinib, with almost half of those patients with diarrhea first experiencing it within 6 days. This usually lasts 4 to 5 days. Lapatinib-induced diarrhea is usually low-grade, with severe diarrhea of NCI CTCAE Grades 3 and 4 occurring in <10% and <1% of patients, respectively. Early identification and intervention is critical for the optimal management of diarrhea. Patients should be instructed to report any change in bowel patterns immediately. Prompt treatment of diarrhea with anti-diarrheal agents (such as loperamide) after the first unformed stool is recommended. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, use of antibiotics such as fluoroquinolones (especially if diarrhea is persistent beyond 24 hours, there is fever, or Grade 3 or 4 neutropenia), and interruption or discontinuation of therapy with Lapatinib.
- Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies . Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. Lapatinib should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are ≥Grade 3 (NCI CTCAE).
- QT prolongation was observed in an uncontrolled, open-label, dose-escalation study of lapatinib in advanced cancer patients . Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to lapatinib administration.
- Severe cutaneous reactions have been reported with Lapatinib. If life-threatening reactions such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (e.g., progressive skin rash often with blisters or mucosal lesions) are suspected, discontinue treatment with Lapatinib.
- HER2-Positive Metastatic Breast Cancer: The safety of Lapatinib has been evaluated in more than 12,000 patients in clinical trials. The efficacy and safety of Lapatinib in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial . Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 1.
- The most common adverse reactions (>20%) during therapy with Lapatinib plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. *Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.
- The most common Grade 3 and 4 adverse reactions (NCI CTCAE v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.
National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
- Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are ≥Grade 3 (NCI CTCAE), or a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received combination treatment with Lapatinib/capecitabine, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3). Among 654 patients who received combination treatment with Lapatinib/letrozole, 26 patients experienced Grade 1 or 2 and 6 patients had Grade 3 or 4 LVEF adverse reactions.
- Hepatotoxicity: Lapatinib has been associated with hepatotoxicity.
- Interstitial Lung Disease/Pneumonitis: Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies
- Immune System Disorders: Hypersensitivity reactions including anaphylaxis.
- Skin and Subcutaneous Tissue Disorders: Nail disorders including paronychia.
- Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) in vitro at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing Lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4, CYP2C8, or P-gp. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes in vitro, however, the clinical significance is unknown.
- Midazolam: Following coadministration of Lapatinib and midazolam (CYP3A4 substrate), 24-hour systemic exposure (AUC) of orally administered midazolam increased 45%, while 24-hour AUC of intravenously administered midazolam increased 22%.
- Paclitaxel: In cancer patients receiving Lapatinib and paclitaxel (CYP2C8 and P-gp substrate), 24-hour systemic exposure (AUC) of paclitaxel was increased 23%. This increase in paclitaxel exposure may have been underestimated from the in vivo evaluation due to study design limitations.
- Digoxin: Following coadministration of Lapatinib and digoxin (P-gp substrate), systemic AUC of an oral digoxin dose increased approximately 2.8-fold. Serum digoxin concentrations should be monitored prior to initiation of Lapatinib and throughout coadministration. If digoxin serum concentration is >1.2 ng/mL, the digoxin dose should be reduced by half.
- Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly . Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes.
- Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control.
- Carbamazepine: In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately 72%.
- Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Lapatinib is administered with drugs that inhibit P-gp, increased concentrations of lapatinib are likely, and caution should be exercised.
- The aqueous solubility of lapatinib is pH dependent, with higher pH resulting in lower solubility. However, esomeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 7 days, did not result in a clinically meaningful reduction in lapatinib steady-state exposure.
- There are no adequate and well-controlled studies with Lapatinib in pregnant women. Women should be advised not to become pregnant when taking Lapatinib. 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.
- Based on findings in animals, Lapatinib can cause fetal harm when administered to a pregnant woman. Lapatinib administered to rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses. There are no adequate and well-controlled studies with Lapatinib in pregnant women. Women should be advised not to become pregnant when taking Lapatinib. 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.
- In a study where pregnant rats were dosed with lapatinib during organogenesis and through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine), 91% of the pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead. The highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human clinical exposure based on AUC).
- Lapatinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC following 1,250-mg dose of lapatinib plus capecitabine) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.
- The pharmacokinetics of lapatinib were examined in subjects with pre-existing moderate (n = 8) or severe (n = 4) hepatic impairment (Child-Pugh Class B/C, respectively) and in 8 healthy control subjects. Systemic exposure (AUC) to lapatinib after a single oral 100-mg dose increased approximately 14% and 63% in subjects with moderate and severe pre-existing hepatic impairment, respectively. Administration of Lapatinib in patients with severe hepatic impairment should be undertaken with caution due to increased exposure to the drug. A dose reduction should be considered for patients with severe pre-existing hepatic impairment. In patients who develop severe hepatotoxicity while on therapy, Lapatinib should be discontinued and patients should not be retreated with Lapatinib.
- Asymptomatic and symptomatic cases of overdose have been reported. The doses ranged from 2,500 to 9,000 mg daily and where reported, the duration varied between 1 and 17 days. Symptoms observed include lapatinib-associated events and in some cases sore scalp, sinus tachycardia (with otherwise normal ECG), and/or mucosal inflammation.
- Because lapatinib is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib.
- Treatment of overdose with Lapatinib should consist of general supportive measures.
- An additive effect was demonstrated in an in vitro study when lapatinib and 5-FU (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non–cross-resistance between these two agents.
- Hormone receptor-positive breast cancer cells (with ER and/or PgR ) that coexpress the HER2 tend to be resistant to established endocrine therapies. Similarly, hormone receptor-positive breast cancer cells that initially lack EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy.
- Lapatinib is a yellow solid, and its solubility in water is 0.007 mg/mL and in 0.1N HCl is 0.001 mg/mL at 25°C.
- Each 250 mg tablet of Lapatinib contains 405 mg of lapatinib ditosylate monohydrate, equivalent to 398 mg of lapatinib ditosylate or 250 mg lapatinib free base.
- The inactive ingredients of Lapatinib are: Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Orange film-coat: FD&C yellow No. 6/sunset yellow FCF aluminum lake, hypromellose, macrogol/PEG 400, polysorbate 80, titanium dioxide.
- Absorption following oral administration of Lapatinib is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of Lapatinib results in achievement of steady state within 6 to 7 days, indicating an effective half-life of 24 hours.
- At the dose of 1,250 mg daily, steady-state geometric mean (95% confidence interval) values of Cmax were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 mcg.h/mL (23.4 to 56 mcg.h/mL).
- Divided daily doses of Lapatinib resulted in approximately 2-fold higher exposure at steady state (steady-state AUC) compared to the same total dose administered once daily.
- Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values were approximately 3- and 4-fold higher (Cmax approximately 2.5- and 3-fold higher) when administered with a low-fat (5% fat-500 calories) or with a high-fat (50% fat-1,000 calories) meal, respectively.
- Lapatinib is highly bound (>99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters breast cancer-resistance protein (BCRP, ABCG2) and P-glycoprotein (P-gp, ABCB1). Lapatinib has also been shown to inhibit P-gp, BCRP, and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.
- Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.
- At clinical doses, the terminal phase half-life following a single dose was 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours.
- Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (<2%) renal excretion. Recovery of parent lapatinib in feces accounts for a median of 27% (range 3% to 67%) of an oral dose.
- Effects of Age, Gender, or Race: Studies of the effects of age, gender, or race on the pharmacokinetics of lapatinib have not been performed.
- Lapatinib was not clastogenic or mutagenic in the Chinese hamster ovary chromosome aberration assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome aberration assay or the in vivo rat bone marrow chromosome aberration assay at single doses up to 2,000 mg/kg. However, an impurity in the drug product (up to 4 ppm or 8 mcg/day) was genotoxic when tested alone in both in vitro and in vivo assays.
- There were no effects on male or female rat mating or fertility at doses up to 120 mg/kg/day in females and 180 mg/kg/day in males (approximately 6.4 times and 2.6 times the expected human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine, respectively). The effect of lapatinib on human fertility is unknown. However, when female rats were given oral doses of lapatinib during breeding and through the first 6 days of gestation, a significant decrease in the number of live fetuses was seen at 120 mg/kg/day and in the fetal body weights at ≥60 mg/kg/day (approximately 6.4 times and 3.3 times the expected human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine, respectively).
- The efficacy and safety of Lapatinib in combination with capecitabine in breast cancer were evaluated in a randomized, Phase 3 trial. Patients eligible for enrollment had HER2 (ErbB2) overexpressing (IHC 3+ or IHC 2+ confirmed by FISH), locally advanced or metastatic breast cancer, progressing after prior treatment that included anthracyclines, taxanes, and trastuzumab.
- Patients were randomized to receive either Lapatinib 1,250 mg once daily (continuously) plus capecitabine 2,000 mg/m2/day on Days 1-14 every 21 days, or to receive capecitabine alone at a dose of 2,500 mg/m2/day on Days 1-14 every 21 days. The endpoint was time to progression (TTP). TTP was defined as time from randomization to tumor progression or death related to breast cancer. Based on the results of a pre-specified interim analysis, further enrollment was discontinued. Three hundred and ninety-nine (399) patients were enrolled in this study. The median age was 53 years and 14% were older than 65 years. Ninety-one percent (91%) were Caucasian. Ninety-seven percent (97%) had stage IV breast cancer, 48% were estrogen receptor+ (ER+) or progesterone receptor+ (PR+), and 95% were ErbB2 IHC 3+ or IHC 2+ with FISH confirmation. Approximately 95% of patients had prior treatment with anthracyclines, taxanes, and trastuzumab.
- Efficacy analyses 4 months after the interim analysis are presented in Table 5, Figure 1, and Figure 2.
- At the time of above efficacy analysis, the overall survival data were not mature (32% events). However, based on the TTP results, the study was unblinded and patients receiving capecitabine alone were allowed to cross over to treatment with Lapatinib plus capecitabine. The survival data were followed for an additional 2 years to be mature and the analysis is summarized in Table 6.
- Clinical Studies Describing Limitation of Use: In two randomized trials, Lapatinib-based chemotherapy regimens have been shown to be less effective than trastuzumab-based chemotherapy regimens. The first randomized, open-label study compared the safety and efficacy of Lapatinib in combination with capecitabine relative to trastuzumab in combination with capecitabine in women with HER2-positive metastatic breast cancer (N = 540). The study was stopped early based on the findings of a pre-planned interim analysis showing a low incidence of CNS events (primary endpoint) and superior efficacy of the trastuzumab plus capecitabine. The median progression-free survival was 6.6 months in the group receiving Lapatinib in combination with capecitabine compared with 8.0 months in the group receiving the trastuzumab combination . Overall survival was analyzed when 26% of deaths occurred in the group receiving Lapatinib in combination with capecitabine and 22% in the group receiving the trastuzumab combination .
- The second randomized, open-label study compared the safety and efficacy of taxane-based chemotherapy plus Lapatinib to taxane-based chemotherapy plus trastuzumab as first-line therapy in women with HER2-positive, metastatic breast cancer (N = 652). The study was stopped early based on findings from a pre-planned interim analysis. The median progression-free survival was 11.3 months in the trastuzumab combination treatment arm compared to 9.0 months in patients treated with Lapatinib in the combination arm for the intent-to-treat population .
- The efficacy and safety of Lapatinib in combination with letrozole were evaluated in a double-blind, placebo-controlled, multi-center study. A total of 1,286 postmenopausal women with hormone receptor-positive (ER-positive and/or PgR-positive) metastatic breast cancer, who had not received prior therapy for metastatic disease, were randomly assigned to receive either Lapatinib (1,500 mg once daily) plus letrozole (2.5 mg once daily) (n = 642) or letrozole (2.5 mg once daily) alone (n = 644). Of all patients randomized to treatment, 219 (17%) patients had tumors overexpressing the HER2 receptor, defined as fluorescence in situ hybridization (FISH) ≥2 or 3+ immunohistochemistry (IHC). There were 952 (74%) patients who were HER2-negative and 115 (9%) patients did not have their HER2 receptor status confirmed. The primary objective was to evaluate and compare progression-free survival (PFS) in the HER2-positive population. Progression-free survival was defined as the interval of time between date of randomization and the earlier date of first documented sign of disease progression or death due to any cause.
- The baseline demographic and disease characteristics were balanced between the two treatment arms. The median age was 63 years and 45% were 65 years of age or older. Eighty-four percent (84%) of the patients were white. Approximately 50% of the HER2-positive population had prior adjuvant/neo-adjuvant chemotherapy and 56% had prior hormonal therapy. Only 2 patients had prior trastuzumab.
- In the HER2-positive subgroup (n = 219), the addition of Lapatinib to letrozole resulted in an improvement in PFS. In the HER2-negative subgroup, there was no improvement in PFS of the combination of Lapatinib plus letrozole compared to the letrozole plus placebo. Overall response rate (ORR) was also improved with the combination of Lapatinib plus letrozole. The overall survival (OS) data were not mature. Efficacy analyses for the hormone receptor-positive, HER2-positive and HER2-negative subgroups are presented in Table 7 and Figure 3.
- Bottles of 150 tablets: NDC
- Lapatinib has been reported to decrease left ventricular ejection fraction which may result in shortness of breath, palpitations, and/or fatigue. Patients should inform their physician if they develop these symptoms while taking Lapatinib.
- Lapatinib often causes diarrhea which may be severe in some cases. Patients should be told how to manage and/or prevent diarrhea and to inform their physician immediately if there is any change in bowel patterns or severe diarrhea occurs during treatment with Lapatinib.
- Lapatinib may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.
- Lapatinib may interact with grapefruit. Patients should not take Lapatinib with grapefruit products.
- Lapatinib should be taken at least one hour before or one hour after a meal, in contrast to capecitabine which should be taken with food or within 30 minutes after food.
- The dose of Lapatinib should be taken once daily. Dividing the daily dose is not recommended.
- ↑ Guan Z, Xu B, DeSilvio ML, Shen Z, Arpornwirat W, Tong Z; et al. (2013). "Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer". J Clin Oncol. 31 (16): 1947–53. doi:10.1200/JCO.2011.40.5241. PMID 23509322.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Moy B, Goss PE (2006). "Lapatinib: current status and future directions in breast cancer". Oncologist. 11 (10): 1047–57. doi:10.1634/theoncologist.11-10-1047. PMID 17110623.
- ↑ Kaufman B, Trudeau M, Awada A, Blackwell K, Bachelot T, Salazar V; et al. (2009). "Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study". Lancet Oncol. 10 (6): 581–8. doi:10.1016/S1470-2045(09)70087-7. PMID 19394894.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | Lapatinib
- Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain
- capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.
- Limitation of Use: Patients should have disease progression on trastuzumab prior to initiation of treatment with Lapatinib in combination with capecitabine.
- Letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.
- Lapatinib in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer.
- HER2-Positive Metastatic Breast Cancer: The recommended dose of Lapatinib is 1,250 mg given orally once daily on Days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in 2 doses approximately 12 hours apart) on Days 1-14 in a repeating 21-day cycle. Lapatinib should be taken at least one hour before or one hour after a meal. The dose of Lapatinib should be once daily (5 tablets administered all at once); dividing the daily dose is not recommended . Capecitabine should be taken with food or within 30 minutes after food. If a day’s dose is missed, the patient should not double the dose the next day. Treatment should be continued until disease progression or unacceptable toxicity occurs.
- Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer: The recommended dose of Lapatinib is 1,500 mg given orally once daily continuously in combination with letrozole. When coadministered with Lapatinib, the recommended dose of letrozole is 2.5 mg once daily. Lapatinib should be taken at least one hour before or one hour after a meal. The dose of Lapatinib should be once daily (6 tablets administered all at once); dividing the daily dose is not recommended.
- Cardiac Events: Lapatinib should be discontinued in patients with a decreased left ventricular ejection fraction (LVEF) that is Grade 2 or greater by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3) and in patients with an LVEF that drops below the institution’s lower limit of normal. Lapatinib in combination with capecitabine may be restarted at a reduced dose (1,000 mg/day) and in combination with letrozole may be restarted at a reduced dose of 1,250 mg/day after a minimum of 2 weeks if the LVEF recovers to normal and the patient is asymptomatic.
- Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh Class C) should have their dose of Lapatinib reduced. A dose reduction from 1,250 mg/day to 750 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day to 1,000 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) in patients with severe hepatic impairment is predicted to adjust the area under the curve (AUC) to the normal range and should be considered. However, there are no clinical data with this dose adjustment in patients with severe hepatic impairment.
- Diarrhea: Lapatinib should be interrupted in patients with diarrhea which is NCI CTCAE Grade 3 or Grade 1 or 2 with complicating features (moderate to severe abdominal cramping, nausea or vomiting ≥NCI CTCAE Grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration). Lapatinib may be reintroduced at a lower dose (reduced from 1,250 mg/day to 1,000 mg/day or from 1,500 mg/day to 1,250 mg/day) when diarrhea resolves to Grade 1 or less. Lapatinib should be permanently discontinued in patients with diarrhea which is NCI CTCAE Grade 4
- Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit may also increase plasma concentrations of lapatinib and should be avoided. If patients must be coadministered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, a dose reduction to 500 mg/day of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inhibitors and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the lapatinib dose is adjusted upward to the indicated dose
- Concomitant Strong CYP3A4 Inducers: The concomitant use of strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John’s wort). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated gradually from 1,250 mg/day up to 4,500 mg/day (HER2-positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor-positive, HER2-positive breast cancer indication) based on tolerability. This dose of lapatinib is predicted to adjust the lapatinib AUC to the range observed without inducers and should be considered. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued the lapatinib dose should be reduced to the indicated dose
- Other Toxicities: Discontinuation or interruption of dosing with Lapatinib may be considered when patients develop ≥Grade 2 NCI CTCAE toxicity and can be restarted at the standard dose of 1,250 or 1,500 mg/day when the toxicity improves to Grade 1 or less. If the toxicity recurs, then Lapatinib in combination with capecitabine should be restarted at a lower dose (1,000 mg/day) and in combination with letrozole should be restarted at a lower dose of 1,250 mg/day.
- See manufacturer’s prescribing information for the coadministered product dosage adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.
- Paclitaxel 80 mg/m(2) IV once a week for 3 weeks every 4 weeks and either placebo or lapatinib 1500 mg once daily. [1]
- Oral lapatinib 1500 mg daily [2]
- Oral lapatinib 1500 mg/day [3]
- Lapatinib has been reported to decrease LVEF . In clinical trials, the majority (>57%) of LVEF decreases occurred within the first 12 weeks of treatment; however, data on long-term exposure are limited. Caution should be taken if Lapatinib is to be administered to patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of treatment with Lapatinib to ensure that the patient has a baseline LVEF that is within the institution’s normal limits. LVEF should continue to be evaluated during treatment with Lapatinib to ensure that LVEF does not decline below the institution’s normal limits.
- Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with Lapatinib should be discontinued and patients should not be retreated with Lapatinib.
- Diarrhea has been reported during treatment with Lapatinib. The diarrhea may be severe, and deaths have been reported. Diarrhea generally occurs early during treatment with Lapatinib, with almost half of those patients with diarrhea first experiencing it within 6 days. This usually lasts 4 to 5 days. Lapatinib-induced diarrhea is usually low-grade, with severe diarrhea of NCI CTCAE Grades 3 and 4 occurring in <10% and <1% of patients, respectively. Early identification and intervention is critical for the optimal management of diarrhea. Patients should be instructed to report any change in bowel patterns immediately. Prompt treatment of diarrhea with anti-diarrheal agents (such as loperamide) after the first unformed stool is recommended. Severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, use of antibiotics such as fluoroquinolones (especially if diarrhea is persistent beyond 24 hours, there is fever, or Grade 3 or 4 neutropenia), and interruption or discontinuation of therapy with Lapatinib.
- Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies . Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis. Lapatinib should be discontinued in patients who experience pulmonary symptoms indicative of interstitial lung disease/pneumonitis which are ≥Grade 3 (NCI CTCAE).
- QT prolongation was observed in an uncontrolled, open-label, dose-escalation study of lapatinib in advanced cancer patients . Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to lapatinib administration.
- Severe cutaneous reactions have been reported with Lapatinib. If life-threatening reactions such as erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (e.g., progressive skin rash often with blisters or mucosal lesions) are suspected, discontinue treatment with Lapatinib.
- HER2-Positive Metastatic Breast Cancer: The safety of Lapatinib has been evaluated in more than 12,000 patients in clinical trials. The efficacy and safety of Lapatinib in combination with capecitabine in breast cancer was evaluated in 198 patients in a randomized, Phase 3 trial . Adverse reactions which occurred in at least 10% of patients in either treatment arm and were higher in the combination arm are shown in Table 1.
- The most common adverse reactions (>20%) during therapy with Lapatinib plus capecitabine were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. *Diarrhea was the most common adverse reaction resulting in discontinuation of study medication.
- The most common Grade 3 and 4 adverse reactions (NCI CTCAE v3) were diarrhea and palmar-plantar erythrodysesthesia. Selected laboratory abnormalities are shown in Table 2.
National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
- Decreases in Left Ventricular Ejection Fraction: Due to potential cardiac toxicity with HER2 (ErbB2) inhibitors, LVEF was monitored in clinical trials at approximately 8-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are ≥Grade 3 (NCI CTCAE), or a ≥20% decrease in left ventricular cardiac ejection fraction relative to baseline which is below the institution's lower limit of normal. Among 198 patients who received combination treatment with Lapatinib/capecitabine, 3 experienced Grade 2 and one had Grade 3 LVEF adverse reactions (NCI CTCAE v3). Among 654 patients who received combination treatment with Lapatinib/letrozole, 26 patients experienced Grade 1 or 2 and 6 patients had Grade 3 or 4 LVEF adverse reactions.
- Hepatotoxicity: Lapatinib has been associated with hepatotoxicity.
- Interstitial Lung Disease/Pneumonitis: Lapatinib has been associated with interstitial lung disease and pneumonitis in monotherapy or in combination with other chemotherapies
- Immune System Disorders: Hypersensitivity reactions including anaphylaxis.
- Skin and Subcutaneous Tissue Disorders: Nail disorders including paronychia.
- Lapatinib inhibits CYP3A4, CYP2C8, and P-glycoprotein (P-gp, ABCB1) in vitro at clinically relevant concentrations and is a weak inhibitor of CYP3A4 in vivo. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing Lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4, CYP2C8, or P-gp. Lapatinib did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2C9, CYP2C19, and CYP2D6 or UGT enzymes in vitro, however, the clinical significance is unknown.
- Midazolam: Following coadministration of Lapatinib and midazolam (CYP3A4 substrate), 24-hour systemic exposure (AUC) of orally administered midazolam increased 45%, while 24-hour AUC of intravenously administered midazolam increased 22%.
- Paclitaxel: In cancer patients receiving Lapatinib and paclitaxel (CYP2C8 and P-gp substrate), 24-hour systemic exposure (AUC) of paclitaxel was increased 23%. This increase in paclitaxel exposure may have been underestimated from the in vivo evaluation due to study design limitations.
- Digoxin: Following coadministration of Lapatinib and digoxin (P-gp substrate), systemic AUC of an oral digoxin dose increased approximately 2.8-fold. Serum digoxin concentrations should be monitored prior to initiation of Lapatinib and throughout coadministration. If digoxin serum concentration is >1.2 ng/mL, the digoxin dose should be reduced by half.
- Lapatinib undergoes extensive metabolism by CYP3A4, and concomitant administration of strong inhibitors or inducers of CYP3A4 alter lapatinib concentrations significantly . Dose adjustment of lapatinib should be considered for patients who must receive concomitant strong inhibitors or concomitant strong inducers of CYP3A4 enzymes.
- Ketoconazole: In healthy subjects receiving ketoconazole, a CYP3A4 inhibitor, at 200 mg twice daily for 7 days, systemic exposure (AUC) to lapatinib was increased to approximately 3.6-fold of control and half-life increased to 1.7-fold of control.
- Carbamazepine: In healthy subjects receiving the CYP3A4 inducer, carbamazepine, at 100 mg twice daily for 3 days and 200 mg twice daily for 17 days, systemic exposure (AUC) to lapatinib was decreased approximately 72%.
- Lapatinib is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Lapatinib is administered with drugs that inhibit P-gp, increased concentrations of lapatinib are likely, and caution should be exercised.
- The aqueous solubility of lapatinib is pH dependent, with higher pH resulting in lower solubility. However, esomeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 7 days, did not result in a clinically meaningful reduction in lapatinib steady-state exposure.
- There are no adequate and well-controlled studies with Lapatinib in pregnant women. Women should be advised not to become pregnant when taking Lapatinib. 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.
- Based on findings in animals, Lapatinib can cause fetal harm when administered to a pregnant woman. Lapatinib administered to rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses. There are no adequate and well-controlled studies with Lapatinib in pregnant women. Women should be advised not to become pregnant when taking Lapatinib. 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.
- In a study where pregnant rats were dosed with lapatinib during organogenesis and through lactation, at a dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine), 91% of the pups had died by the fourth day after birth, while 34% of the 60 mg/kg/day pups were dead. The highest no-effect dose for this study was 20 mg/kg/day (approximately equal to the human clinical exposure based on AUC).
- Lapatinib was studied for effects on embryo-fetal development in pregnant rats and rabbits given oral doses of 30, 60, and 120 mg/kg/day. There were no teratogenic effects; however, minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC following 1,250-mg dose of lapatinib plus capecitabine) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.
- The pharmacokinetics of lapatinib were examined in subjects with pre-existing moderate (n = 8) or severe (n = 4) hepatic impairment (Child-Pugh Class B/C, respectively) and in 8 healthy control subjects. Systemic exposure (AUC) to lapatinib after a single oral 100-mg dose increased approximately 14% and 63% in subjects with moderate and severe pre-existing hepatic impairment, respectively. Administration of Lapatinib in patients with severe hepatic impairment should be undertaken with caution due to increased exposure to the drug. A dose reduction should be considered for patients with severe pre-existing hepatic impairment. In patients who develop severe hepatotoxicity while on therapy, Lapatinib should be discontinued and patients should not be retreated with Lapatinib.
- Asymptomatic and symptomatic cases of overdose have been reported. The doses ranged from 2,500 to 9,000 mg daily and where reported, the duration varied between 1 and 17 days. Symptoms observed include lapatinib-associated events and in some cases sore scalp, sinus tachycardia (with otherwise normal ECG), and/or mucosal inflammation.
- Because lapatinib is not significantly renally excreted and is highly bound to plasma proteins, hemodialysis would not be expected to be an effective method to enhance the elimination of lapatinib.
- Treatment of overdose with Lapatinib should consist of general supportive measures.
- An additive effect was demonstrated in an in vitro study when lapatinib and 5-FU (the active metabolite of capecitabine) were used in combination in the 4 tumor cell lines tested. The growth inhibitory effects of lapatinib were evaluated in trastuzumab-conditioned cell lines. Lapatinib retained significant activity against breast cancer cell lines selected for long-term growth in trastuzumab-containing medium in vitro. These in vitro findings suggest non–cross-resistance between these two agents.
- Hormone receptor-positive breast cancer cells (with ER [Estrogen Receptor] and/or PgR [Progesterone Receptor]) that coexpress the HER2 tend to be resistant to established endocrine therapies. Similarly, hormone receptor-positive breast cancer cells that initially lack EGFR or HER2 upregulate these receptor proteins as the tumor becomes resistant to endocrine therapy.
- Lapatinib is a yellow solid, and its solubility in water is 0.007 mg/mL and in 0.1N HCl is 0.001 mg/mL at 25°C.
- Each 250 mg tablet of Lapatinib contains 405 mg of lapatinib ditosylate monohydrate, equivalent to 398 mg of lapatinib ditosylate or 250 mg lapatinib free base.
- The inactive ingredients of Lapatinib are: Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Orange film-coat: FD&C yellow No. 6/sunset yellow FCF aluminum lake, hypromellose, macrogol/PEG 400, polysorbate 80, titanium dioxide.
- Absorption following oral administration of Lapatinib is incomplete and variable. Serum concentrations appear after a median lag time of 0.25 hours (range 0 to 1.5 hours). Peak plasma concentrations (Cmax) of lapatinib are achieved approximately 4 hours after administration. Daily dosing of Lapatinib results in achievement of steady state within 6 to 7 days, indicating an effective half-life of 24 hours.
- At the dose of 1,250 mg daily, steady-state geometric mean (95% confidence interval) values of Cmax were 2.43 mcg/mL (1.57 to 3.77 mcg/mL) and AUC were 36.2 mcg.h/mL (23.4 to 56 mcg.h/mL).
- Divided daily doses of Lapatinib resulted in approximately 2-fold higher exposure at steady state (steady-state AUC) compared to the same total dose administered once daily.
- Systemic exposure to lapatinib is increased when administered with food. Lapatinib AUC values were approximately 3- and 4-fold higher (Cmax approximately 2.5- and 3-fold higher) when administered with a low-fat (5% fat-500 calories) or with a high-fat (50% fat-1,000 calories) meal, respectively.
- Lapatinib is highly bound (>99%) to albumin and alpha-1 acid glycoprotein. In vitro studies indicate that lapatinib is a substrate for the transporters breast cancer-resistance protein (BCRP, ABCG2) and P-glycoprotein (P-gp, ABCB1). Lapatinib has also been shown to inhibit P-gp, BCRP, and the hepatic uptake transporter OATP 1B1, in vitro at clinically relevant concentrations.
- Lapatinib undergoes extensive metabolism, primarily by CYP3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidated metabolites, none of which accounts for more than 14% of the dose recovered in the feces or 10% of lapatinib concentration in plasma.
- At clinical doses, the terminal phase half-life following a single dose was 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours.
- Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (<2%) renal excretion. Recovery of parent lapatinib in feces accounts for a median of 27% (range 3% to 67%) of an oral dose.
- Effects of Age, Gender, or Race: Studies of the effects of age, gender, or race on the pharmacokinetics of lapatinib have not been performed.
- Lapatinib was not clastogenic or mutagenic in the Chinese hamster ovary chromosome aberration assay, microbial mutagenesis (Ames) assay, human lymphocyte chromosome aberration assay or the in vivo rat bone marrow chromosome aberration assay at single doses up to 2,000 mg/kg. However, an impurity in the drug product (up to 4 ppm or 8 mcg/day) was genotoxic when tested alone in both in vitro and in vivo assays.
- There were no effects on male or female rat mating or fertility at doses up to 120 mg/kg/day in females and 180 mg/kg/day in males (approximately 6.4 times and 2.6 times the expected human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine, respectively). The effect of lapatinib on human fertility is unknown. However, when female rats were given oral doses of lapatinib during breeding and through the first 6 days of gestation, a significant decrease in the number of live fetuses was seen at 120 mg/kg/day and in the fetal body weights at ≥60 mg/kg/day (approximately 6.4 times and 3.3 times the expected human clinical exposure based on AUC following 1,250-mg dose of lapatinib plus capecitabine, respectively).
- The efficacy and safety of Lapatinib in combination with capecitabine in breast cancer were evaluated in a randomized, Phase 3 trial. Patients eligible for enrollment had HER2 (ErbB2) overexpressing (IHC 3+ or IHC 2+ confirmed by FISH), locally advanced or metastatic breast cancer, progressing after prior treatment that included anthracyclines, taxanes, and trastuzumab.
- Patients were randomized to receive either Lapatinib 1,250 mg once daily (continuously) plus capecitabine 2,000 mg/m2/day on Days 1-14 every 21 days, or to receive capecitabine alone at a dose of 2,500 mg/m2/day on Days 1-14 every 21 days. The endpoint was time to progression (TTP). TTP was defined as time from randomization to tumor progression or death related to breast cancer. Based on the results of a pre-specified interim analysis, further enrollment was discontinued. Three hundred and ninety-nine (399) patients were enrolled in this study. The median age was 53 years and 14% were older than 65 years. Ninety-one percent (91%) were Caucasian. Ninety-seven percent (97%) had stage IV breast cancer, 48% were estrogen receptor+ (ER+) or progesterone receptor+ (PR+), and 95% were ErbB2 IHC 3+ or IHC 2+ with FISH confirmation. Approximately 95% of patients had prior treatment with anthracyclines, taxanes, and trastuzumab.
- Efficacy analyses 4 months after the interim analysis are presented in Table 5, Figure 1, and Figure 2.
- At the time of above efficacy analysis, the overall survival data were not mature (32% events). However, based on the TTP results, the study was unblinded and patients receiving capecitabine alone were allowed to cross over to treatment with Lapatinib plus capecitabine. The survival data were followed for an additional 2 years to be mature and the analysis is summarized in Table 6.
- Clinical Studies Describing Limitation of Use: In two randomized trials, Lapatinib-based chemotherapy regimens have been shown to be less effective than trastuzumab-based chemotherapy regimens. The first randomized, open-label study compared the safety and efficacy of Lapatinib in combination with capecitabine relative to trastuzumab in combination with capecitabine in women with HER2-positive metastatic breast cancer (N = 540). The study was stopped early based on the findings of a pre-planned interim analysis showing a low incidence of CNS events (primary endpoint) and superior efficacy of the trastuzumab plus capecitabine. The median progression-free survival was 6.6 months in the group receiving Lapatinib in combination with capecitabine compared with 8.0 months in the group receiving the trastuzumab combination [HR = 1.30 (95% CI: 1.04, 1.64)]. Overall survival was analyzed when 26% of deaths occurred in the group receiving Lapatinib in combination with capecitabine and 22% in the group receiving the trastuzumab combination [HR = 1.34 (95% CI: 0.95, 1.92)].
- The second randomized, open-label study compared the safety and efficacy of taxane-based chemotherapy plus Lapatinib to taxane-based chemotherapy plus trastuzumab as first-line therapy in women with HER2-positive, metastatic breast cancer (N = 652). The study was stopped early based on findings from a pre-planned interim analysis. The median progression-free survival was 11.3 months in the trastuzumab combination treatment arm compared to 9.0 months in patients treated with Lapatinib in the combination arm for the intent-to-treat population [HR = 1.37 (95% CI: 1.13, 1.65)].
- The efficacy and safety of Lapatinib in combination with letrozole were evaluated in a double-blind, placebo-controlled, multi-center study. A total of 1,286 postmenopausal women with hormone receptor-positive (ER-positive and/or PgR-positive) metastatic breast cancer, who had not received prior therapy for metastatic disease, were randomly assigned to receive either Lapatinib (1,500 mg once daily) plus letrozole (2.5 mg once daily) (n = 642) or letrozole (2.5 mg once daily) alone (n = 644). Of all patients randomized to treatment, 219 (17%) patients had tumors overexpressing the HER2 receptor, defined as fluorescence in situ hybridization (FISH) ≥2 or 3+ immunohistochemistry (IHC). There were 952 (74%) patients who were HER2-negative and 115 (9%) patients did not have their HER2 receptor status confirmed. The primary objective was to evaluate and compare progression-free survival (PFS) in the HER2-positive population. Progression-free survival was defined as the interval of time between date of randomization and the earlier date of first documented sign of disease progression or death due to any cause.
- The baseline demographic and disease characteristics were balanced between the two treatment arms. The median age was 63 years and 45% were 65 years of age or older. Eighty-four percent (84%) of the patients were white. Approximately 50% of the HER2-positive population had prior adjuvant/neo-adjuvant chemotherapy and 56% had prior hormonal therapy. Only 2 patients had prior trastuzumab.
- In the HER2-positive subgroup (n = 219), the addition of Lapatinib to letrozole resulted in an improvement in PFS. In the HER2-negative subgroup, there was no improvement in PFS of the combination of Lapatinib plus letrozole compared to the letrozole plus placebo. Overall response rate (ORR) was also improved with the combination of Lapatinib plus letrozole. The overall survival (OS) data were not mature. Efficacy analyses for the hormone receptor-positive, HER2-positive and HER2-negative subgroups are presented in Table 7 and Figure 3.
- Bottles of 150 tablets: NDC
- Lapatinib has been reported to decrease left ventricular ejection fraction which may result in shortness of breath, palpitations, and/or fatigue. Patients should inform their physician if they develop these symptoms while taking Lapatinib.
- Lapatinib often causes diarrhea which may be severe in some cases. Patients should be told how to manage and/or prevent diarrhea and to inform their physician immediately if there is any change in bowel patterns or severe diarrhea occurs during treatment with Lapatinib.
- Lapatinib may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.
- Lapatinib may interact with grapefruit. Patients should not take Lapatinib with grapefruit products.
- Lapatinib should be taken at least one hour before or one hour after a meal, in contrast to capecitabine which should be taken with food or within 30 minutes after food.
- The dose of Lapatinib should be taken once daily. Dividing the daily dose is not recommended.
- ↑ Guan Z, Xu B, DeSilvio ML, Shen Z, Arpornwirat W, Tong Z; et al. (2013). "Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer". J Clin Oncol. 31 (16): 1947–53. doi:10.1200/JCO.2011.40.5241. PMID 23509322.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Moy B, Goss PE (2006). "Lapatinib: current status and future directions in breast cancer". Oncologist. 11 (10): 1047–57. doi:10.1634/theoncologist.11-10-1047. PMID 17110623.
- ↑ Kaufman B, Trudeau M, Awada A, Blackwell K, Bachelot T, Salazar V; et al. (2009). "Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study". Lancet Oncol. 10 (6): 581–8. doi:10.1016/S1470-2045(09)70087-7. PMID 19394894.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Lapatinib | |
028eb30b89635acf3cca35352b403a0a83a4ec89 | wikidoc | Lathyrism | Lathyrism
Lathyrism or Neurolathyrism is a neurological disease of humans and domestic animals, caused by eating certain legumes of the genus Lathyrus. This problem is mainly associated with Lathyrus sativus (also known as Grass pea, Khesari Dhal or Almorta) and to a lesser degree with Lathyrus cicera, Lathyrus ochrus and Lathyrus clymenum. The lathyrism resulting from the ingestion of Lathyrus odoratus seeds (Sweet peas) is often referred to as odoratism.
# Symptoms
The consumption of large quantities of Lathyrus grain containing high concentrates of the neurotoxin beta-oxalyl-L-alpha,beta-diaminopropionic acid (or ODAP) causes paralysis, characterized by lack of strength in or inability to move the lower limbs. The poison responsible in the peas is the glutamate analogue beta-(N)-oxalylamino-L-alanine acid (BOAA), also known as beta-N-oxalyl-diamino-propionic acid (beta-ODAP).
# Prevalence
This disease is prevalent in some areas of Bangladesh, Ethiopia, India and Nepal, and affects more men than women. The reason for this is unclear, female hormones have been suggested to offer a measure of protection, but also less food allocation and less oxidatively stressful activity are plausible.
# Causes
The toxicological cause of the disease has been attributed to the neurotoxin beta-oxalyl-L-alpha,beta-diaminopropionic acid (ODAP) which acts as a structural analogue of the neurotransmitter glutamate. Ingestion of legumes containing the toxin results mostly from ignorance of their toxicity and usually occurs where the despair of poverty and malnutrition leaves little other food options.
# Prevention
Recent research suggests that sulfur amino acids have a protective effect against the toxicity of ODAP.
Food preparation is also an important factor. Toxic amino acids are readily soluble in water and can be leached. Bacterial (lactic acid) and fungal (tempeh) fermentation is useful to reduce ODAP content. Moist heat (boiling, steaming) denatures proteinase inhibitors which otherwise add to the toxic effect of raw grasspea through depletion of protective sulfur amino acids.
The underlying cause for excessive consumption of grasspea is a lack of alternative food sources. This is a consequence of poverty and political conflict. The prevention of lathyrism is therefore a socio-economic challenge.
# Historical occurrence
The first mentioned intoxication goes back to ancient India and also Hippocrates mentiones a neurological disorder 46 B.C. in Greeze caused by Lathyrus seed. Lathyrism was occurring in regular basis.
During the Spain War of Independence against Napoleon, grasspea served as a famine food. This was the subject of one of Francisco de Goya's famous aquatint prints titled Gracias a la Almorta ("Thanks to the Grasspea"), depicting poor people surviving on a porridge made from grasspea flour, one of them laying on the floor, already crippled by it.
In the film 'Ashes' by Andrzej Wajda based on the novel Popioly translated as 'Lost army' by Stefan Zeromski spanning the period 1798-1812, a horse is poisoned by grain from a Spanish village. The footage of the horse losing control of its hindlegs suggests that it was fed with Almortas. The scene with the horse falling down a steep cliff is very graphic.
# Modern occurrence
During the post-war period in Spain, there were several outbreaks of lathyrism, caused by the shortage of food, which led people to consume excessive amounts of Almorta flour.
In Spain, a seed mixture known as comuña consisting of Lathyrus sativus, L. cicera, Vicia sativa and V. ervilia provides a potent mixture of toxic amino acids to poison monogastric (single stomached) animals. Particularly the toxin beta-cyanoalanine from seeds of V. sativa enhances the toxicity of such a mixture through its inhibition of sulfur amino acid metabolism and hence depletion of protective reduced thiols. Its use for sheep does not pose any lathyrism problems if doses do not exceed 50 percent of the ration.
# Related conditions
A related disease has been identified and named Osteolathyrism, caused by the toxin beta-amino-propionitrile (BAPN) because it affects the bones and connecting tissues, instead the nervous system. It is a skeletal disorder characterized by hernias, dissecting aortic aneurysms, lameness of the hind legs, exostoses, and kyphoscoliosis and other skeletal deformities, apparently as the result of defective aging of collagen tissue. The cause of this disease is attributed to beta-aminopropionitrile (BAPN), which inhibits the copper-containing enzyme lysyl oxidase, responsible for cross-linking procollagen and proelastin. BAPN is also a metabolic product of a compound present in sprouts of grasspea, pea and lentils. | Lathyrism
Lathyrism or Neurolathyrism is a neurological disease of humans and domestic animals, caused by eating certain legumes of the genus Lathyrus. This problem is mainly associated with Lathyrus sativus (also known as Grass pea, Khesari Dhal or Almorta) and to a lesser degree with Lathyrus cicera, Lathyrus ochrus and Lathyrus clymenum[1]. The lathyrism resulting from the ingestion of Lathyrus odoratus seeds (Sweet peas) is often referred to as odoratism.
# Symptoms
The consumption of large quantities of Lathyrus grain containing high concentrates of the neurotoxin beta-oxalyl-L-alpha,beta-diaminopropionic acid (or ODAP) causes paralysis, characterized by lack of strength in or inability to move the lower limbs. The poison responsible in the peas is the glutamate analogue beta-(N)-oxalylamino-L-alanine acid (BOAA), also known as beta-N-oxalyl-diamino-propionic acid (beta-ODAP).
# Prevalence
This disease is prevalent in some areas of Bangladesh, Ethiopia, India and Nepal,[2] and affects more men than women. The reason for this is unclear, female hormones have been suggested to offer a measure of protection, but also less food allocation and less oxidatively stressful activity [work] are plausible.
# Causes
The toxicological cause of the disease has been attributed to the neurotoxin beta-oxalyl-L-alpha,beta-diaminopropionic acid (ODAP) which acts as a structural analogue of the neurotransmitter glutamate. Ingestion of legumes containing the toxin results mostly from ignorance of their toxicity and usually occurs where the despair of poverty and malnutrition leaves little other food options.
# Prevention
Recent research suggests that sulfur amino acids have a protective effect against the toxicity of ODAP.[3]
Food preparation is also an important factor. Toxic amino acids are readily soluble in water and can be leached. Bacterial (lactic acid) and fungal (tempeh) fermentation is useful to reduce ODAP content. Moist heat (boiling, steaming) denatures proteinase inhibitors which otherwise add to the toxic effect of raw grasspea through depletion of protective sulfur amino acids.
The underlying cause for excessive consumption of grasspea is a lack of alternative food sources. This is a consequence of poverty and political conflict. The prevention of lathyrism is therefore a socio-economic challenge.
# Historical occurrence
The first mentioned intoxication goes back to ancient India and also Hippocrates mentiones a neurological disorder 46 B.C. in Greeze caused by Lathyrus seed.[4] Lathyrism was occurring in regular basis.
During the Spain War of Independence against Napoleon, grasspea served as a famine food. This was the subject of one of Francisco de Goya's famous aquatint prints titled Gracias a la Almorta ("Thanks to the Grasspea"), depicting poor people surviving on a porridge made from grasspea flour, one of them laying on the floor, already crippled by it.
In the film 'Ashes' [English title] by Andrzej Wajda based on the novel Popioly [Polish title] translated as 'Lost army' [English title] by Stefan Zeromski spanning the period 1798-1812, a horse is poisoned by grain from a Spanish village. The footage of the horse losing control of its hindlegs suggests that it was fed with Almortas. The scene with the horse falling down a steep cliff is very graphic.
# Modern occurrence
During the post-war period in Spain, there were several outbreaks of lathyrism, caused by the shortage of food, which led people to consume excessive amounts of Almorta flour.[5]
In Spain, a seed mixture known as comuña[6] consisting of Lathyrus sativus, L. cicera, Vicia sativa and V. ervilia provides a potent mixture of toxic amino acids to poison monogastric (single stomached) animals. Particularly the toxin beta-cyanoalanine from seeds of V. sativa enhances the toxicity of such a mixture through its inhibition of sulfur amino acid metabolism [conversion of methionine to cysteine leading to excretion of cystathionine in urine] and hence depletion of protective reduced thiols. Its use for sheep does not pose any lathyrism problems if doses do not exceed 50 percent of the ration.[7]
# Related conditions
A related disease has been identified and named Osteolathyrism, caused by the toxin beta-amino-propionitrile (BAPN) because it affects the bones and connecting tissues, instead the nervous system. It is a skeletal disorder characterized by hernias, dissecting aortic aneurysms, lameness of the hind legs, exostoses, and kyphoscoliosis and other skeletal deformities, apparently as the result of defective aging of collagen tissue. The cause of this disease is attributed to beta-aminopropionitrile (BAPN), which inhibits the copper-containing enzyme lysyl oxidase, responsible for cross-linking procollagen and proelastin. BAPN is also a metabolic product of a compound present in sprouts of grasspea, pea and lentils.[8] | https://www.wikidoc.org/index.php/Lathyrism | |
f2b7d7e548158d4d8d72f172f21681654f907d05 | wikidoc | Left lung | Left lung
# Overview
The Left lung is divided into two lobes, an upper and a lower, by the oblique fissure, which extends from the costal to the mediastinal surface of the lung both above and below the hilus.
As seen on the surface, this fissure begins on the mediastinal surface of the lung at the upper and posterior part of the hilus, and runs backward and upward to the posterior border, which it crosses at a point about 6 cm. below the apex.
It then extends downward and forward over the costal surface, and reaches the lower border a little behind its anterior extremity, and its further course can be followed upward and backward across the mediastinal surface as far as the lower part of the hilus.
# Lobes
The superior lobe lies above and in front of this fissure, and includes the apex, the anterior border, and a considerable part of the costal surface and the greater part of the mediastinal surface of the lung.
The inferior lobe, the larger of the two, is situated below and behind the fissure, and comprises almost the whole of the base, a large portion of the costal surface, and the greater part of the posterior border.
# Impressions
On the mediastinal surface, immediately above the hilus, is a well-marked curved furrow produced by the aortic arch, and running upward from this toward the apex is a groove accommodating the left subclavian artery; a slight impression in front of the latter and close to the margin of the lung lodges the left innominate vein.
Behind the hilus and pulmonary ligament is a vertical furrow produced by the descending aorta, and in front of this, near the base of the lung, the lower part of the esophagus causes a shallow impression.
# Additional images
- diagram of the respiratory system
- Anatomy of lungs.
- Front view of heart and lungs.
- Transverse section of thorax, showing relations of pulmonary artery.
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
- The thymus of a full-time fetus, exposed in situ. | Left lung
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Left lung is divided into two lobes, an upper and a lower, by the oblique fissure, which extends from the costal to the mediastinal surface of the lung both above and below the hilus.
As seen on the surface, this fissure begins on the mediastinal surface of the lung at the upper and posterior part of the hilus, and runs backward and upward to the posterior border, which it crosses at a point about 6 cm. below the apex.
It then extends downward and forward over the costal surface, and reaches the lower border a little behind its anterior extremity, and its further course can be followed upward and backward across the mediastinal surface as far as the lower part of the hilus.
# Lobes
The superior lobe lies above and in front of this fissure, and includes the apex, the anterior border, and a considerable part of the costal surface and the greater part of the mediastinal surface of the lung.
The inferior lobe, the larger of the two, is situated below and behind the fissure, and comprises almost the whole of the base, a large portion of the costal surface, and the greater part of the posterior border.
# Impressions
On the mediastinal surface, immediately above the hilus, is a well-marked curved furrow produced by the aortic arch, and running upward from this toward the apex is a groove accommodating the left subclavian artery; a slight impression in front of the latter and close to the margin of the lung lodges the left innominate vein.
Behind the hilus and pulmonary ligament is a vertical furrow produced by the descending aorta, and in front of this, near the base of the lung, the lower part of the esophagus causes a shallow impression.
# Additional images
- diagram of the respiratory system
- Anatomy of lungs.
- Front view of heart and lungs.
- Transverse section of thorax, showing relations of pulmonary artery.
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
- The thymus of a full-time fetus, exposed in situ. | https://www.wikidoc.org/index.php/Left_lung | |
5680795aeac6d49aec427a835e8819e57b2346a9 | wikidoc | Leptoprin | Leptoprin
Leptoprin is a dietary supplement marketed by "A.G. Waterhouse", a front for Basic Research of Salt Lake City, Utah. It was formerly known as Anorex (see anorexia). Despite the pharmaceutical-sounding name, the company that makes Leptoprin (and Leptopril) is not a pharmaceutical company.
The method of advertising the product is unique, and begins with a woman identified as "Mellisa Pace" asking the question "When is a diet pill worth $153 a bottle?" The ad goes on to claim that Leptoprin is "developed for the significantly overweight", that it is "much too powerful" for the "casual dieter".
There is also a less expensive "generic" version of the formulation called Leptopril, which is advertised as being developed by "Generix Labs". The two products are in fact exactly the same, being marketed to two different consumer personalities by the same company.
# Analysis
While the advertisement makes this sound as if this diet aid is different from other over the counter diet products it is in fact not significantly different from other diet aids. Specifically, it is based on the ECA Stack.
Some of the statements made during the advertisement, presumably with the intention of impressing the potential buyer, are that the product is:
- 1. Patented - what many people don't know is that any specific formulation of chemicals, vitamins, or herbs can be patented, regardless of whether they are effective. Many vitamin complexes have patented formulations, as do some herbal formulations.
- 2. Backed by a published clinical trial - While this was published in a journal called Current Therapeutic Research (Volume 60, Issue 4 , April 1999, Pages 220-227), the results of the trial were not clinically significant between the control group (non-Leptoprin) and the Leptoprin group. The trial did not determine that the product was effective for weight loss.
- 3. Designed for the significantly overweight - While it may have been designed for the significantly overweight, the published clinical study did not support its efficacy for this group of people.
# Ingredients
The ingredients of Leptoprin/Leptopril are:
- Vitamin B6 25mg (1250% RDA)
- Acetylsalicylic acid (Aspirin) 324mg
- Caffeine 200mg
- Green Tea Extract (no amount listed)
- L-Tyrosine (no amount listed)
- Kelp 100mg
- Ephedrine 20mg
- Cayenne (no amount listed)
- Rice flour base
The Ingredients of Leptoprin SF are:
- Calcium (amino acid chelate) 132mg (33.3% RDA)
- Leptoprin-SF 1493.5 mg A trademarked proprietary blend of the following:
Calcium phosphate
Commiphora Mukul Extract
Garcinia cambogia (HCA 125 mg)
L-Tyrosine
Acetylsalicylic acid 162.5 mg
Dipotassium Phosphate
Sodium phosphate
Disodium Phosphate
Phosphatidyl Choline
Scutellaria (root)
Bupleurum (root)
Epimedium (herb)
- Calcium phosphate
- Commiphora Mukul Extract
- Garcinia cambogia (HCA 125 mg)
- L-Tyrosine
- Acetylsalicylic acid 162.5 mg
- Dipotassium Phosphate
- Sodium phosphate
- Disodium Phosphate
- Phosphatidyl Choline
- Scutellaria (root)
- Bupleurum (root)
- Epimedium (herb)
- Rice flour base
There is nothing in the product that cannot be purchased less expensively in other brands or products. For this reason, many people believe this advertising campaign is deceptive. | Leptoprin
Template:Expert
Template:Weasel
Leptoprin is a dietary supplement marketed by "A.G. Waterhouse", a front for Basic Research of Salt Lake City, Utah. It was formerly known as Anorex (see anorexia). Despite the pharmaceutical-sounding name, the company that makes Leptoprin (and Leptopril) is not a pharmaceutical company.
The method of advertising the product is unique, and begins with a woman identified as "Mellisa Pace" asking the question "When is a diet pill worth $153 a bottle?" The ad goes on to claim that Leptoprin is "developed for the significantly overweight", that it is "much too powerful" for the "casual dieter".
There is also a less expensive "generic" version of the formulation called Leptopril, which is advertised as being developed by "Generix Labs". The two products are in fact exactly the same, being marketed to two different consumer personalities by the same company.[1]
# Analysis
While the advertisement makes this sound as if this diet aid is different from other over the counter diet products it is in fact not significantly different from other diet aids. Specifically, it is based on the ECA Stack.
Some of the statements made during the advertisement, presumably with the intention of impressing the potential buyer, are that the product is:
- 1. Patented - what many people don't know is that any specific formulation of chemicals, vitamins, or herbs can be patented, regardless of whether they are effective. Many vitamin complexes have patented formulations, as do some herbal formulations.
- 2. Backed by a published clinical trial - While this was published in a journal called Current Therapeutic Research (Volume 60, Issue 4 , April 1999, Pages 220-227), the results of the trial were not clinically significant between the control group (non-Leptoprin) and the Leptoprin group. The trial did not determine that the product was effective for weight loss.
- 3. Designed for the significantly overweight - While it may have been designed for the significantly overweight, the published clinical study did not support its efficacy for this group of people.
# Ingredients
The ingredients of Leptoprin/Leptopril are:
- Vitamin B6 25mg (1250% RDA)
- Acetylsalicylic acid (Aspirin) 324mg
- Caffeine 200mg
- Green Tea Extract (no amount listed)
- L-Tyrosine (no amount listed)
- Kelp 100mg
- Ephedrine 20mg
- Cayenne (no amount listed)
- Rice flour base
The Ingredients of Leptoprin SF are:
- Calcium (amino acid chelate) 132mg (33.3% RDA)
- Leptoprin-SF 1493.5 mg A trademarked proprietary blend of the following:
Calcium phosphate
Commiphora Mukul Extract
Garcinia cambogia (HCA 125 mg)
L-Tyrosine
Acetylsalicylic acid 162.5 mg
Dipotassium Phosphate
Sodium phosphate
Disodium Phosphate
Phosphatidyl Choline
Scutellaria (root)
Bupleurum (root)
Epimedium (herb)
- Calcium phosphate
- Commiphora Mukul Extract
- Garcinia cambogia (HCA 125 mg)
- L-Tyrosine
- Acetylsalicylic acid 162.5 mg
- Dipotassium Phosphate
- Sodium phosphate
- Disodium Phosphate
- Phosphatidyl Choline
- Scutellaria (root)
- Bupleurum (root)
- Epimedium (herb)
- Rice flour base
There is nothing in the product that cannot be purchased less expensively in other brands or products. For this reason, many people believe this advertising campaign is deceptive.[1] | https://www.wikidoc.org/index.php/Leptoprin | |
1479b34878d1e9a0fa6fadd2e9f66f004a87901f | wikidoc | Lesinurad | Lesinurad
Acute renal failure has occurred with Lesinurad and was more common when Lesinurad was given alone.
Lesinurad should be used in combination with a xanthine oxidase inhibitor.
Lesinurad is indicated in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.
- Limitations of Use
- Lesinurad is not recommended for the treatment of asymptomatic hyperuricemia.
- Lesinurad should not be used as monotherapy.
- Recommended Dosing
Lesinurad tablets are for oral use and should be co-administered with a xanthine oxidase inhibitor, including allopurinol or febuxostat.
Lesinurad is recommended at 200 mg once daily. This is also the maximum daily dose. Lesinurad should be taken by mouth, in the morning with food and water.
Lesinurad may be added when target serum uric acid levels are not achieved on the medically appropriate dose of the xanthine oxidase inhibitor alone.
Use of Lesinurad is not recommended for patients taking daily doses of allopurinol less than 300 mg (or less than 200 mg in patients with estimated creatinine clearance (eCLcr) less than 60 mL/min). Take Lesinurad at the same time as the morning dose of xanthine oxidase inhibitor. If treatment with the xanthine oxidase inhibitor is interrupted, Lesinurad should also be interrupted. Failure to follow these instructions may increase the risk of renal events.
Patients should be instructed to stay well hydrated (eg, 2 liters (68 oz) of liquid per day).
- Patients with Renal Impairment
No dose adjustment is needed in patients with mild or moderate renal impairment (eCLcr of 45 mL/min or greater). Lesinurad should not be initiated in patients with an eCLcr less than 45 mL/min. Assessment of renal function is recommended prior to initiation of Lesinurad therapy and periodically thereafter. More frequent renal function monitoring is recommended in patients with an eCLcr below 60 mL/min. Lesinurad should be discontinued when eCLcr is persistently less than 45 mL/min.
- Gout Flares
Gout flares may occur after initiation of urate lowering therapy, including Lesinurad, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Gout flare prophylaxis is recommended when starting Lesinurad, according to practice guidelines.
If a gout flare occurs during Lesinurad treatment, Lesinurad need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient.
- Severe renal impairment (eCLcr less than 30 mL/min), end stage renal disease, kidney transplant recipients, or patients on dialysis.
- Tumor lysis syndrome or Lesch-Nyhan syndrome.
Treatment with Lesinurad 200 mg in combination with a xanthine oxidase inhibitor was associated with an increased incidence of serum creatinine elevations, most of which were reversible. Adverse reactions related to renal function have occurred after initiating Lesinurad. A higher incidence of serum creatinine elevations and renal-related adverse reactions, including serious adverse reactions of , was observed with Lesinurad 400 mg, with the highest incidence as monotherapy. Lesinurad should not be used as monotherapy.
Lesinurad should not be initiated in patients with an eCLcr less than 45 mL/min. Renal function should be evaluated prior to initiation of Lesinurad and periodically thereafter, as clinically indicated. More frequent renal function monitoring is recommended in patients with an eCLcr less than 60 mL/min or with serum creatinine elevations 1.5 to 2 times the pre-treatment value. Lesinurad treatment should be interrupted if serum creatinine is elevated to greater than 2 times the pre-treatment value. In patients who report symptoms that may indicate acute uric acid nephropathy including flank pain, nausea or vomiting, interrupt treatment and measure serum creatinine promptly. Lesinurad should not be restarted without another explanation for the serum creatinine abnormalities.
- Cardiovascular Events
In clinical trials, major adverse cardiovascular events (defined as cardiovascular deaths, non-fatal myocardial infarctions, or non-fatal strokes) were observed with Lesinurad. A causal relationship with Lesinurad has not been established.
Although other doses have been studied, the recommended dose of Lesinurad is 200 mg once daily in combination with a xanthine oxidase inhibitor.
In 3 randomized, placebo-controlled studies of Lesinurad in combination with a xanthine oxidase inhibitor (Studies 1 and 2 were with allopurinol and Study 3 was with febuxostat) for up to 12 months, a total of 511, 510, and 516 patients were treated with Lesinurad 200 mg, Lesinurad 400 mg, and placebo, respectively. The mean duration of treatment with Lesinurad was 11.2 months. The mean age of the population was 52 years (18-82), and 95% were males. At baseline, 62% of the patient population showed mild or moderate renal impairment (eCLcr less than 90 mL/min) and 79% of patients had at least one co-morbid condition including hypertension (65%), hyperlipidemia (45%), diabetes (17%), and kidney stones (12%).
- Renal Events
Lesinurad causes an increase in renal uric acid excretion, which may lead to renal events including transient increases in serum creatinine, renal-related adverse reactions, and kidney stones. These renal events occurred more frequently in patients receiving Lesinurad 400 mg, when used as monotherapy or in combination with a xanthine oxidase inhibitor.
The number of patients with serum creatinine elevations in the 12-month placebo-controlled trials in combination with a xanthine oxidase inhibitor are shown in Table 1. Most of these elevations on Lesinurad 200 mg and Lesinurad 400 mg resolved without treatment interruption (Table 1).
- Table 1: Patients with Elevated Serum Creatinine Values in the Placebo-Controlled Clinical Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)
ZURAMPIC: Lesinurad's Brand name
Renal-related adverse reactions, including blood creatinine increases and renal failure, and nephrolithiasis reported in patients receiving Lesinurad 200 mg, Lesinurad 400 mg and in combination with a xanthine oxidase inhibitor are shown in Table 2. The incidence of reports of “blood creatinine increased” was higher with Lesinurad and was highest with Lesinurad 400 mg. Renal-related adverse reactions by baseline renal function category are shown in Table 3. Blood creatinine increased occurred more frequently in patients treated with Lesinurad in combination with a xanthine oxidase inhibitor across baseline renal function categories (Table 3).
- Table 2: Incidence of Renal-Related Adverse Reactions and Nephrolithiasis in Placebo-Controlled Clinical Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)
ZURAMPIC: Lesinurad's Brand name
- Table 3: Incidence of Renal-Related Adverse Reactions by Baseline Renal Function Category in Placebo-Controlled Clinical Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)
ZURAMPIC: Lesinurad's Brand name
Renal-related adverse reactions resulted in a similar discontinuation rate on Lesinurad 200 mg in combination with a xanthine oxidase inhibitor (1.2%) and a xanthine oxidase inhibitor alone (1%) and a higher rate on Lesinurad 400 mg in combination with a xanthine oxidase inhibitor (3.3%). Serious renal-related adverse reactions were reported in patients on Lesinurad 400 mg in combination with a xanthine oxidase inhibitor (1%) and a xanthine oxidase inhibitor alone (0.4%) and in no patients on Lesinurad 200 mg in combination with a xanthine oxidase inhibitor during the 12-month controlled period of the studies. Serious renal-related adverse reactions were reported with Lesinurad 200 mg and Lesinurad 400 mg in the uncontrolled long-term extensions.
Monotherapy: In a 6-month double-blind, placebo-controlled monotherapy study, renal failure (9.3%), blood creatinine increased (8.4%), and (0.9%) were reported in patients receiving Lesinurad 400 mg alone and in no patients receiving placebo. Serum creatinine elevations 1.5-fold or greater occurred in 24.3 % of patients receiving Lesinurad 400 mg and in no patients receiving placebo.
- Cardiovascular Safety
Cardiovascular events and deaths were adjudicated as Major Adverse Cardiovascular Events (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the Phase 3 randomized controlled studies of Lesinurad. In the randomized controlled studies, the numbers of patients with adjudicated MACE events (incidences per 100 patient-years of exposure) were: 3 (0.71) for , 4 (0.96) for Lesinurad 200 mg, and 8 (1.94) for Lesinurad 400 mg when used in combination with a xanthine oxidase inhibitor. Incidence rate ratios for Lesinurad 200 mg and 400 mg compared with placebo were 1.36 (95% CI: 0.23, 9.25) and 2.71 (95% CI: 0.66, 16.00), respectively.
- Other Adverse Reactions
Adverse reactions occurring in 2% or more of patients on Lesinurad 200 mg in combination with a xanthine oxidase inhibitor and at least 1% greater than that observed in patients on placebo with a xanthine oxidase inhibitor are summarized in Table 4.
- Table 4: Adverse Reactions Occurring in ≥ 2% of Lesinurad 200 mg-Treated Patients and at Least 1% Greater than Seen in Patients Receiving Placebo in Controlled Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)
ZURAMPIC: Lesinurad's Brand name
Lesinurad exposure is increased when Lesinurad is co-administered with inhibitors of CYP2C9, and in CYP2C9 poor metabolizers. Lesinurad should be used with caution in patients taking moderate inhibitors of CYP2C9 (eg, fluconazole, amiodarone), and in CYP2C9 poor metabolizers.
Lesinurad exposure is decreased when Lesinurad is co-administered with moderate inducers of CYP2C9 (eg, rifampin, carbamazepine), which may decrease the therapeutic effect of Lesinurad.
- CYP3A Substrates
In interaction studies conducted in healthy subjects with Lesinurad and CYP3A substrates, Lesinurad reduced the plasma concentrations of sildenafil and amlodipine. Although there was not a clinically significant interaction with atorvastatin, HMG-CoA reductase inhibitors that are sensitive CYP3A substrates may be affected. The possibility of reduced efficacy of concomitant drugs that are CYP3A substrates should be considered and their efficacy (eg, blood pressure and cholesterol levels) should be monitored.
- Epoxide Hydrolase Inhibitors
In vitro studies suggest that Lesinurad is not an inhibitor of epoxide hydrolase; however, inhibitors of epoxide hydrolase (ie, valproic acid) may interfere with metabolism of Lesinurad. Lesinurad should not be administered with inhibitors of epoxide hydrolase.
- Hormonal Contraceptives
Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Lesinurad is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Lesinurad.
- Aspirin
Aspirin at doses higher than 325 mg per day may decrease the efficacy of Lesinurad in combination with allopurinol. Aspirin at doses of 325 mg or less per day (ie, for cardiovascular protection) does not decrease the efficacy of Lesinurad and can be coadministered with Lesinurad.
There are no available human data on use of Lesinurad in pregnant women to inform a drug-associated risk. No teratogenicity or effects on fetal development were observed in embryo-fetal development studies with oral administration of Lesinurad to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to approximately 45 and 10 times, respectively, the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed in a pre- and postnatal development study with administration of Lesinurad to pregnant rats from organogenesis through lactation at a dose approximately 5 times the MRHD.
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.
- Data
- Animal Data
In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-17, Lesinurad was not teratogenic and did not affect fetal development or survival at exposures up to approximately 45 times the MRHD (on an AUC basis at maternal oral doses up to 300 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-20, Lesinurad was not teratogenic and did not affect fetal development at exposures up to approximately 10 times the MRHD (on an AUC basis at maternal oral doses up to 75 mg/kg/day). Severe maternal toxicity, including mortality, was observed in rats and rabbits at exposures equal to or greater than approximately 45 and 4 times the MRHD (on an AUC basis at maternal oral doses of 300 mg/kg/day in rats and 25 mg/kg/day and higher in rabbits), respectively.
In a pre- and postnatal development study in pregnant female rats dosed from gestation day 7 through lactation day 20, Lesinurad had no effects on delivery or growth and development of offspring at a dose approximately 5 times the MRHD (on a mg/m2 basis at a maternal dose oral dose of 100 mg/kg/day). In rats, plasma and milk concentrations of Lesinurad were approximately equal.
The efficacy and safety of Lesinurad were evaluated in studies that included gout patients with mild and moderate renal impairment. There were no clear differences in safety and effectiveness of Lesinurad in patients with mild renal impairment compared to patients with normal renal function and no dose adjustment is recommended.
Across all Lesinurad and placebo treatment groups, patients with moderate renal impairment had a higher occurrence of renal related adverse reactions compared to patients with mild renal impairment or normal renal function. The experience with Lesinurad in patients with an eCLcr less than 45 mL/min is limited and there was a trend toward lesser efficacy. Lesinurad should not be initiated in patients with an eCLcr less than 45 mL/min. No dose adjustment is recommended in patients with an eCLcr 45 to less than 60 mL/min, however, more frequent renal function monitoring is recommended. Lesinurad should be discontinued when eCLcr is persistently less than 45 mL/min.
The efficacy and safety of Lesinurad have not been evaluated in gout patients with severe renal impairment (eCLcr less than 30 mL/min), with end-stage renal disease, or receiving dialysis. Lesinurad is not expected to be effective in these patient populations.
Lesinurad is available as blue film-coated tablets for oral administration containing 200 mg Lesinurad and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, hypromellose 2910, crospovidone, and magnesium stearate. Lesinurad tablets are coated with Opadry blue.
In gout patients, Lesinurad lowered serum uric acid levels and increased renal clearance and fractional excretion of uric acid. Following single and multiple oral doses of Lesinurad to gout patients, dose-dependent decreases in serum uric acid levels and increases in urinary uric acid excretion were observed.
- Effect on Cardiac Repolarization
The effect of Lesinurad on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and gout patients. Lesinurad at doses up to 1600 mg did not demonstrate an effect on the QTc interval.
- Absorption
The absolute bioavailability of Lesinurad is approximately 100%. Lesinurad is rapidly absorbed after oral administration. Following administration of a single dose of a Lesinurad tablet in either fed or fasted state, maximum plasma concentrations (Cmax) were attained within 1 to 4 hours. Cmax and AUC exposures of Lesinurad increased proportionally with single doses of Lesinurad from 5 to 1200 mg.
Administration with a high-fat meal (800 to 1000 calories with 50% of calories being derived from fat content) decreases Lesinurad Cmax by up to 18% but does not alter AUC as compared with fasted state. In clinical trials, Lesinurad was administered with food.
- Distribution
Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin. Plasma protein binding of Lesinurad is not meaningfully altered in patients with renal or hepatic impairment. The mean steady state volume of distribution of Lesinurad was approximately 20 L following intravenous dosing of Lesinurad.
- Elimination
The elimination half-life (t½) of Lesinurad was approximately 5 hours. Lesinurad does not accumulate following multiple doses. The total body clearance is approximately 6 L/hr.
- Metabolism
Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome P450 CYP2C9 enzyme. Plasma exposure of metabolites is minimal (< 10% of unchanged Lesinurad). Metabolites are not known to contribute to the uric acid lowering effects of Lesinurad. A transient oxide metabolite is rapidly eliminated by microsomal epoxide hydrolase in the liver and not detected in .
Patients who are CYP2C9 poor metabolizers are deficient in CYP2C9 enzyme activity. A cross-study pharmacogenomic analysis assessed the association between CYP2C9 polymorphism and Lesinurad exposure in patients receiving single or multiple doses of Lesinurad at 200 mg, 400 mg or 600 mg. At the 400 mg dose, Lesinurad exposure was approximately 1.8-fold higher in CYP2C9 poor metabolizers (i.e., subjects with CYP2C9 *2/*2 , and *3/*3 genotype) compared to CYP2C9 extensive metabolizers (i.e., CYP2C9 *1/*1 genotype). Use with caution in CYP2C9 poor metabolizers, and in patients taking moderate inhibitors of CYP2C9.
- Excretion
Within 7 days following single dosing of radiolabeled Lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in feces. Most of the radioactivity recovered in urine (> 60% of dose) occurred in the first 24 hours. Unchanged Lesinurad in urine accounted for approximately 30% of the dose.
- Special Populations
- Renal Impairment
Two dedicated studies were performed to assess PK in renal impairment (classified using the Cockcroft-Gault formula) subjects. In both studies, Cmax was comparable in renal impairment subjects compared to healthy subjects.
Study 1 was a single-dose, open-label study evaluating the pharmacokinetics of Lesinurad 200 mg in subjects with mild (eCLcr 60 to less than 90 mL/min) and moderate renal impairment (eCLcr 30 to less than 60 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6; eCLcr greater than or equal to 90 mL/min), plasma AUC of Lesinurad was increased by approximately 30% and 73% in subjects with mild (N=8) and moderate (N=10) renal impairment, respectively.
Study 2 was a single-dose, open-label study evaluating the pharmacokinetics of Lesinurad 400 mg in subjects with moderate and severe renal impairment (eCLcr less than 30 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6), plasma AUC of Lesinurad was increased by approximately 50% and 113% in subjects with moderate (N=6) and severe (N=6) renal impairment, respectively.
- Hepatic Impairment
Following administration of a single dose of Lesinurad at 400 mg in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, Lesinurad Cmax was comparable and Lesinurad AUC was 7% and 33% higher, respectively, compared to individuals with normal . There is no clinical experience in patients with severe (Child-Pugh class C) hepatic impairment.
- Effect of Age, Gender, Race and Ethnicity on Pharmacokinetics
Based on the population pharmacokinetic analysis, age, gender, race and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of Lesinurad.
- Pediatric Use
Studies characterizing the pharmacokinetics of Lesinurad in pediatric patients have not been conducted.
- Drug-Drug Interactions
- Effects of Other Drugs on Lesinurad
Based on in vitro data, Lesinurad is a substrate for CYP2C9, OAT1 and OAT3; however, no clinical studies have been conducted with OAT1 and OAT3 inhibitors (eg, probenecid).
Figure 1 shows the effect of co-administered drugs on the pharmacokinetics of Lesinurad.
- Figure 1: Effect of Co-administered Drugs on the Pharmacokinetics of Lesinurad
- Effects of Lesinurad on Other Drugs
Lesinurad is a weak inducer of CYP3A and has no relevant effect on any other CYP enzyme for induction (CYP1A2, CYP2C8, CYP2C9, CYP2B6, or CYP2C19) or inhibition (CYP1A2, CYP2B6, CYP2D6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4).
Based on in vitro studies, Lesinurad is an inhibitor of OATP1B1, OCT1, OAT1, and OAT3; however, Lesinurad is not an in vivo inhibitor of these transporters. In vivo drug interaction studies indicate that Lesinurad does not decrease the renal clearance of furosemide (substrate of OAT1/3), or affect the exposure of atorvastatin (substrate of OATP1B1) or metformin (substrate of OCT1). Based on in vitro studies, Lesinurad has no relevant effect on P-glycoprotein.
Figure 2 shows the effect of Lesinurad on co-administered drugs.
- Figure 2: Effect of Lesinurad on the Pharmacokinetics of Co-administered Drugs
The carcinogenic potential of Lesinurad was evaluated in Sprague-Dawley rats and TgRasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received Lesinurad for 91 to 100 weeks at oral doses up to 200 mg/kg/day (approximately 35 times the MRHD on an AUC basis). No evidence of tumorigenicity was observed in TgRasH2 mice that received Lesinurad for 26 weeks at oral doses up to 125 and 250 mg/kg/day in male and female mice, respectively.
Lesinurad tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo rat bone marrow micronucleus assay.
Fertility and reproductive performance were unaffected in male or female rats that received Lesinurad at oral doses up to 300 mg/kg/day (approximately 15 times the MRHD on a mg/m2 basis).
The efficacy of Lesinurad 200 mg and 400 mg once daily was studied in 3 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with hyperuricemia and gout in combination with a xanthine oxidase inhibitor, allopurinol or febuxostat. All studies were of 12 months duration and patients received prophylaxis for gout flares with colchicine or non-steroidal anti-inflammatory drugs (NSAIDs) during the first 5 months of Lesinurad treatment.
Although other doses have been studied, the recommended dose of Lesinurad is 200 mg once daily in combination with a xanthine oxidase inhibitor.
Study 1 and Study 2 enrolled patients with who were on a stable dose of allopurinol of at least 300 mg (or 200 mg for moderate renal impairment) that had a serum uric acid > 6.5 mg/dL and reported at least 2 gout flares in the prior 12 months. Mean years since gout diagnosis were 12 years. More than half of the patients (61%) had mild or moderate renal impairment and 19% of the patients had tophi. Patients continued their allopurinol dose and were randomized 1:1:1 to receive Lesinurad 200 mg, Lesinurad 400 mg, or placebo once daily. The average dose of allopurinol in the studies was 310 mg (range: 200-900 mg).
As shown in Table 5, Lesinurad 200 mg in combination with allopurinol was superior to allopurinol alone in lowering serum to less than 6 mg/dL at Month 6.
- Table 5: Proportion of Patients Achieving Target Serum Uric Acid Levels (< 6 mg/dL) in Two Studies of Lesinurad in Combination with Allopurinol
ZURAMPIC: Lesinurad's Brand name
The estimated effect of Lesinurad 200 mg on serum in the subgroup of patients taking thiazide diuretics at baseline was similar to the estimated effect in the overall population. The estimated effect was also similar in the subgroup of patients taking low dose aspirin at baseline.
As shown in Figure 3, reduction in average serum uric acid levels to < 6 mg/dL was noted for Lesinurad 200 mg in combination with allopurinol at the Month 1 visit and was maintained throughout the 12-month study.
- Figure 3: Mean Serum Uric Acid Levels Over Time in Pooled Clinical Studies with Lesinurad in Combination with Allopurinol (Study 1 and Study 2)
ZURAMPIC: Lesinurad's Brand name
Study 3 enrolled gout patients with measurable tophi. Patients received febuxostat 80 mg once daily for 3 weeks and then were randomized 1:1:1 to once daily doses of Lesinurad 200 mg, Lesinurad 400 mg, or placebo in combination with febuxostat. A total of 66% of patients had mild or moderate . Fifty percent of patients did not reach target serum < 5.0 mg/dL at Baseline after 3 weeks of febuxostat treatment.
As shown in Table 6, there was not statistical evidence of a difference in the proportion of patients treated with Lesinurad 200 mg in combination with febuxostat achieving a serum uric acid < 5 mg/dL by Month 6, compared with patients receiving febuxostat alone. However, the average decrease in serum uric acid with Lesinurad 200 mg in Study 3 was similar to that seen in Study 1 and Study 2 (see Figure 3 and Figure 4).
- Table 6: Proportion of Patients Achieving Target Serum Uric Acid Levels (< 5 mg/dL) in a Study with Lesinurad in Combination with Febuxostat in Tophaceous Gout
ZURAMPIC: Lesinurad's Brand name
As shown in Figure 4, reduction in average serum uric acid levels to < 5 mg/dL was noted for Lesinurad 200 mg in combination with febuxostat at the Month 1 visit and was maintained throughout the 12-month study.
- Figure 4: Mean Serum Uric Acid Levels Over Time in a Study with Lesinurad in Combination with Febuxostat in Tophaceous Gout (Study 3)
ZURAMPIC: Lesinurad's Brand name
In each of the three pivotal studies of Lesinurad in combination with a xanthine oxidase inhibitor, the rates of gout flare requiring treatment from the end of Month 6 to the end of Month 12 were not statistically different between Lesinurad 200 mg in combination with allopurinol or febuxostat compared with allopurinol or febuxostat alone. In Study 3, the proportion of patients who experienced a complete resolution of ≥ 1 target tophus was not statistically different between Lesinurad 200 mg in combination with febuxostat compared with febuxostat alone.
The estimated differences between Lesinurad and placebo in the proportions of patients achieving target serum uric levels in the renal impairment subgroups were largely consistent with the results in the overall population in the three studies. However, there were limited data in patients with eCLcr less than 45 mL/min and there was a trend toward decreasing magnitudes of effect with decreasing : in patients with eCLcr less than 45 mL/min, the estimated difference between Lesinurad 200 mg and placebo in the proportion achieving serum uric acid < 6.0 mg/dL at Month 6 was 10% (95% CI: -17, 37), as compared with 27% (95% CI: 9, 45) in the 45 to less than 60 mL/min subgroup and 30% (95% CI: 23, 37) in the 60 mL/min or greater subgroup, based on integrated data from Study 1 and Study 2.
- 0310-1475-05 Bottle of 5 tablets
- 0310-1475-30 Bottle of 30 tablets
- 0310-1475-90 Bottle of 90 tablets
- Administration
Advise patients:
- To take Lesinurad in the morning with food and water at the same time as a xanthine oxidase inhibitor, allopurinol, or febuxostat.
- Not to take Lesinurad alone and to discontinue Lesinurad if treatment with the xanthine oxidase inhibitor medication is discontinued.
- Not to take a missed dose of Lesinurad later in the day, to wait to take Lesinurad on the next day, and not to double the dose.
- To stay well hydrated (eg, 2 liters of liquid per day).
- Renal Events
Inform patients that renal events including transient increases in blood creatinine level and acute renal failure have occurred in some patients who take Lesinurad. Advise patients that periodic monitoring of blood creatinine levels are recommended.
- Gout Flares
Inform patients that gout flares may occur after initiation of Lesinurad and of the importance of taking gout flare medication to help prevent gout flares. Advise patients not to discontinue Lesinurad if a gout flare occurs during treatment.
- ↑ "Zurampic (lesinurad) Tablets, for Oral Use. Full Prescribing Information" (PDF). AstraZeneca AB, S-151 85 Sodertalje, Sweden. Retrieved 23 December 2015..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} | Lesinurad
Acute renal failure has occurred with Lesinurad and was more common when Lesinurad was given alone.
Lesinurad should be used in combination with a xanthine oxidase inhibitor.
Lesinurad is indicated in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.
- Limitations of Use
- Lesinurad is not recommended for the treatment of asymptomatic hyperuricemia.
- Lesinurad should not be used as monotherapy.
- Recommended Dosing
Lesinurad tablets are for oral use and should be co-administered with a xanthine oxidase inhibitor, including allopurinol or febuxostat.
Lesinurad is recommended at 200 mg once daily. This is also the maximum daily dose. Lesinurad should be taken by mouth, in the morning with food and water.
Lesinurad may be added when target serum uric acid levels are not achieved on the medically appropriate dose of the xanthine oxidase inhibitor alone.
Use of Lesinurad is not recommended for patients taking daily doses of allopurinol less than 300 mg (or less than 200 mg in patients with estimated creatinine clearance (eCLcr) less than 60 mL/min). Take Lesinurad at the same time as the morning dose of xanthine oxidase inhibitor. If treatment with the xanthine oxidase inhibitor is interrupted, Lesinurad should also be interrupted. Failure to follow these instructions may increase the risk of renal events.
Patients should be instructed to stay well hydrated (eg, 2 liters (68 oz) of liquid per day).
- Patients with Renal Impairment
No dose adjustment is needed in patients with mild or moderate renal impairment (eCLcr of 45 mL/min or greater). Lesinurad should not be initiated in patients with an eCLcr less than 45 mL/min. Assessment of renal function is recommended prior to initiation of Lesinurad therapy and periodically thereafter. More frequent renal function monitoring is recommended in patients with an eCLcr below 60 mL/min. Lesinurad should be discontinued when eCLcr is persistently less than 45 mL/min.
- Gout Flares
Gout flares may occur after initiation of urate lowering therapy, including Lesinurad, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Gout flare prophylaxis is recommended when starting Lesinurad, according to practice guidelines.
If a gout flare occurs during Lesinurad treatment, Lesinurad need not be discontinued. The gout flare should be managed concurrently, as appropriate for the individual patient.
- Severe renal impairment (eCLcr less than 30 mL/min), end stage renal disease, kidney transplant recipients, or patients on dialysis.
- Tumor lysis syndrome or Lesch-Nyhan syndrome.
Treatment with Lesinurad 200 mg in combination with a xanthine oxidase inhibitor was associated with an increased incidence of serum creatinine elevations, most of which were reversible. Adverse reactions related to renal function have occurred after initiating Lesinurad. A higher incidence of serum creatinine elevations and renal-related adverse reactions, including serious adverse reactions of [acute renal failure], was observed with Lesinurad 400 mg, with the highest incidence as monotherapy. Lesinurad should not be used as monotherapy.
Lesinurad should not be initiated in patients with an eCLcr less than 45 mL/min. Renal function should be evaluated prior to initiation of Lesinurad and periodically thereafter, as clinically indicated. More frequent renal function monitoring is recommended in patients with an eCLcr less than 60 mL/min or with serum creatinine elevations 1.5 to 2 times the pre-treatment value. Lesinurad treatment should be interrupted if serum creatinine is elevated to greater than 2 times the pre-treatment value. In patients who report symptoms that may indicate acute uric acid nephropathy including flank pain, nausea or vomiting, interrupt treatment and measure serum creatinine promptly. Lesinurad should not be restarted without another explanation for the serum creatinine abnormalities.
- Cardiovascular Events
In clinical trials, major adverse cardiovascular events (defined as cardiovascular deaths, non-fatal myocardial infarctions, or non-fatal strokes) were observed with Lesinurad. A causal relationship with Lesinurad has not been established.
Although other doses have been studied, the recommended dose of Lesinurad is 200 mg once daily in combination with a xanthine oxidase inhibitor.
In 3 randomized, placebo-controlled studies of Lesinurad in combination with a xanthine oxidase inhibitor (Studies 1 and 2 were with allopurinol and Study 3 was with febuxostat) for up to 12 months, a total of 511, 510, and 516 patients were treated with Lesinurad 200 mg, Lesinurad 400 mg, and placebo, respectively. The mean duration of treatment with Lesinurad was 11.2 months. The mean age of the population was 52 years (18-82), and 95% were males. At baseline, 62% of the patient population showed mild or moderate renal impairment (eCLcr less than 90 mL/min) and 79% of patients had at least one co-morbid condition including hypertension (65%), hyperlipidemia (45%), diabetes (17%), and kidney stones (12%).
- Renal Events
Lesinurad causes an increase in renal uric acid excretion, which may lead to renal events including transient increases in serum creatinine, renal-related adverse reactions, and kidney stones. These renal events occurred more frequently in patients receiving Lesinurad 400 mg, when used as monotherapy or in combination with a xanthine oxidase inhibitor.
The number of patients with serum creatinine elevations in the 12-month placebo-controlled trials in combination with a xanthine oxidase inhibitor are shown in Table 1. Most of these elevations on Lesinurad 200 mg and Lesinurad 400 mg resolved without treatment interruption (Table 1).
- Table 1: Patients with Elevated Serum Creatinine Values in the Placebo-Controlled Clinical Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)
ZURAMPIC: Lesinurad's Brand name
Renal-related adverse reactions, including blood creatinine increases and renal failure, and nephrolithiasis reported in patients receiving Lesinurad 200 mg, Lesinurad 400 mg and [placebo] in combination with a xanthine oxidase inhibitor are shown in Table 2. The incidence of reports of “blood creatinine increased” was higher with Lesinurad and was highest with Lesinurad 400 mg. Renal-related adverse reactions by baseline renal function category are shown in Table 3. Blood creatinine increased occurred more frequently in patients treated with Lesinurad in combination with a xanthine oxidase inhibitor across baseline renal function categories (Table 3).
- Table 2: Incidence of Renal-Related Adverse Reactions and Nephrolithiasis in Placebo-Controlled Clinical Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)
ZURAMPIC: Lesinurad's Brand name
- Table 3: Incidence of Renal-Related Adverse Reactions by Baseline Renal Function Category in Placebo-Controlled Clinical Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)
ZURAMPIC: Lesinurad's Brand name
Renal-related adverse reactions resulted in a similar discontinuation rate on Lesinurad 200 mg in combination with a xanthine oxidase inhibitor (1.2%) and a xanthine oxidase inhibitor alone (1%) and a higher rate on Lesinurad 400 mg in combination with a xanthine oxidase inhibitor (3.3%). Serious renal-related adverse reactions were reported in patients on Lesinurad 400 mg in combination with a xanthine oxidase inhibitor (1%) and a xanthine oxidase inhibitor alone (0.4%) and in no patients on Lesinurad 200 mg in combination with a xanthine oxidase inhibitor during the 12-month controlled period of the studies. Serious renal-related adverse reactions were reported with Lesinurad 200 mg and Lesinurad 400 mg in the uncontrolled long-term extensions.
Monotherapy: In a 6-month double-blind, placebo-controlled monotherapy study, renal failure (9.3%), blood creatinine increased (8.4%), and [nephrolithiasis] (0.9%) were reported in patients receiving Lesinurad 400 mg alone and in no patients receiving placebo. Serum creatinine elevations 1.5-fold or greater occurred in 24.3 % of patients receiving Lesinurad 400 mg and in no patients receiving placebo.
- Cardiovascular Safety
Cardiovascular events and deaths were adjudicated as Major Adverse Cardiovascular Events (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the Phase 3 randomized controlled studies of Lesinurad. In the randomized controlled studies, the numbers of patients with adjudicated MACE events (incidences per 100 patient-years of exposure) were: 3 (0.71) for [placebo], 4 (0.96) for Lesinurad 200 mg, and 8 (1.94) for Lesinurad 400 mg when used in combination with a xanthine oxidase inhibitor. Incidence rate ratios for Lesinurad 200 mg and 400 mg compared with placebo were 1.36 (95% CI: 0.23, 9.25) and 2.71 (95% CI: 0.66, 16.00), respectively.
- Other Adverse Reactions
Adverse reactions occurring in 2% or more of patients on Lesinurad 200 mg in combination with a xanthine oxidase inhibitor and at least 1% greater than that observed in patients on placebo with a xanthine oxidase inhibitor are summarized in Table 4.
- Table 4: Adverse Reactions Occurring in ≥ 2% of Lesinurad 200 mg-Treated Patients and at Least 1% Greater than Seen in Patients Receiving Placebo in Controlled Studies with Lesinurad in Combination with a Xanthine Oxidase Inhibitor (XOI)
ZURAMPIC: Lesinurad's Brand name
Lesinurad exposure is increased when Lesinurad is co-administered with inhibitors of CYP2C9, and in CYP2C9 poor metabolizers. Lesinurad should be used with caution in patients taking moderate inhibitors of CYP2C9 (eg, fluconazole, amiodarone), and in CYP2C9 poor metabolizers.
Lesinurad exposure is decreased when Lesinurad is co-administered with moderate inducers of CYP2C9 (eg, rifampin, carbamazepine), which may decrease the therapeutic effect of Lesinurad.
- CYP3A Substrates
In interaction studies conducted in healthy subjects with Lesinurad and CYP3A substrates, Lesinurad reduced the plasma concentrations of sildenafil and amlodipine. Although there was not a clinically significant interaction with atorvastatin, HMG-CoA reductase inhibitors that are sensitive CYP3A substrates may be affected. The possibility of reduced efficacy of concomitant drugs that are CYP3A substrates should be considered and their efficacy (eg, blood pressure and cholesterol levels) should be monitored.
- Epoxide Hydrolase Inhibitors
In vitro studies suggest that Lesinurad is not an inhibitor of epoxide hydrolase; however, inhibitors of epoxide hydrolase (ie, valproic acid) may interfere with metabolism of Lesinurad. Lesinurad should not be administered with inhibitors of epoxide hydrolase.
- Hormonal Contraceptives
Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Lesinurad is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Lesinurad.
- Aspirin
Aspirin at doses higher than 325 mg per day may decrease the efficacy of Lesinurad in combination with allopurinol. Aspirin at doses of 325 mg or less per day (ie, for cardiovascular protection) does not decrease the efficacy of Lesinurad and can be coadministered with Lesinurad.
There are no available human data on use of Lesinurad in pregnant women to inform a drug-associated risk. No teratogenicity or effects on fetal development were observed in embryo-fetal development studies with oral administration of Lesinurad to pregnant rats and rabbits during organogenesis at doses that produced maternal exposures up to approximately 45 and 10 times, respectively, the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed in a pre- and postnatal development study with administration of Lesinurad to pregnant rats from organogenesis through lactation at a dose approximately 5 times the MRHD.
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.
- Data
- Animal Data
In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-17, Lesinurad was not teratogenic and did not affect fetal development or survival at exposures up to approximately 45 times the MRHD (on an AUC basis at maternal oral doses up to 300 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-20, Lesinurad was not teratogenic and did not affect fetal development at exposures up to approximately 10 times the MRHD (on an AUC basis at maternal oral doses up to 75 mg/kg/day). Severe maternal toxicity, including mortality, was observed in rats and rabbits at exposures equal to or greater than approximately 45 and 4 times the MRHD (on an AUC basis at maternal oral doses of 300 mg/kg/day in rats and 25 mg/kg/day and higher in rabbits), respectively.
In a pre- and postnatal development study in pregnant female rats dosed from gestation day 7 through lactation day 20, Lesinurad had no effects on delivery or growth and development of offspring at a dose approximately 5 times the MRHD (on a mg/m2 basis at a maternal dose oral dose of 100 mg/kg/day). In rats, plasma and milk concentrations of Lesinurad were approximately equal.
The efficacy and safety of Lesinurad were evaluated in studies that included gout patients with mild and moderate renal impairment. There were no clear differences in safety and effectiveness of Lesinurad in patients with mild renal impairment compared to patients with normal renal function and no dose adjustment is recommended.
Across all Lesinurad and placebo treatment groups, patients with moderate renal impairment had a higher occurrence of renal related adverse reactions compared to patients with mild renal impairment or normal renal function. The experience with Lesinurad in patients with an eCLcr less than 45 mL/min is limited and there was a trend toward lesser efficacy. Lesinurad should not be initiated in patients with an eCLcr less than 45 mL/min. No dose adjustment is recommended in patients with an eCLcr 45 to less than 60 mL/min, however, more frequent renal function monitoring is recommended. Lesinurad should be discontinued when eCLcr is persistently less than 45 mL/min.
The efficacy and safety of Lesinurad have not been evaluated in gout patients with severe renal impairment (eCLcr less than 30 mL/min), with end-stage renal disease, or receiving dialysis. Lesinurad is not expected to be effective in these patient populations.
Lesinurad is available as blue film-coated tablets for oral administration containing 200 mg Lesinurad and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, hypromellose 2910, crospovidone, and magnesium stearate. Lesinurad tablets are coated with Opadry blue.
In gout patients, Lesinurad lowered serum uric acid levels and increased renal clearance and fractional excretion of uric acid. Following single and multiple oral doses of Lesinurad to gout patients, dose-dependent decreases in serum uric acid levels and increases in urinary uric acid excretion were observed.
- Effect on Cardiac Repolarization
The effect of Lesinurad on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and gout patients. Lesinurad at doses up to 1600 mg did not demonstrate an effect on the QTc interval.
- Absorption
The absolute bioavailability of Lesinurad is approximately 100%. Lesinurad is rapidly absorbed after oral administration. Following administration of a single dose of a Lesinurad tablet in either fed or fasted state, maximum plasma concentrations (Cmax) were attained within 1 to 4 hours. Cmax and AUC exposures of Lesinurad increased proportionally with single doses of Lesinurad from 5 to 1200 mg.
Administration with a high-fat meal (800 to 1000 calories with 50% of calories being derived from fat content) decreases Lesinurad Cmax by up to 18% but does not alter AUC as compared with fasted state. In clinical trials, Lesinurad was administered with food.
- Distribution
Lesinurad is extensively bound to proteins in plasma (greater than 98%), mainly to albumin. Plasma protein binding of Lesinurad is not meaningfully altered in patients with renal or hepatic impairment. The mean steady state volume of distribution of Lesinurad was approximately 20 L following intravenous dosing of Lesinurad.
- Elimination
The elimination half-life (t½) of Lesinurad was approximately 5 hours. Lesinurad does not accumulate following multiple doses. The total body clearance is approximately 6 L/hr.
- Metabolism
Lesinurad undergoes oxidative metabolism mainly via the polymorphic cytochrome P450 CYP2C9 enzyme. Plasma exposure of metabolites is minimal (< 10% of unchanged Lesinurad). Metabolites are not known to contribute to the uric acid lowering effects of Lesinurad. A transient oxide metabolite is rapidly eliminated by microsomal epoxide hydrolase in the liver and not detected in [plasma].
Patients who are CYP2C9 poor metabolizers are deficient in CYP2C9 enzyme activity. A cross-study pharmacogenomic analysis assessed the association between CYP2C9 polymorphism and Lesinurad exposure in patients receiving single or multiple doses of Lesinurad at 200 mg, 400 mg or 600 mg. At the 400 mg dose, Lesinurad exposure was approximately 1.8-fold higher in CYP2C9 poor metabolizers (i.e., subjects with CYP2C9 *2/*2 [N=1], and *3/*3 [N=1] genotype) compared to CYP2C9 extensive metabolizers (i.e., CYP2C9 *1/*1 [N=41] genotype). Use with caution in CYP2C9 poor metabolizers, and in patients taking moderate inhibitors of CYP2C9.
- Excretion
Within 7 days following single dosing of radiolabeled Lesinurad, 63% of administered radioactive dose was recovered in urine and 32% of administered radioactive dose was recovered in feces. Most of the radioactivity recovered in urine (> 60% of dose) occurred in the first 24 hours. Unchanged Lesinurad in urine accounted for approximately 30% of the dose.
- Special Populations
- Renal Impairment
Two dedicated studies were performed to assess PK in renal impairment (classified using the Cockcroft-Gault formula) subjects. In both studies, Cmax was comparable in renal impairment subjects compared to healthy subjects.
Study 1 was a single-dose, open-label study evaluating the pharmacokinetics of Lesinurad 200 mg in subjects with mild (eCLcr 60 to less than 90 mL/min) and moderate renal impairment (eCLcr 30 to less than 60 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6; eCLcr greater than or equal to 90 mL/min), plasma AUC of Lesinurad was increased by approximately 30% and 73% in subjects with mild (N=8) and moderate (N=10) renal impairment, respectively.
Study 2 was a single-dose, open-label study evaluating the pharmacokinetics of Lesinurad 400 mg in subjects with moderate and severe renal impairment (eCLcr less than 30 mL/min) compared to healthy subjects. Compared to healthy subjects (N=6), plasma AUC of Lesinurad was increased by approximately 50% and 113% in subjects with moderate (N=6) and severe (N=6) renal impairment, respectively.
- Hepatic Impairment
Following administration of a single dose of Lesinurad at 400 mg in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, Lesinurad Cmax was comparable and Lesinurad AUC was 7% and 33% higher, respectively, compared to individuals with normal [hepatic function]. There is no clinical experience in patients with severe (Child-Pugh class C) hepatic impairment.
- Effect of Age, Gender, Race and Ethnicity on Pharmacokinetics
Based on the population pharmacokinetic analysis, age, gender, race and ethnicity do not have a clinically meaningful effect on the pharmacokinetics of Lesinurad.
- Pediatric Use
Studies characterizing the pharmacokinetics of Lesinurad in pediatric patients have not been conducted.
- Drug-Drug Interactions
- Effects of Other Drugs on Lesinurad
Based on in vitro data, Lesinurad is a substrate for CYP2C9, OAT1 and OAT3; however, no clinical studies have been conducted with OAT1 and OAT3 inhibitors (eg, probenecid).
Figure 1 shows the effect of co-administered drugs on the pharmacokinetics of Lesinurad.
- Figure 1: Effect of Co-administered Drugs on the Pharmacokinetics of Lesinurad
- Effects of Lesinurad on Other Drugs
Lesinurad is a weak inducer of CYP3A and has no relevant effect on any other CYP enzyme for induction (CYP1A2, CYP2C8, CYP2C9, CYP2B6, or CYP2C19) or inhibition (CYP1A2, CYP2B6, CYP2D6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4).
Based on in vitro studies, Lesinurad is an inhibitor of OATP1B1, OCT1, OAT1, and OAT3; however, Lesinurad is not an in vivo inhibitor of these transporters. In vivo drug interaction studies indicate that Lesinurad does not decrease the renal clearance of furosemide (substrate of OAT1/3), or affect the exposure of atorvastatin (substrate of OATP1B1) or metformin (substrate of OCT1). Based on in vitro studies, Lesinurad has no relevant effect on P-glycoprotein.
Figure 2 shows the effect of Lesinurad on co-administered drugs.
- Figure 2: Effect of Lesinurad on the Pharmacokinetics of Co-administered Drugs
The carcinogenic potential of Lesinurad was evaluated in Sprague-Dawley rats and TgRasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received Lesinurad for 91 to 100 weeks at oral doses up to 200 mg/kg/day (approximately 35 times the MRHD on an AUC basis). No evidence of tumorigenicity was observed in TgRasH2 mice that received Lesinurad for 26 weeks at oral doses up to 125 and 250 mg/kg/day in male and female mice, respectively.
Lesinurad tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo rat bone marrow micronucleus assay.
Fertility and reproductive performance were unaffected in male or female rats that received Lesinurad at oral doses up to 300 mg/kg/day (approximately 15 times the MRHD on a mg/m2 basis).
The efficacy of Lesinurad 200 mg and 400 mg once daily was studied in 3 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with hyperuricemia and gout in combination with a xanthine oxidase inhibitor, allopurinol or febuxostat. All studies were of 12 months duration and patients received prophylaxis for gout flares with colchicine or non-steroidal anti-inflammatory drugs (NSAIDs) during the first 5 months of Lesinurad treatment.
Although other doses have been studied, the recommended dose of Lesinurad is 200 mg once daily in combination with a xanthine oxidase inhibitor.
Study 1 and Study 2 enrolled patients with [gout] who were on a stable dose of allopurinol of at least 300 mg (or 200 mg for moderate renal impairment) that had a serum uric acid > 6.5 mg/dL and reported at least 2 gout flares in the prior 12 months. Mean years since gout diagnosis were 12 years. More than half of the patients (61%) had mild or moderate renal impairment and 19% of the patients had tophi. Patients continued their allopurinol dose and were randomized 1:1:1 to receive Lesinurad 200 mg, Lesinurad 400 mg, or placebo once daily. The average dose of allopurinol in the studies was 310 mg (range: 200-900 mg).
As shown in Table 5, Lesinurad 200 mg in combination with allopurinol was superior to allopurinol alone in lowering serum [uric acid] to less than 6 mg/dL at Month 6.
- Table 5: Proportion of Patients Achieving Target Serum Uric Acid Levels (< 6 mg/dL) in Two Studies of Lesinurad in Combination with Allopurinol
ZURAMPIC: Lesinurad's Brand name
The estimated effect of Lesinurad 200 mg on serum [uric acid] in the subgroup of patients taking thiazide diuretics at baseline was similar to the estimated effect in the overall population. The estimated effect was also similar in the subgroup of patients taking low dose aspirin at baseline.
As shown in Figure 3, reduction in average serum uric acid levels to < 6 mg/dL was noted for Lesinurad 200 mg in combination with allopurinol at the Month 1 visit and was maintained throughout the 12-month study.
- Figure 3: Mean Serum Uric Acid Levels Over Time in Pooled Clinical Studies with Lesinurad in Combination with Allopurinol (Study 1 and Study 2)
ZURAMPIC: Lesinurad's Brand name
Study 3 enrolled gout patients with measurable tophi. Patients received febuxostat 80 mg once daily for 3 weeks and then were randomized 1:1:1 to once daily doses of Lesinurad 200 mg, Lesinurad 400 mg, or placebo in combination with febuxostat. A total of 66% of patients had mild or moderate [renal impairment]. Fifty percent of patients did not reach target serum [uric acid] < 5.0 mg/dL at Baseline after 3 weeks of febuxostat treatment.
As shown in Table 6, there was not statistical evidence of a difference in the proportion of patients treated with Lesinurad 200 mg in combination with febuxostat achieving a serum uric acid < 5 mg/dL by Month 6, compared with patients receiving febuxostat alone. However, the average decrease in serum uric acid with Lesinurad 200 mg in Study 3 was similar to that seen in Study 1 and Study 2 (see Figure 3 and Figure 4).
- Table 6: Proportion of Patients Achieving Target Serum Uric Acid Levels (< 5 mg/dL) in a Study with Lesinurad in Combination with Febuxostat in Tophaceous Gout
ZURAMPIC: Lesinurad's Brand name
As shown in Figure 4, reduction in average serum uric acid levels to < 5 mg/dL was noted for Lesinurad 200 mg in combination with febuxostat at the Month 1 visit and was maintained throughout the 12-month study.
- Figure 4: Mean Serum Uric Acid Levels Over Time in a Study with Lesinurad in Combination with Febuxostat in Tophaceous Gout (Study 3)
ZURAMPIC: Lesinurad's Brand name
In each of the three pivotal studies of Lesinurad in combination with a xanthine oxidase inhibitor, the rates of gout flare requiring treatment from the end of Month 6 to the end of Month 12 were not statistically different between Lesinurad 200 mg in combination with allopurinol or febuxostat compared with allopurinol or febuxostat alone. In Study 3, the proportion of patients who experienced a complete resolution of ≥ 1 target tophus was not statistically different between Lesinurad 200 mg in combination with febuxostat compared with febuxostat alone.
The estimated differences between Lesinurad and placebo in the proportions of patients achieving target serum uric levels in the renal impairment subgroups were largely consistent with the results in the overall population in the three studies. However, there were limited data in patients with eCLcr less than 45 mL/min and there was a trend toward decreasing magnitudes of effect with decreasing [renal function]: in patients with eCLcr less than 45 mL/min, the estimated difference between Lesinurad 200 mg and placebo in the proportion achieving serum uric acid < 6.0 mg/dL at Month 6 was 10% (95% CI: -17, 37), as compared with 27% (95% CI: 9, 45) in the 45 to less than 60 mL/min subgroup and 30% (95% CI: 23, 37) in the 60 mL/min or greater subgroup, based on integrated data from Study 1 and Study 2.
- 0310-1475-05 Bottle of 5 tablets
- 0310-1475-30 Bottle of 30 tablets
- 0310-1475-90 Bottle of 90 tablets
- Administration
Advise patients:
- To take Lesinurad in the morning with food and water at the same time as a xanthine oxidase inhibitor, allopurinol, or febuxostat.
- Not to take Lesinurad alone and to discontinue Lesinurad if treatment with the xanthine oxidase inhibitor medication is discontinued.
- Not to take a missed dose of Lesinurad later in the day, to wait to take Lesinurad on the next day, and not to double the dose.
- To stay well hydrated (eg, 2 liters [68 oz] of liquid per day).
- Renal Events
Inform patients that renal events including transient increases in blood creatinine level and acute renal failure have occurred in some patients who take Lesinurad. Advise patients that periodic monitoring of blood creatinine levels are recommended.
- Gout Flares
Inform patients that gout flares may occur after initiation of Lesinurad and of the importance of taking gout flare [prophylaxis] medication to help prevent gout flares. Advise patients not to discontinue Lesinurad if a gout flare occurs during treatment.
- ↑ "Zurampic (lesinurad) Tablets, for Oral Use. Full Prescribing Information" (PDF). AstraZeneca AB, S-151 85 Sodertalje, Sweden. Retrieved 23 December 2015..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/Lesinurad | |
2591c7534db97fc43b0c526e3ff36d2e52a7ba8b | wikidoc | Leucocyte | Leucocyte
Leukocytosis is an elevation of the white blood cell count (the leukocyte count) above the normal range.
Although it may be a sign of illness, leukocytosis in-and-of itself is not a disorder, nor is it a disease. It is simply a laboratory finding.
A leukocyte count above 25 to 30 x 109/L is termed a leukemoid reaction, which is the reaction of a healthy bone marrow to extreme stress, trauma, or infection. (It is different from leukemia and from leukoerythroblastosis, in which immature blood cells are present in peripheral blood.)
# Leukocyte counts
The normal adult human leukocyte count in peripheral blood is 4.4-10.8 x 109/L. A white blood cell count of 11.0 x 109/L or more suggests leukocytosis.
# Causes
Leukocytosis is very common in acutely ill patients. It occurs in response to a wide variety of conditions, including viral, bacterial, fungal, or parasitic infection, cancer, hemorrhage, and exposure to certain medications or chemicals including steroids. Leukocytosis can also be the first indication of neoplastic growth of leukocytes.
For lung diseases such as pneumonia and tuberculosis, WBC count are very important for the diagnosis of the disease,as leucocytosis is usually present.
The mechanism that causes leukocytosis can be of several forms: an increased release of leukocytes from bone marrow storage pools, decreased margination of leukocytes onto vessel walls, decreased extravasation of leukocytes from the vessels into tissues, or an increase in number of precursor cells in the marrow.
# Classification
Leukocytosis can be subcategorized by the type of white blood cell that is increased in number. Leukocytosis in which neutrophil count is elevated is neutrophilia; leukocytosis in which lymphocyte count is elevated is lymphocytosis; leukocytosis in which monocyte count is elevated is monocytosis; and leukocytosis in which eosinophil count is elevated is eosinophilia.
de:Leukozytose | Leucocyte
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Leukocytosis is an elevation of the white blood cell count (the leukocyte count) above the normal range.
Although it may be a sign of illness, leukocytosis in-and-of itself is not a disorder, nor is it a disease. It is simply a laboratory finding.
A leukocyte count above 25 to 30 x 109/L is termed a leukemoid reaction, which is the reaction of a healthy bone marrow to extreme stress, trauma, or infection. (It is different from leukemia and from leukoerythroblastosis, in which immature blood cells are present in peripheral blood.)
# Leukocyte counts
The normal adult human leukocyte count in peripheral blood is 4.4-10.8 x 109/L. A white blood cell count of 11.0 x 109/L or more suggests leukocytosis.
# Causes
Leukocytosis is very common in acutely ill patients. It occurs in response to a wide variety of conditions, including viral, bacterial, fungal, or parasitic infection, cancer, hemorrhage, and exposure to certain medications or chemicals including steroids. Leukocytosis can also be the first indication of neoplastic growth of leukocytes.
For lung diseases such as pneumonia and tuberculosis, WBC count are very important for the diagnosis of the disease,as leucocytosis is usually present.
The mechanism that causes leukocytosis can be of several forms: an increased release of leukocytes from bone marrow storage pools, decreased margination of leukocytes onto vessel walls, decreased extravasation of leukocytes from the vessels into tissues, or an increase in number of precursor cells in the marrow.
# Classification
Leukocytosis can be subcategorized by the type of white blood cell that is increased in number. Leukocytosis in which neutrophil count is elevated is neutrophilia; leukocytosis in which lymphocyte count is elevated is lymphocytosis; leukocytosis in which monocyte count is elevated is monocytosis; and leukocytosis in which eosinophil count is elevated is eosinophilia.
Template:Hematology
de:Leukozytose
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Leucocyte | |
ee8254bbdc358972024d04b11b7c46cb1340592a | wikidoc | Lewy body | Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells. They are identified under the microscope when histology is performed on the brain.
Lewy bodies appear as spherical masses that displace other cell components. There are two morphological types: classical (brain stem) Lewy bodies and cortical Lewy bodies. A classical Lewy body is an eosinophilic cytoplasmic inclusion that consists of a dense core surrounded by a halo of 10-nm wide radiating fibrils, the primary structural component of which is alpha-synucleinL. In contrast, a cortical Lewy body is less well-defined and lacks the halo. Nonetheless, it is still made up of alpha-synuclein fibrils.
# Cell biology
A Lewy body is composed of the protein alpha-synuclein associated with other proteins such as ubiquitin, neurofilament protein, and alpha B crystallin. It is believed that Lewy bodies represent an aggresome response in the cell.
# Associated diseases
The main disease associated with the presence of Lewy bodies is Parkinson's disease. Lewy bodies are also present in neurons in dementia with Lewy bodies and the Lewy body variant of Alzheimer's disease, as well as Hallervorden-Spatz syndrome.
Inclusions composed of alpha synuclein, different to Lewy bodies, can be found in glial cells in multiple system atrophy. These are termed glial cytoplasmic inclusions. Multiple system atrophy can be clinically confused with Parkinson's disease.
# History
Lewy bodies were first seen and linked to Parkinson's disease ("paralysis agitans") in 1912 by the neurologist Frederic Lewy (1885-1950). | Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells. They are identified under the microscope when histology is performed on the brain.
Lewy bodies appear as spherical masses that displace other cell components. There are two morphological types: classical (brain stem) Lewy bodies and cortical Lewy bodies. A classical Lewy body is an eosinophilic cytoplasmic inclusion that consists of a dense core surrounded by a halo of 10-nm wide radiating fibrils, the primary structural component of which is alpha-synucleinL. In contrast, a cortical Lewy body is less well-defined and lacks the halo. Nonetheless, it is still made up of alpha-synuclein fibrils.
# Cell biology
A Lewy body is composed of the protein alpha-synuclein associated with other proteins such as ubiquitin, neurofilament protein, and alpha B crystallin. It is believed that Lewy bodies represent an aggresome response in the cell.
# Associated diseases
The main disease associated with the presence of Lewy bodies is Parkinson's disease. Lewy bodies are also present in neurons in dementia with Lewy bodies and the Lewy body variant of Alzheimer's disease, as well as Hallervorden-Spatz syndrome.
Inclusions composed of alpha synuclein, different to Lewy bodies, can be found in glial cells in multiple system atrophy. These are termed glial cytoplasmic inclusions. Multiple system atrophy can be clinically confused with Parkinson's disease.
# History
Lewy bodies were first seen and linked to Parkinson's disease ("paralysis agitans") in 1912 by the neurologist Frederic Lewy (1885-1950). | https://www.wikidoc.org/index.php/Lewy_bodies | |
8d0fe18622c7b7285d7a40df1bc4bf9150c8ccea | wikidoc | Lie bumps | Lie bumps
# Overview
Lie bumps (transient lingual papillitis
and fungiform papillary glossitis
) are painful, hypertrophic, red and white papillae on the tongue.
# Description
Lie bumps are relatively common — a 1996 study found that 56% of the respondents to their survey reported these lesions. The most common presentation of this was found to be in young women, involving one or several fungiform papillae. The symptoms last several days and resolve on their own with no treatment.
# Cause
The name "lie bumps" is a result of a myth stating that telling a lie would cause one.
Lie bumps are often attributed to irritation of the tongue's papillae (taste buds) by sharp food or teeth. However, very little has been written about this condition in scientific articles or textbooks and scientific studies have failed to produce a definite cause. Possible causes include: "stress, gastrointestinal upset, menstruation, acidic or sour food, and local trauma" (direct physical irritation) of the tongue.
# Treatment
There is no specific treatment for this problem, other than using ice or numbing medicines to ease the pain. Anecdotal remedies include gargling with salt water and direct application of hydrogen peroxide. | Lie bumps
# Overview
Lie bumps (transient lingual papillitis[1]
and fungiform papillary glossitis[2]
) are painful, hypertrophic, red and white papillae on the tongue.[1]
# Description
Lie bumps are relatively common — a 1996 study found that 56% of the respondents to their survey reported these lesions.[1] The most common presentation of this was found to be in young women, involving one or several fungiform papillae.[1] The symptoms last several days and resolve on their own with no treatment.[1]
# Cause
The name "lie bumps" is a result of a myth stating that telling a lie would cause one.[3]
Lie bumps are often attributed to irritation of the tongue's papillae (taste buds) by sharp food or teeth.[3] However, very little has been written about this condition in scientific articles or textbooks and scientific studies have failed to produce a definite cause.[1] Possible causes include: "stress, gastrointestinal upset, menstruation, acidic or sour food, and local trauma" (direct physical irritation) of the tongue.[1]
# Treatment
There is no specific treatment for this problem, other than using ice or numbing medicines to ease the pain. [4] Anecdotal remedies include gargling with salt water and direct application of hydrogen peroxide.[not in citation given] | https://www.wikidoc.org/index.php/Lie_Bumps | |
55ea7f293534b039e32a83520d88073f5fe1604d | wikidoc | Limerence | Limerence
Limerence refers to an involuntary cognitive and emotional state of intense romantic desire for another person. The term was coined by psychologist Dorothy Tennov to describe the ultimate, near-obsessional form of romantic love.
# Overview
The concept is an attempt at a scientific study into the nature of romantic love. Limerence can often be what is meant when one expresses having intense feelings of attachment and preoccupations with the love object.
According to Tennov, there are at least two types of love: limerence, what she calls "loving attachment", and "loving affection," the bond that exists between an individual and his or her parents and children.
Limerence is characterized by intrusive thinking and pronounced sensitivity to external events that reflect the disposition of the limerent object towards the individual. It can be experienced as intense joy or as extreme despair, depending on whether the feelings are reciprocated.
Unlike English, many other languages have traditional terms to denote limerence, like the German Verliebtheit, Scandinavian forelskelse, Brazilian Portuguese paixonite, or Russian влюблённость (vlyublyonnost); these expressions may roughly be translated to “fallen-in-love-ness”.
# Origins
The concept of limerence first originated in Tennov's research in the mid-1960s. She interviewed over 500 people on the topic of love. Tennov coined the term "limerence" in 1977, publishing it in her 1979 book "Love and Limerence: The Experience of Being in Love".
Tennov differentiates between limerence and other emotions by asserting that love involves concern for the other person's welfare and feeling. While limerence does not require it, those concerns may certainly be incorporated.
Affection and fondness exist only as a disposition towards another person, irrespective of whether those feelings are reciprocated, whereas limerence demands return. Physical contact with the object is neither essential nor sufficient to an individual experiencing limerence, unlike one experiencing sexual attraction.
New Relationship Energy (NRE) thrives on open communication and known mutuality of feelings and is mostly seen as a positive bonding experience, while limerence can dissipate once reciprocity is established, and is characterized by uncertainty and anxiety.
New Relationship Energy also carries implications of active contrast with relationships in different stages, while limerence does not. Limerence can be longer-lived than transient forms of romantic feelings such as infatuation and puppy love, enduring for months, years and even a lifetime in the absence of knowledge about reciprocity.
# Components
Limerence involves intrusive thinking about the limerent object. Other characteristics include acute longing for reciprocation, fear of rejection, and unsettling shyness in the limerent object's presence. In cases of unrequited limerence, transient relief may be found by vividly imagining reciprocation from the limerent object.
Feelings of limerence can be intensified through adversity, obstacles, or distance. A limerent person may have acute sensitivity to any act, thought, or condition that can be interpreted favorably. This may include a tendency to devise, fabricate, or invent "reasonable" explanations for why neutral actions are a sign of hidden passion in the limerent object.
A person experiencing limerence has a general intensity of feeling that leaves other concerns in the background. In their thoughts, a limerent person tends to emphasize what is admirable in the limerent object and to avoid any negative or problematic attributes.
## Intrusive thinking
During the height of limerence, thoughts of the limerent object (or person) are both persistent, involuntary and intrusive. Limerence is first and foremost a condition of cognitive obsession. All events, associations, stimuli, and experiences return thoughts to the limerent object with unnerving consistency.
The constant thoughts about the limerent object define all other experiences. If a certain thought has no previous connection with the limerent object, immediately one is made. Limerent fantasy is unsatisfactory unless rooted in reality, because the fantasizer may want the fantasy to seem realistic and somewhat possible.
Fantasies that are concerned with farfetched ideas are usually dropped by the fantasizer. Sometimes it is retrospective; actual events are replayed from memory with great vividness. This form predominates when what is viewed as evidence of possible reciprocation can be re-experienced (a kind of selective or revisionist history).
Otherwise, the long fantasy is anticipatory; it begins in the everyday world and climaxes at the attainment of the limerent goal. A limerent fantasy can also involve an unusual, often tragic, event.
The long fantasies form bridges between the limerent's ordinary life and that intensely desired ecstatic moment. The duration and complexity of a fantasy depend on the availability of time and freedom from distractions. The bliss of the imagined moment of consummation is greater when events imagined to precede it are possible.
In fact they often represent grave departures from the probable. Not always is it entirely pleasant, and when rejection seems likely the thoughts focus on despair, sometimes to the point of suicide. The pleasantness or unpleasantness of the state seems almost unrelated to the intensity of the reaction.
Although the direction of feeling, i.e. happy versus unhappy, shifts rapidly, the intensity of intrusive and involuntary thinking alters less rapidly, and alters only in response to an accumulation of experiences with the particular limerent object.
For example, fantasies may include "rescuing" the limerent object from a situation of peril and being rewarded in some way implying reciprocation. Another example of limerent fantasy would include a limerent object proclaiming love in a climactic fashion, such as in dying moments.
Fantasies also are occasionally dreamed by the one experiencing limerence. Dreams give out strong emotion and happiness when experienced, but often end with despair when the subject awakens. Dreams can reawaken strong feelings toward the limerent object after the feelings have declined.
## Fear of rejection
Along with the emphasis on positive qualities perceived in the limerent object, and preoccupation with the hope for return of feelings, there is a fear that limerence will be met by the very opposite of reciprocation: rejection. Considerable self-doubt and uncertainty is experienced and it causes pain, but also enhances desire to a certain extent.
However in most cases, this is what helps to eventually destroy the limerence if a suitably long period of time has passed without reciprocation. Typically, limerence lasts about 3 years, but, as previously mentioned, can last decades or even a lifetime.
Limerent fear of rejection is usually confined to shyness in the presence of the limerent object, but it can also spread to situations involving other potential limerent objects, though generally it does not affect other spheres of life.
Although it appears that limerence blossoms under some forms of adversity, extreme caution and shyness may prevent a relationship from occurring, even when both parties are interested. This results from a fear of exposing one's undesirable characteristics to the limerent object.
## Hope
Limerence develops and is sustained when there is a certain balance of hope and uncertainty. The base for limerent hope is not in objective reality but reality as it is perceived. The inclination is to sift through nuances of speech and subtleties of behavior for evidence of limerent hope. "Little things" are noticed and endlessly analyzed for meaning.
The belief that the limerent object does not and will not reciprocate can only come about with great difficulty. Limerence can be carried quite far before acknowledgment of rejection is genuine, especially if it has not been addressed openly by the object of limerence.
Excessive concern over trivia may not be entirely unfounded. Body language can indicate a return of feeling. What the limerent object said and did is recalled with vividness, mostly due to the release of certain 'romance chemicals'. Alternative meanings of those behaviors recalled are searched out.
Each word and gesture is permanently available for review, especially those which can be interpreted as evidence in favor of "return of feeling." When objects, people, places or situations are encountered with the limerent object, they are vividly remembered, especially if the limerent object 'interacted' with them in some way.
## Physical effects
The physiological correlations of limerence are heart palpitations, trembling, pallor, flushing, pupil dilation and general weakness. Awkwardness, stuttering, shyness, and confusion predominate at the behavioral level.
There is apprehension, nervousness, and anxiety due to terrible worry that any action may bring about disaster. Many of the commonly associated physiological reactions are the result of the limerent fear. Some people however may find that these effects come most strongly either immediately at or some time after contact with the object of limerence, and this is accompanied with an acute feeling of ecstasy or despair, depending on the turn of events beforehand.
The super-sensitivity that is heightened by fear of rejection can get in the way of interpreting the limerent object's body language and lead to inaction and wasted opportunities. Body signals may be emitted that confuse and interfere with attaining the limerent object.
A condition of sustained alertness, a heightening of awareness and an enormous fund of energy to deploy in pursuit of the limerent aim is developed. The sensation of limerence is felt in the midpoint of the chest, or in some cases in the abdominal region. This can be interpreted as ecstasy at times of mutuality, but its presence is most noticeable during despair at times of rejection.
## Game-playing
No matter how intensely reciprocation is desired it cannot simply be requested. To ask is to risk premature self-disclosure. The interplay is delicate, with the reactions of each person inextricably bound to the behavior of the other - or at least so in the mind of the Limerant.
Progression toward ecstatic mutuality may not involve externally created difficulties but feinting and parrying, minor deceptions, and falsehoods. The uncertainty required by the limerent reaction may often be merely a matter of perception. Despite ideals and philosophy, a process begins that bears unquestionable similarity to a game. The prize is not trifling: reciprocation produces ecstasy.
Whether it will be won, whether it will be shared, and what the final outcome may be depends on the effectiveness of actions and those of the limerent object; indeed on skill. Deviations from straightforward honesty become essential limerent strategies.
Fears lead to proceeding with a caution that will hopefully protect from disaster. Reason to hope combined with reason to doubt keeps passion at fever pitch and too-ready limerent availability cools. Open declaration of true feelings may stop the process.
Limerent uncertainty as well as projection can be viewed as the consequence of the limerent inclination to hide feelings. Because one of the invariant characteristics of limerence is extreme emotional dependency on the limerent object’s behavior, the actual course of limerence must depend on the actions and reactions of both people.
Uncertainty increases limerence; increased limerence dictates altered action, which serves to increase or decrease limerence in the other according to the interpretation given. The interplay is delicate if the relationship hovers near mutuality; a subtle imbalance, constantly shifting, appears to maintain it.
In most cases each person knows who is more limerent, but this is not always so. In most cases the limerents may believe a certain viewpoint, but the constant uncertainty means they are doubting or questioning themselves for most of the time regarding the other person. This can vary widely between different people.
## Sexuality
Awareness of physical attraction plays a key role in the development of limerence, but is not enough to satisfy the limerent desire, and is almost never the main focus -- instead, the limerent focuses on what could be defined as the "beneficial attributes".
A person, to become the limerent object, must be a potential sex partner. Limerence can be intensified after a sexual relationship has begun, and with more intense limerence there is greater desire for sexual contact. However, while sexual surrender once indicated the end of uncertainty in the limerent object, in modern times this is not necessarily the case.
Sexual fantasies are distinct from limerent ones. Limerent fantasy is rooted in reality and is intrusive rather than voluntary. Sexual fantasies are under more or less voluntary control and may also involve strangers, imaginary individuals, and situations that could not take place.
People can become aroused by the thought of sexual partners, acts, and situations that are not truly desired, whereas every detail of the limerent fantasy is passionately desired actually to take place. Limerence sometimes increases sexual interest in other partners when the limerent object is unreceptive or unavailable, such as when married people find sex with their spouses more pleasurable when they become limerent over someone else.
Limerent anxieties and shyness may interfere with sexual functioning. The continual concern to appear at the very best is not always compatible with the immodest behaviors and poses that arise in sexual situations.
# Limerent reaction
The limerent reaction is a composite reaction; that is, it actually describes a unique series of reactions. These reactions occur only where misperceptions meet adversity in the context of a romance. Perhaps because of this unique specificity, limerent reactions can be uniquely quantified and predicted according to the schema described below.
Involvement increases if obstacles are externally imposed or if the limerent object’s feelings are doubted. Only if the limerent object were to be revealed as highly undesirable might limerence subside. The presence of some degree of doubt causes the intensity of the feelings to rise further. The stage is reached at which the reaction is virtually impossible to dislodge.
This adversity may be superficial or deep, internal or external, so that an individual may generate deep adversity where none exists. Also "romance," as it were, need not be present in any genuine way for a limerent reaction to proceed.
The course of limerence results in a more intrusive thinking pattern. This thinking pattern is an expectant and often joyous period with the initial focusing on the limerent object’s admirable qualities; crystallization. Then, under appropriate conditions of hope and uncertainty, the limerence intensifies further.
With evidence of reciprocation from the limerent object, a state of extreme pleasure, even euphoria, is enjoyed. Thoughts are mainly occupied with considering and reconsidering what is attractive in the limerent object, replaying whatever events may have thus far transpired with the limerent object, and appreciating personal qualities which are perceived as possibly having sparked interest in the limerent object.
At peak crystallization, almost all waking thoughts revolve around the limerent object. After this peak, the feelings eventually decline.
Fantasies are preferred to virtually any other activity with the exception of activities that are believed to help obtain the limerent object, and activities that involve actually being in the presence of the limerent object. The motivation to attain a "relationship" continues to intensify so long as a proper mix of hope and uncertainty exist.
Tennov estimates, based on both questionnaire and interview data, that the average limerent reaction duration, from the moment of initiation until a feeling of neutrality is reached, is approximately three years. The extremes may be as brief as a few weeks or several years. When limerence is brief, maximum intensity may not have been attained.
Limerence generally lasts between 18 months and three years, but further studies on unrequited limerence have suggested longer durations.
# Bond varieties
Once the limerent reaction has initiated, one of three varieties of bonds may form, defined over a set duration of time, in relation to the experience or non-experience of limerence. The constitution of these bonds may vary over the course of the relationship, in ways that may either increase or decrease the intensity of the limerence.
The basis and interesting characteristic of this delineation made by Tennov, is that based on her research and interviews with people, all human bonded relationships can be divided into three varieties being defined by the amount of limerence or non-limerence each partner contributes to the relationship.
With an affectional bond, neither partner is limerent. With a Limerent-Nonlimerent bond, one partner is limerent. In a Limerent-Limerent bond, both partners are limerent.
Affectional bonding characterize those affectionate sexual relationships where neither partner is limerent; couples tend to be in love, but do not report continuous and unwanted intrusive thinking, feeling intense need for exclusivity, or define their goals in terms of reciprocity. These types of bonded couples tend to emphasize compatibility of interests, mutual preferences in leisure activities, ability to work together, and in some cases a degree of relative contentment.
The bulk of relationships, however, according to Tennov, are those between a limerent person and a nonlimerent other, i.e. limerent-nonlimerent bonding. These bonds are characterized by unequal reciprocation.
Lastly, those relationship bonds in which there exists mutual reciprocation are defined as limerent-limerent bondings. Tennov argues since limerence itself is an "unstable state" that mutually limerent bonds would be expected to be short-lived; mixed relationships probably last longer than limerent-limerent relationships; and affectional bondings tend to be characterized as "old marrieds" whose interactions are typically both stable and mutually gratifying.
# Impact
Tennov's research has been continued by Albert Wakin, who knew Tennov at the University of Bridgeport but didn't assist in her research, and Duyen Vo, a graduate student of Southern Connecticut State University. They are refining the term to refer to the negative pathological aspects of Limerence. The term "Limerence" has been invoked in many popular media, including self-help books, popular magazines, and websites.
Still, according to a paper by Wakin and Vo, "In spite of the public’s exposure to limerence, the professional community, particularly clinical, is largely unaware of the concept." In 2008, they presented their updated research to the American Association of Behavioral and Social Sciences. Wakin and Vo reported that more research must be gathered before the condition is suited for the Diagnostic and Statistical Manual of Mental Disorders (DSM). | Limerence
Template:Close Relationships
Limerence refers to an involuntary cognitive and emotional state of intense romantic desire for another person. The term was coined by psychologist Dorothy Tennov to describe the ultimate, near-obsessional form of romantic love.[1]
# Overview
The concept is an attempt at a scientific study into the nature of romantic love. Limerence can often be what is meant when one expresses having intense feelings of attachment and preoccupations with the love object.
According to Tennov, there are at least two types of love: limerence, what she calls "loving attachment", and "loving affection," the bond that exists between an individual and his or her parents and children.[2]
Limerence is characterized by intrusive thinking and pronounced sensitivity to external events that reflect the disposition of the limerent object towards the individual. It can be experienced as intense joy or as extreme despair, depending on whether the feelings are reciprocated.
Unlike English, many other languages have traditional terms to denote limerence, like the German Verliebtheit, Scandinavian forelskelse, Brazilian Portuguese paixonite, or Russian влюблённость (vlyublyonnost); these expressions may roughly be translated to “fallen-in-love-ness”.
# Origins
The concept of limerence first originated in Tennov's research in the mid-1960s. She interviewed over 500 people on the topic of love. Tennov coined the term "limerence" in 1977, publishing it in her 1979 book "Love and Limerence: The Experience of Being in Love".
Tennov differentiates between limerence and other emotions by asserting that love involves concern for the other person's welfare and feeling. While limerence does not require it, those concerns may certainly be incorporated.
Affection and fondness exist only as a disposition towards another person, irrespective of whether those feelings are reciprocated, whereas limerence demands return. Physical contact with the object is neither essential nor sufficient to an individual experiencing limerence, unlike one experiencing sexual attraction.
New Relationship Energy (NRE) thrives on open communication and known mutuality of feelings and is mostly seen as a positive bonding experience, while limerence can dissipate once reciprocity is established, and is characterized by uncertainty and anxiety.
New Relationship Energy also carries implications of active contrast with relationships in different stages, while limerence does not. Limerence can be longer-lived than transient forms of romantic feelings such as infatuation and puppy love, enduring for months, years and even a lifetime[citation needed] in the absence of knowledge about reciprocity.
# Components
Limerence involves [3] intrusive thinking about the limerent object. Other characteristics include acute longing for reciprocation, fear of rejection, and unsettling shyness in the limerent object's presence. In cases of unrequited limerence, transient relief may be found by vividly imagining reciprocation from the limerent object.
Feelings of limerence can be intensified through adversity, obstacles, or distance. A limerent person may have acute sensitivity to any act, thought, or condition that can be interpreted favorably. This may include a tendency to devise, fabricate, or invent "reasonable" explanations for why neutral actions are a sign of hidden passion in the limerent object.
A person experiencing limerence has a general intensity of feeling that leaves other concerns in the background. In their thoughts, a limerent person tends to emphasize what is admirable in the limerent object and to avoid any negative or problematic attributes.
## Intrusive thinking
During the height of limerence, thoughts of the limerent object (or person) are both persistent, involuntary and intrusive. Limerence is first and foremost a condition of cognitive obsession. All events, associations, stimuli, and experiences return thoughts to the limerent object with unnerving consistency.
The constant thoughts about the limerent object define all other experiences. If a certain thought has no previous connection with the limerent object, immediately one is made. Limerent fantasy is unsatisfactory unless rooted in reality[citation needed], because the fantasizer may want the fantasy to seem realistic and somewhat possible.
Fantasies that are concerned with farfetched ideas are usually dropped by the fantasizer.[citation needed] Sometimes it is retrospective; actual events are replayed from memory with great vividness. This form predominates when what is viewed as evidence of possible reciprocation can be re-experienced (a kind of selective or revisionist history).
Otherwise, the long fantasy is anticipatory; it begins in the everyday world and climaxes at the attainment of the limerent goal. A limerent fantasy can also involve an unusual, often tragic, event.
The long fantasies form bridges between the limerent's ordinary life and that intensely desired ecstatic moment. The duration and complexity of a fantasy depend on the availability of time and freedom from distractions. The bliss of the imagined moment of consummation is greater when events imagined to precede it are possible.
In fact they often represent grave departures from the probable. Not always is it entirely pleasant, and when rejection seems likely the thoughts focus on despair, sometimes to the point of suicide. The pleasantness or unpleasantness of the state seems almost unrelated to the intensity of the reaction.
Although the direction of feeling, i.e. happy versus unhappy, shifts rapidly, the intensity of intrusive and involuntary thinking alters less rapidly, and alters only in response to an accumulation of experiences with the particular limerent object.
For example, fantasies may include "rescuing" the limerent object from a situation of peril and being rewarded in some way implying reciprocation. Another example of limerent fantasy would include a limerent object proclaiming love in a climactic fashion, such as in dying moments.
Fantasies also are occasionally dreamed by the one experiencing limerence. Dreams give out strong emotion and happiness when experienced, but often end with despair when the subject awakens. Dreams can reawaken strong feelings toward the limerent object after the feelings have declined.
## Fear of rejection
Along with the emphasis on positive qualities perceived in the limerent object, and preoccupation with the hope for return of feelings, there is a fear that limerence will be met by the very opposite of reciprocation: rejection. Considerable self-doubt and uncertainty is experienced and it causes pain, but also enhances desire to a certain extent.
However in most cases, this is what helps to eventually destroy the limerence if a suitably long period of time has passed without reciprocation. Typically, limerence lasts about 3 years, but, as previously mentioned, can last decades or even a lifetime.
Limerent fear of rejection is usually confined to shyness in the presence of the limerent object, but it can also spread to situations involving other potential limerent objects, though generally it does not affect other spheres of life.
Although it appears that limerence blossoms under some forms of adversity, extreme caution and shyness may prevent a relationship from occurring, even when both parties are interested. This results from a fear of exposing one's undesirable characteristics to the limerent object.
## Hope
Limerence develops and is sustained when there is a certain balance of hope and uncertainty. The base for limerent hope is not in objective reality but reality as it is perceived. The inclination is to sift through nuances of speech and subtleties of behavior for evidence of limerent hope. "Little things" are noticed and endlessly analyzed for meaning.
The belief that the limerent object does not and will not reciprocate can only come about with great difficulty. Limerence can be carried quite far before acknowledgment of rejection is genuine, especially if it has not been addressed openly by the object of limerence.
Excessive concern over trivia may not be entirely unfounded. Body language can indicate a return of feeling. What the limerent object said and did is recalled with vividness, mostly due to the release of certain 'romance chemicals'. Alternative meanings of those behaviors recalled are searched out.
Each word and gesture is permanently available for review, especially those which can be interpreted as evidence in favor of "return of feeling." When objects, people, places or situations are encountered with the limerent object, they are vividly remembered, especially if the limerent object 'interacted' with them in some way.
## Physical effects
The physiological correlations of limerence are heart palpitations, trembling, pallor, flushing, pupil dilation and general weakness. Awkwardness, stuttering, shyness, and confusion predominate at the behavioral level.
There is apprehension, nervousness, and anxiety due to terrible worry that any action may bring about disaster. Many of the commonly associated physiological reactions are the result of the limerent fear. Some people however may find that these effects come most strongly either immediately at or some time after contact with the object of limerence, and this is accompanied with an acute feeling of ecstasy or despair, depending on the turn of events beforehand.
The super-sensitivity that is heightened by fear of rejection can get in the way of interpreting the limerent object's body language and lead to inaction and wasted opportunities. Body signals may be emitted that confuse and interfere with attaining the limerent object.
A condition of sustained alertness, a heightening of awareness and an enormous fund of energy to deploy in pursuit of the limerent aim is developed. The sensation of limerence is felt in the midpoint of the chest, or in some cases in the abdominal region.[citation needed] This can be interpreted as ecstasy at times of mutuality, but its presence is most noticeable during despair at times of rejection.
## Game-playing
No matter how intensely reciprocation is desired it cannot simply be requested. To ask is to risk premature self-disclosure. The interplay is delicate, with the reactions of each person inextricably bound to the behavior of the other - or at least so in the mind of the Limerant.
Progression toward ecstatic mutuality may not involve externally created difficulties but feinting and parrying, minor deceptions, and falsehoods. The uncertainty required by the limerent reaction may often be merely a matter of perception. Despite ideals and philosophy, a process begins that bears unquestionable similarity to a game. The prize is not trifling: reciprocation produces ecstasy.
Whether it will be won, whether it will be shared, and what the final outcome may be depends on the effectiveness of actions and those of the limerent object; indeed on skill. Deviations from straightforward honesty become essential limerent strategies.
Fears lead to proceeding with a caution that will hopefully protect from disaster. Reason to hope combined with reason to doubt keeps passion at fever pitch and too-ready limerent availability cools. Open declaration of true feelings may stop the process.
Limerent uncertainty as well as projection can be viewed as the consequence of the limerent inclination to hide feelings. Because one of the invariant characteristics of limerence is extreme emotional dependency on the limerent object’s behavior, the actual course of limerence must depend on the actions and reactions of both people.
Uncertainty increases limerence; increased limerence dictates altered action, which serves to increase or decrease limerence in the other according to the interpretation given. The interplay is delicate if the relationship hovers near mutuality; a subtle imbalance, constantly shifting, appears to maintain it.
In most cases each person knows who is more limerent, but this is not always so. In most cases the limerents may believe a certain viewpoint, but the constant uncertainty means they are doubting or questioning themselves for most of the time regarding the other person. This can vary widely between different people.
## Sexuality
Awareness of physical attraction plays a key role in the development of limerence, but is not enough to satisfy the limerent desire, and is almost never the main focus -- instead, the limerent focuses on what could be defined as the "beneficial attributes".
A person, to become the limerent object, must be a potential sex partner. Limerence can be intensified after a sexual relationship has begun, and with more intense limerence there is greater desire for sexual contact. However, while sexual surrender once indicated the end of uncertainty in the limerent object, in modern times this is not necessarily the case.
Sexual fantasies are distinct from limerent ones. Limerent fantasy is rooted in reality and is intrusive rather than voluntary. Sexual fantasies are under more or less voluntary control and may also involve strangers, imaginary individuals, and situations that could not take place.
People can become aroused by the thought of sexual partners, acts, and situations that are not truly desired, whereas every detail of the limerent fantasy is passionately desired actually to take place. Limerence sometimes increases sexual interest in other partners when the limerent object is unreceptive or unavailable, such as when married people find sex with their spouses more pleasurable when they become limerent over someone else.
Limerent anxieties and shyness may interfere with sexual functioning. The continual concern to appear at the very best is not always compatible with the immodest behaviors and poses that arise in sexual situations.
# Limerent reaction
The limerent reaction is a composite reaction; that is, it actually describes a unique series of reactions. These reactions occur only where misperceptions meet adversity in the context of a romance. Perhaps because of this unique specificity, limerent reactions can be uniquely quantified and predicted according to the schema described below.
Involvement increases if obstacles are externally imposed or if the limerent object’s feelings are doubted. Only if the limerent object were to be revealed as highly undesirable might limerence subside. The presence of some degree of doubt causes the intensity of the feelings to rise further. The stage is reached at which the reaction is virtually impossible to dislodge.
This adversity may be superficial or deep, internal or external, so that an individual may generate deep adversity where none exists. Also "romance," as it were, need not be present in any genuine way for a limerent reaction to proceed.
The course of limerence results in a more intrusive thinking pattern. This thinking pattern is an expectant and often joyous period with the initial focusing on the limerent object’s admirable qualities; crystallization. Then, under appropriate conditions of hope and uncertainty, the limerence intensifies further.
With evidence of reciprocation from the limerent object, a state of extreme pleasure, even euphoria, is enjoyed. Thoughts are mainly occupied with considering and reconsidering what is attractive in the limerent object, replaying whatever events may have thus far transpired with the limerent object, and appreciating personal qualities which are perceived as possibly having sparked interest in the limerent object.
At peak crystallization, almost all waking thoughts revolve around the limerent object. After this peak, the feelings eventually decline.
Fantasies are preferred to virtually any other activity with the exception of activities that are believed to help obtain the limerent object, and activities that involve actually being in the presence of the limerent object. The motivation to attain a "relationship" continues to intensify so long as a proper mix of hope and uncertainty exist.
Tennov estimates, based on both questionnaire and interview data, that the average limerent reaction duration, from the moment of initiation until a feeling of neutrality is reached, is approximately three years. The extremes may be as brief as a few weeks or several years. When limerence is brief, maximum intensity may not have been attained.
Limerence generally lasts between 18 months and three years, but further studies on unrequited limerence have suggested longer durations.
# Bond varieties
Once the limerent reaction has initiated, one of three varieties of bonds may form, defined over a set duration of time, in relation to the experience or non-experience of limerence. The constitution of these bonds may vary over the course of the relationship, in ways that may either increase or decrease the intensity of the limerence.
The basis and interesting characteristic of this delineation made by Tennov, is that based on her research and interviews with people, all human bonded relationships can be divided into three varieties being defined by the amount of limerence or non-limerence each partner contributes to the relationship.
With an affectional bond, neither partner is limerent. With a Limerent-Nonlimerent bond, one partner is limerent. In a Limerent-Limerent bond, both partners are limerent.
Affectional bonding characterize those affectionate sexual relationships where neither partner is limerent; couples tend to be in love, but do not report continuous and unwanted intrusive thinking, feeling intense need for exclusivity, or define their goals in terms of reciprocity. These types of bonded couples tend to emphasize compatibility of interests, mutual preferences in leisure activities, ability to work together, and in some cases a degree of relative contentment.
The bulk of relationships, however, according to Tennov, are those between a limerent person and a nonlimerent other, i.e. limerent-nonlimerent bonding. These bonds are characterized by unequal reciprocation.
Lastly, those relationship bonds in which there exists mutual reciprocation are defined as limerent-limerent bondings. Tennov argues since limerence itself is an "unstable state" that mutually limerent bonds would be expected to be short-lived; mixed relationships probably last longer than limerent-limerent relationships; and affectional bondings tend to be characterized as "old marrieds" whose interactions are typically both stable and mutually gratifying.
# Impact
Tennov's research has been continued by Albert Wakin, who knew Tennov at the University of Bridgeport but didn't assist in her research, and Duyen Vo, a graduate student of Southern Connecticut State University.[4] They are refining the term to refer to the negative pathological aspects of Limerence. The term "Limerence" has been invoked in many popular media, including self-help books, popular magazines, and websites.
Still, according to a paper by Wakin and Vo, "In spite of the public’s exposure to limerence, the professional community, particularly clinical, is largely unaware of the concept." [5] In 2008, they presented their updated research to the American Association of Behavioral and Social Sciences. Wakin and Vo reported that more research must be gathered before the condition is suited for the Diagnostic and Statistical Manual of Mental Disorders (DSM).[4] | https://www.wikidoc.org/index.php/Limerence | |
bf11a493adb453cb784a258ea38930284b0da99d | wikidoc | Linamarin | Linamarin
Linamarin is a cyanogenic glucoside found in the leaves and roots of plants such as cassava, lima beans, and flax. Upon exposure to enzymes and gut flora in the human intestine, linamarin and its methylated relative lotaustralin can decompose to the toxic chemical hydrogen cyanide; hence food uses of plants that contain significant quantities of linamarin are inhibited by extensive preparation and detoxification requirements. Linamarin itself is not acutely toxic, although neurotoxic effects of long-term exposure have been suggested. Consumption of linamarin-containing cassava products is widespread in the developing world and has been associated with dietary toxicity, particularly with the upper motor neuron disease known as konzo to the African populations in which it was first described, through the work of Hans Rosling. Dietary exposure to linamarin has also been reported as a risk factor in developing glucose intolerance and diabetes, although studies in experimental animals have been inconsistent in reproducing this effect and may indicate that the primary effect is in aggravating existing conditions rather than inducing diabetes on its own.
The generation of cyanide from linamarin is usually enzymatic and occurs when linamarin is exposed to linamarase, an enzyme normally expressed in the cell walls of cassava plants. Because the resulting cyanide derivatives are volatile, processing methods that induce such exposure are common traditional means of cassava preparation; foodstuffs are usually made from cassava after extended blanching, boiling, or fermentation. Food products made from cassava plants include garri (toasted cassava tubers), porridge-like fufu, the dough agbelima, and cassava flour.
Recent research efforts have developed a transgenic cassava plant that stably downregulates linamarin production via RNA interference. | Linamarin
Template:Chembox new
Linamarin is a cyanogenic glucoside found in the leaves and roots of plants such as cassava, lima beans, and flax. Upon exposure to enzymes and gut flora in the human intestine, linamarin and its methylated relative lotaustralin can decompose to the toxic chemical hydrogen cyanide; hence food uses of plants that contain significant quantities of linamarin are inhibited by extensive preparation and detoxification requirements. Linamarin itself is not acutely toxic, although neurotoxic effects of long-term exposure have been suggested. Consumption of linamarin-containing cassava products is widespread in the developing world and has been associated with dietary toxicity, particularly with the upper motor neuron disease known as konzo to the African populations in which it was first described, through the work of Hans Rosling.[1] Dietary exposure to linamarin has also been reported as a risk factor in developing glucose intolerance and diabetes, although studies in experimental animals have been inconsistent in reproducing this effect[2] and may indicate that the primary effect is in aggravating existing conditions rather than inducing diabetes on its own.[3]
The generation of cyanide from linamarin is usually enzymatic and occurs when linamarin is exposed to linamarase, an enzyme normally expressed in the cell walls of cassava plants. Because the resulting cyanide derivatives are volatile, processing methods that induce such exposure are common traditional means of cassava preparation; foodstuffs are usually made from cassava after extended blanching, boiling, or fermentation.[4] Food products made from cassava plants include garri (toasted cassava tubers), porridge-like fufu, the dough agbelima, and cassava flour.
Recent research efforts have developed a transgenic cassava plant that stably downregulates linamarin production via RNA interference.[5] | https://www.wikidoc.org/index.php/Linamarin | |
afde183bdae12bd6d3a63189482f8ffc184d827e | wikidoc | Linezolid | Linezolid
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# Overview
Linezolid is an oxazolidinone-class antibacterial that is FDA approved for the treatment of following infections caused by susceptible gram-positive bacteria: nosocomial pneumonia; community-acquired pneumonia; complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis; uncomplicated skin and skin structure infections; vancomycin-resistant enterococcus faecium infections. Common adverse reactions include diarrhea, vomiting, headache, nausea, and anemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae.
- Community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only).
- Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid has not been studied in the treatment of decubitus ulcers.
- Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.
- Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia.
- The recommended dosage for Linezolid formulations for the treatment of infections is described in Table 1.
- No dose adjustment is necessary when switching from intravenous to oral administration.
- Intravenous Administration
- Linezolid I.V. Injection is supplied in single-use, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the infusion bags in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid I.V. Injection may exhibit a yellow color that can intensify over time without adversely affecting potency.
- Linezolid I.V. Injection should be administered by intravenous infusion over a period of 30 to 120 minutes. Do not use this intravenous infusion bag in series connections. Additives should not be introduced into this solution. If Linezolid I.V. Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product.
- If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Linezolid I.V. Injection with an infusion solution compatible with Linezolid I.V. Injection and with any other drug(s) administered via this common line.
- Constitution of Oral Suspension
- Linezolid for Oral Suspension is supplied as a powder/granule for constitution. Gently tap bottle to loosen powder. Add a total of 123 mL distilled water in two portions. After adding the first half, shake vigorously to wet all of the powder. Then add the second half of the water and shake vigorously to obtain a uniform suspension. After constitution, each 5 mL of the suspension contains 100 mg of linezolid. Before using, gently mix by inverting the bottle 3 to 5 times. Do not shake. Store constituted suspension at room temperature. Use within 21 days after constitution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosing Information
- IV linezolid
- Dosing Information
- IV linezolid 600 mg every 12 hours
- Dosing Information
- Linezolid 600 mg
### Non–Guideline-Supported Use
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae.
- Community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only).
- Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid has not been studied in the treatment of decubitus ulcers.
- Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.
- Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia.
- The recommended dosage for Linezolid formulations for the treatment of infections is described in Table 1.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Dosing Information
- IV linezolid
# Contraindications
- Hypersensitivity
- Linezolid formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.
- Monoamine Oxidase Inhibitors
- Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.
# Warnings
### Precautions
- Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.
- Peripheral and optic neuropathies have been reported in patients treated with Linezolid, primarily in those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with Linezolid for less than 28 days. Peripheral and optic neuropathy has also been reported in children.
- If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking Linezolid for extended periods (≥ 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with Linezolid. If peripheral or optic neuropathy occurs, the continued use of Linezolid in these patients should be weighed against the potential risks.
- Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of Linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported.
- Unless clinically appropriate and patients are carefully observed for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine, bupropion, or buspirone.
- In some cases, a patient already receiving a serotonergic antidepressant or buspirone may require urgent treatment with linezolid. If alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for two weeks (five weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Symptoms of serotonin syndrome or NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The patient should also be monitored for discontinuation symptoms of the antidepressant.
- An imbalance in mortality was seen in patients treated with linezolid relative to vancomycin/dicloxacillin/oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections . While causality has not been established, this observed imbalance occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only.
- Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections.
- Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Linezolid, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.
- Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine).
- Lactic acidosis has been reported with the use of Linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving Linezolid should receive immediate medical evaluation.
- Convulsions have been reported in patients when treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.
- Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be cautioned of potential hypoglycemic reactions when treated with linezolid.
- If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required.
- Prescribing Linezolid in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# 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.
- Adults:
- The safety of Linezolid formulations was evaluated in 2046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days.
- Of the patients treated for uncomplicated skin and skin structure infections (uSSSIs), 25.4% of Linezolid-treated and 19.6% of comparator-treated patients experienced at least one drug-related adverse event. For all other indications, 20.4% of Linezolid -treated and 14.3% of comparator-treated patients experienced at least one drug-related adverse event.
- Table 2 shows the incidence of all-causality, treatment-emergent adverse reactions reported in at least 1% of adult patients in these trials by dose of Linezolid.
- Of the patients treated for uSSSIs, 3.5% of Linezolid -treated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 2.1% of Linezolid -treated and 1.7% of comparator-treated patients. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting.
- Pediatric Patients:
- The safety of Linezolid formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 3 comparator-controlled clinical trials and were treated for up to 28 days. In the study of hospitalized pediatric patients (birth through 11 years) with Gram-positive infections, who were randomized 2 to 1 (linezolid: vancomycin), mortality was 6.0% (13/215) in the linezolid arm and 3.0% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established.
- Of the pediatric patients treated for uSSSIs, 19.2% of Linezolid-treated and 14.1% of comparator-treated patients experienced at least one drug-related adverse event. For all other indications, 18.8% of Linezolid-treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event.
- Table 3 shows the incidence of all-causality, treatment-emergent adverse reactions reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled Phase 3 trials.
- Of the pediatric patients treated for uSSSIs, 1.6% of Linezolid-treated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 0.9% of Linezolid-treated and 6.1% of comparator-treated patients.
- Laboratory Abnormalities:
- Linezolid has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hours for up to 28 days. In Phase 3 comparator-controlled trials, the percentage of adult patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3 to 10.0%) with Linezolid and 1.5% (range among studies: 0.4 to 7.0%) with a comparator. In a study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with Linezolid and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with Linezolid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of Linezolid appears to be dependent on duration of therapy (generally greater than 2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in Phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for Linezolid; the role of linezolid in these events cannot be determined.
- Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between Linezolid and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 4, 5, 6, and 7.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Linezolid. 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.
- Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported during postmarketing use of Linezolid. Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with Linezolid. Lactic acidosis has been reported with the use of Linezolid. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy. Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and Linezolid. Convulsions have been reported with the use of Linezolid. Anaphylaxis, angioedema, and bullous skin disorders such as those described as Stevens-Johnson syndrome have been reported. Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome. Hypoglycemia, including symptomatic episodes, has been reported.
# Drug Interactions
- Drugs Metabolized by Cytochrome P450
- Linezolid is not an inducer of cytochrome P450 (CYP450) in rats. In addition, linezolid does not inhibit the activities of clinically significant human CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major enzymes. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen.
- Antibiotics
- Aztreonam: The pharmacokinetics of linezolid or aztreonam are not altered when administered together.
- Gentamicin: The pharmacokinetics of linezolid or gentamicin are not altered when administered together.
- Antioxidants
- The potential for drug-drug interactions with linezolid and the antioxidants Vitamin C and Vitamin E was studied in healthy volunteers. Subjects were administered a 600 mg oral dose of linezolid on Day 1, and another 600 mg dose of linezolid on Day 8. On Days 2–9, subjects were given either Vitamin C (1000 mg/day) or Vitamin E (800 IU/ day). The AUC0–∞ of linezolid increased 2.3% when co-administered with Vitamin C and 10.9% when co-administered with Vitamin E. No linezolid dose adjustment is recommended during co-administration with Vitamin C or Vitamin E.
- Strong CYP 3A4 Inducers
- Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid Cmax and a 32% decrease in linezolid AUC0–12 . The clinical significance of this interaction is unknown. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) could cause a similar or smaller decrease in linezolid exposure.
- Monoamine Oxidase Inhibition
- Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
- Adrenergic Agents
- Some individuals receiving Linezolid may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or dopaminergic agents. Commonly used drugs such as phenylpropanolamine and pseudoephedrine have been specifically studied. Initial doses of adrenergic agents, such as dopamine or epinephrine, should be reduced and titrated to achieve the desired response.
- Tyramine: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content.
- Pseudoephedrine HCl or phenylpropanolamine HCl: A reversible enhancement of the pressor response of either pseudoephedrine HCl (PSE) or phenylpropanolamine HCl (PPA) is observed when linezolid is administered to healthy normotensive subjects. A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, linezolid alone, and the combination of steady-state linezolid (600 mg every 12 hours for 3 days) with two doses of PPA (25 mg) or PSE (60 mg) given 4 hours apart. Heart rate was not affected by any of the treatments. Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2 to 3 hours after the second dose of PPA or PSE, and returned to baseline 2 to 3 hours after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mm Hg: placebo = 121 (103 to 158); linezolid alone = 120 (107 to 135); PPA alone = 125 (106 to 139); PPA with linezolid = 147 (129 to 176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mm Hg (range: 20–52 mm Hg) and 38 mm Hg (range: 18–79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively.
- Serotonergic Agents
- Dextromethorphan: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Linezolid was not teratogenic in mice, rats, or rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.06-fold (in rabbits) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen. There are no adequate and well-controlled studies in pregnant women. Linezolid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Non-teratogenic Effects
- In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). A dose of 450 mg/kg/day (6.5-fold the estimated human exposure level based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion.
- In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Slight maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day.
- In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at a dose of 15 mg/kg/day (0.06-fold the estimated human exposure based on AUCs).
- When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation, survival of pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Linezolid in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Linezolid during labor and delivery.
### Nursing Mothers
- Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Linezolid is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of Linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years:
- nosocomial pneumonia
- complicated skin and skin structure infections
- community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)
- vancomycin-resistant Enterococcus faecium infections
- The safety and effectiveness of Linezolid for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years:
- uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes
- Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.
- The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in preterm (gestational age < 34 weeks) neonates < 7 days of age, linezolid clearance is often lower than in full-term neonates < 7 days of age. Consequently, preterm neonates < 7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours.
- In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with Linezolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response.
### Geriatic Use
- Of the 2046 patients treated with Linezolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out
### Gender
There is no FDA guidance on the use of Linezolid with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Linezolid with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Linezolid in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Linezolid in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Linezolid in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Linezolid in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy.
# IV Compatibility
- Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.
- Physical incompatibilities resulted when Linezolid I.V. Injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when Linezolid I.V. Injection was combined with ceftriaxone sodium.
# Overdosage
## Acute Overdose
- In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3000 mg/kg/day and 2000 mg/kg/day, respectively.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Linezolid in the drug label.
# Pharmacology
## Mechanism of Action
- Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of isolates.
## Structure
- Linezolid I.V. Injection, Linezolid Tablets, and Linezolid for Oral Suspension contain linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N--2-oxo-5-oxazolidinyl] methyl]-acetamide.
- The empirical formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below:
- Linezolid I.V. Injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion. Each mL contains 2 mg of linezolid. Inactive ingredients are sodium citrate, citric acid, and dextrose in an aqueous vehicle for intravenous administration. The sodium (Na+) content is 0.38 mg/mL (5 mEq/300-mL bag; 3.3 mEq/200-mL bag; and 1.7 mEq/100-mL bag).
- Linezolid Tablet for oral administration contains 600 mg linezolid as a film-coated compressed tablet. Inactive ingredients are corn starch, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, and carnauba wax. The sodium (Na+) content is 2.92 mg per 600-mg tablet (0.1 mEq/tablet).
- Linezolid for Oral Suspension is supplied as an orange-flavored granule/powder for constitution into a suspension for oral administration. Following constitution, each 5 mL contains 100 mg of linezolid. Inactive ingredients are sucrose, citric acid, sodium citrate, microcrystalline cellulose and carboxymethylcellulose sodium, aspartame, xanthan gum, mannitol, sodium benzoate, colloidal silicon dioxide, sodium chloride, and flavors. The sodium (Na+) content is 8.52 mg/5 mL (0.4 mEq/5 mL).
## Pharmacodynamics
- In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single Linezolid 600 mg dose via a 1 hour IV infusion, a single Linezolid 1200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1200 mg Linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.
## Pharmacokinetics
- The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1.
- Absorption
- Linezolid is extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously without dose adjustment.
- Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5 hours to 2.2 hours and Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0–∞ is similar under both conditions.
- Distribution
- Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration-independent. The volume of distribution of linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers.
- Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2 to 1 and the ratio of linezolid in sweat relative to plasma was 0.55 to 1.
- Metabolism
- Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite A is presumed to be formed via an enzymatic pathway whereas metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. In vitro studies have demonstrated that linezolid is minimally metabolized and may be mediated by human cytochrome P450. However, the metabolic pathway of linezolid is not fully understood.
- Excretion
- Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min which suggests net tubular reabsorption. Virtually no linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B, and 3% as metabolite A.
- A small degree of nonlinearity in clearance was observed with increasing doses of linezolid, which appears to be due to lower renal and nonrenal clearance of linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life.
- Specific Populations
- Geriatric Patients
- The pharmacokinetics of linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary.
- Pediatric Patients
- The pharmacokinetics of linezolid following a single intravenous dose were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from 12 through 17 years, and in pediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of linezolid are summarized in Table 9 for the pediatric populations studied and healthy adult subjects after administration of single intravenous doses.
- The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, plasma clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, weight-based clearance is most rapid in the youngest age groups ranging from < 1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and a shorter half-life as compared with adults. As the age of pediatric patients increases, the weight-based clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is increased inter-subject variability in linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as compared with adults.
- Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed every 8 hours relative to adolescents or adults dosed every 12 hours. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg every 8 hours. Pediatric patients 12 years and older should receive 600 mg every 12 hours.
- Gender
- Females have a slightly lower volume of distribution of linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender does not appear to be necessary.
- Renal Impairment
- The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal impairment; however, the two primary metabolites of linezolid accumulate in patients with renal impairment, with the amount of accumulation increasing with the severity of renal dysfunction (see Table 10). The pharmacokinetics of linezolid and its two metabolites have also been studied in patients with end-stage renal disease (ESRD) receiving hemodialysis. In the ESRD study, 14 patients were dosed with linezolid 600 mg every 12 hours for 14.5 days (see Table 11). Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal impairment. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of linezolid in patients with renal impairment should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by hemodialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid. Approximately 30% of a dose was eliminated in a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis.
- Hepatic Impairment
- The pharmacokinetics of linezolid are not altered in patients (n=7) with mild-to-moderate hepatic impairment (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild-to-moderate hepatic impairment. The pharmacokinetics of linezolid in patients with severe hepatic impairment have not been evaluated.
- Mechanisms of Resistance
- In clinical trials, resistance to linezolid developed in 6 patients infected with Enterococcus faecium (4 patients received 200 mg every 12 hours, lower than the recommended dose, and 2 patients received 600 mg every 12 hours). In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with Enterococcus faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 × 10 –9 to 1 × 10 –11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to linezolid during its clinical use have been published. There are reports of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during clinical use. The linezolid resistance in these organisms is associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. Also linezolid resistance in staphylococci mediated by the enzyme methyltransferase has been reported. This resistance is mediated by the cfr (chloramphenicol-florfenicol) gene located on a plasmid which is transferable between staphylococci.
- Resistance to linezolid has not been reported in Streptococcus spp., including Streptococcus pneumoniae.
- Interaction with Other Antimicrobials
- In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin.
Gram-positive bacteria
Enterococcus faecium (vancomycin-resistant isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
- Gram-positive bacteria
- Enterococcus faecium (vancomycin-resistant isolates only)
- Staphylococcus aureus (including methicillin-resistant isolates)
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Streptococcus pyogenes
- The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for linezolid. However, the safety and effectiveness of linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Gram-positive bacteria
Enterococcus faecalis (including vancomycin-resistant isolates)
Enterococcus faecium (vancomycin-susceptible isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus
Viridans group streptococci
Gram-negative bacteria
Pasteurella multocida
- Gram-positive bacteria
- Enterococcus faecalis (including vancomycin-resistant isolates)
- Enterococcus faecium (vancomycin-susceptible isolates)
- Staphylococcus epidermidis (including methicillin-resistant isolates)
- Staphylococcus haemolyticus
- Viridans group streptococci
- Gram-negative bacteria
- Pasteurella multocida
- Susceptibility Test Methods
- When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
- Dilution techniques
- Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized method1,2 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 12.
- Diffusion techniques
- Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method2,3. This procedure uses paper disks impregnated with 30 mcg linezolid to test the susceptibility of bacteria to linezolid. The disk diffusion interpretive criteria are provided in Table 12.
- A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
- Quality Control
- Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3. Standard linezolid powder should provide the following range of MIC values noted in Table 13. For the diffusion technique using the 30 mcg linezolid disk, the criteria in Table 13 should be achieved.
## Nonclinical Toxicology
- Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.
- Linezolid did not affect the fertility or reproductive performance of adult female rats. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses ≥ 50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.
- In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days 7 to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7-fold greater than mean AUCs observed in pediatric patients aged 3 months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5 to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35.
- Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose- and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss, and suppression of body weight gain, which may have contributed to the observed effects.
- In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.
- These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.
# Clinical Studies
- Nosocomial Pneumonia
- Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a randomized, multi-center, double-blind trial. Patients were treated for 7 to 21 days. One group received Linezolid I.V. Injection 600 mg every 12 hours, and the other group received vancomycin 1 g every 12 hours intravenously. Both groups received concomitant aztreonam (1 to 2 g every 8 hours intravenously), which could be continued if clinically indicated. There were 203 linezolid-treated and 193 vancomycin-treated patients enrolled in the study. One hundred twenty-two (60%) linezolid-treated patients and 103 (53%) vancomycin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 57% for linezolid-treated patients and 60% for vancomycin-treated patients. The cure rates in clinically evaluable patients with ventilator-associated pneumonia were 47% for linezolid-treated patients and 40% for vancomycin-treated patients. A modified intent-to-treat (MITT) analysis of 94 linezolid-treated patients and 83 vancomycin-treated patients included subjects who had a pathogen isolated before treatment. The cure rates in the MITT analysis were 57% in linezolid-treated patients and 46% in vancomycin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 14.
- Complicated Skin and Skin Structure Infections
- Adult patients with clinically documented complicated skin and skin structure infections were enrolled in a randomized, multi-center, double-blind, double-dummy trial comparing study medications administered intravenously followed by medications given orally for a total of 10 to 21 days of treatment. One group of patients received Linezolid I.V. Injection 600 mg every 12 hours followed by Linezolid Tablets 600 mg every 12 hours; the other group received oxacillin 2 g every 6 hours intravenously followed by dicloxacillin 500 mg every 6 hours orally. Patients could receive concomitant aztreonam if clinically indicated. There were 400 linezolid-treated and 419 oxacillin-treated patients enrolled in the study. Two hundred forty-five (61%) linezolid-treated patients and 242 (58%) oxacillin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 90% in linezolid-treated patients and 85% in oxacillin-treated patients. A modified intent-to-treat (MITT) analysis of 316 linezolid-treated patients and 313 oxacillin-treated patients included subjects who met all criteria for study entry. The cure rates in the MITT analysis were 86% in linezolid-treated patients and 82% in oxacillin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 15.
- A separate study provided additional experience with the use of Linezolid in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. This was a randomized, open-label trial in hospitalized adult patients with documented or suspected MRSA infection.
- One group of patients received Linezolid I.V. Injection 600 mg every 12 hours followed by Linezolid Tablets 600 mg every 12 hours. The other group of patients received vancomycin 1 g every 12 hours intravenously. Both groups were treated for 7 to 28 days, and could receive concomitant aztreonam or gentamicin if clinically indicated. The cure rates in microbiologically evaluable patients with MRSA skin and skin structure infection were 26/33 (79%) for linezolid-treated patients and 24/33 (73%) for vancomycin-treated patients.
- Diabetic Foot Infections
- Adult diabetic patients with clinically documented complicated skin and skin structure infections ("diabetic foot infections") were enrolled in a randomized (2:1 ratio), multi-center, open-label trial comparing study medications administered intravenously or orally for a total of 14 to 28 days of treatment. One group of patients received Linezolid 600 mg every 12 hours intravenously or orally; the other group received ampicillin/sulbactam 1.5 to 3 g intravenously or amoxicillin/clavulanate 500 to 875 mg every 8 to 12 hours orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to 2 g every 6 hours was used for the intravenous regimen. Patients in the comparator group could also be treated with vancomycin 1 g every 12 hours intravenously if MRSA was isolated from the foot infection. Patients in either treatment group who had Gram-negative bacilli isolated from the infection site could also receive aztreonam 1 to 2 g every 8–12 hours intravenously. All patients were eligible to receive appropriate adjunctive treatment methods, such as debridement and off-loading, as typically required in the treatment of diabetic foot infections, and most patients received these treatments. There were 241 linezolid-treated and 120 comparator-treated patients in the intent-to-treat (ITT) study population. Two hundred twelve (86%) linezolid-treated patients and 105 (85%) comparator-treated patients were clinically evaluable. In the ITT population, the cure rates were 68.5% (165/241) in linezolid-treated patients and 64% (77/120) in comparator-treated patients, where those with indeterminate and missing outcomes were considered failures. The cure rates in the clinically evaluable patients (excluding those with indeterminate and missing outcomes) were 83% (159/192) and 73% (74/101) in the linezolid- and comparator-treated patients, respectively. A critical post-hoc analysis focused on 121 linezolid-treated and 60 comparator-treated patients who had a Gram-positive pathogen isolated from the site of infection or from blood, who had less evidence of underlying osteomyelitis than the overall study population, and who did not receive prohibited antimicrobials. Based upon that analysis, the cure rates were 71% (86/121) in the linezolid-treated patients and 63% (38/60) in the comparator-treated patients. None of the above analyses were adjusted for the use of adjunctive therapies. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 16.
- Vancomycin-Resistant Enterococcal Infections
- Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multi-center, double-blind trial comparing a high dose of Linezolid (600 mg) with a low dose of Linezolid (200 mg) given every 12 hours either intravenously (IV) or orally for 7 to 28 days. Patients could receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to high-dose linezolid and 66 to low-dose linezolid. The intent-to-treat (ITT) population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in the high-dose arm and 52 in the low-dose arm.
- The cure rates for the ITT population with documented vancomycin-resistant enterococcal infection at baseline are presented in Table 17 by source of infection. These cure rates do not include patients with missing or indeterminate outcomes. The cure rate was higher in the high-dose arm than in the low-dose arm, although the difference was not statistically significant at the 0.05 level.
- Infections due to Gram-positive Bacteria
- A safety and efficacy study provided experience on the use of Linezolid in pediatric patients for the treatment of nosocomial pneumonia, complicated skin and skin structure infections, catheter-related bacteremia, bacteremia of unidentified source, and other infections due to Gram-positive bacterial pathogens, including methicillin-resistant and -susceptible Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Pediatric patients ranging in age from birth through 11 years with infections caused by the documented or suspected Gram-positive bacteria were enrolled in a randomized, open-label, comparator-controlled trial. One group of patients received Linezolid I.V. Injection 10 mg/kg every 8 hours followed by Linezolid for Oral Suspension 10 mg/kg every 8 hours. A second group received vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance. Patients who had confirmed VRE infections were placed in a third arm of the study and received Linezolid 10 mg/kg every 8 hours intravenously and/or orally. All patients were treated for a total of 10 to 28 days and could receive concomitant Gram-negative antibiotics if clinically indicated. In the intent-to-treat (ITT) population, there were 206 patients randomized to linezolid and 102 patients randomized to vancomycin. The cure rates for ITT, MITT, and clinically evaluable patients are presented in Table 18. After the study was completed, 13 additional patients ranging from 4 days through 16 years of age were enrolled in an open-label extension of the VRE arm of the study. Table 19 provides clinical cure rates by pathogen for microbiologically evaluable patients including microbiologically evaluable patients with vancomycin-resistant Enterococcus faecium from the extension of this study.
# How Supplied
- Injection
- Linezolid I.V. Injection is available in single-use, ready-to-use flexible plastic infusion bags in a foil laminate overwrap. The infusion bags and ports are latex-free. The infusion bags are available in the following package sizes:
100 mL bag (200 mg linezolid) NDC 0009-5137-01
200 mL bag (400 mg linezolid) NDC 0009-5139-01
300 mL bag (600 mg linezolid) NDC 0009-5140-01
- 100 mL bag (200 mg linezolid) NDC 0009-5137-01
- 200 mL bag (400 mg linezolid) NDC 0009-5139-01
- 300 mL bag (600 mg linezolid) NDC 0009-5140-01
- Tablets
- Linezolid Tablets are available as follows:
600 mg (white, capsule-shaped, film-coated tablets printed with "Linezolid 600 mg")
100 tablets in HDPE bottle NDC 0009-5135-01
20 tablets in HDPE bottle NDC 0009-5135-02
Unit dose packages of 30 tablets NDC 0009-5135-03
- 600 mg (white, capsule-shaped, film-coated tablets printed with "Linezolid 600 mg")
- 100 tablets in HDPE bottle NDC 0009-5135-01
- 20 tablets in HDPE bottle NDC 0009-5135-02
- Unit dose packages of 30 tablets NDC 0009-5135-03
- Oral Suspension
- Linezolid for Oral Suspension is available as a dry, white to off-white, orange-flavored granule/powder. When constituted as directed, each bottle will contain 150 mL of a suspension providing the equivalent of 100 mg of linezolid per each 5 mL. Linezolid for Oral Suspension is supplied as follows:
100 mg/5 mL in 240-mL glass bottles NDC 0009-5136-01
- 100 mg/5 mL in 240-mL glass bottles NDC 0009-5136-01
- Storage
- Store at 25°C (77°F). Protect from light. Keep bottles tightly closed to protect from moisture. It is recommended that the infusion bags be kept in the overwrap until ready to use. Protect infusion bags from freezing.
## Storage
There is limited information regarding Linezolid Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including Linezolid should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Linezolid is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Linezolid or other antibacterial drugs in the future.
- Patients should be advised that:
- Linezolid may be taken with or without food.
- They should inform their physician if they have a history of hypertension.
- Large quantities of foods or beverages with high tyramine content should be avoided while taking Linezolid. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses ,fermented or air-dried meats ,sauerkraut , soy sauce, tap beers, and red wines. The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.
- They should inform their physician if taking medications containing pseudoephedrine HCl or phenylpropanolamine HCl, such as cold remedies and decongestants.
- They should inform their physician if taking serotonin re-uptake inhibitors or other antidepressants.
- Phenylketonurics: Each 5 mL of the 100 mg/5 mL Linezolid for Oral Suspension contains 20 mg phenylalanine. The other Linezolid formulations do not contain phenylalanine. Contact your physician or pharmacist.
- They should inform their physician if they experience changes in vision.
- They should inform their physician if they have a history of seizures.
- Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
- Inform patient, particularly those with diabetes mellitus that hypoglycemic reactions, such as diaphoresis and tremulousness, along with low blood glucose measurements may occur when treated with linezolid. If such reactions occur, patients should contact a physician or other health professional for proper treatment.
# Precautions with Alcohol
- Alcohol-Linezolid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ZYVOX
# Look-Alike Drug Names
- ZYVOX® — Vioxx®
- ZYVOX® — Zovirax®
# Drug Shortage Status
# Price | Linezolid
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
Linezolid is an oxazolidinone-class antibacterial that is FDA approved for the treatment of following infections caused by susceptible gram-positive bacteria: nosocomial pneumonia; community-acquired pneumonia; complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis; uncomplicated skin and skin structure infections; vancomycin-resistant enterococcus faecium infections. Common adverse reactions include diarrhea, vomiting, headache, nausea, and anemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae.
- Community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only).
- Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid has not been studied in the treatment of decubitus ulcers.
- Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.
- Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia.
- The recommended dosage for Linezolid formulations for the treatment of infections is described in Table 1.
- No dose adjustment is necessary when switching from intravenous to oral administration.
- Intravenous Administration
- Linezolid I.V. Injection is supplied in single-use, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the infusion bags in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid I.V. Injection may exhibit a yellow color that can intensify over time without adversely affecting potency.
- Linezolid I.V. Injection should be administered by intravenous infusion over a period of 30 to 120 minutes. Do not use this intravenous infusion bag in series connections. Additives should not be introduced into this solution. If Linezolid I.V. Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product.
- If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Linezolid I.V. Injection with an infusion solution compatible with Linezolid I.V. Injection and with any other drug(s) administered via this common line.
- Constitution of Oral Suspension
- Linezolid for Oral Suspension is supplied as a powder/granule for constitution. Gently tap bottle to loosen powder. Add a total of 123 mL distilled water in two portions. After adding the first half, shake vigorously to wet all of the powder. Then add the second half of the water and shake vigorously to obtain a uniform suspension. After constitution, each 5 mL of the suspension contains 100 mg of linezolid. Before using, gently mix by inverting the bottle 3 to 5 times. Do not shake. Store constituted suspension at room temperature. Use within 21 days after constitution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosing Information
- IV linezolid[1]
- Dosing Information
- IV linezolid 600 mg every 12 hours[2]
- Dosing Information
- Linezolid 600 mg[3]
### Non–Guideline-Supported Use
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae.
- Community-acquired pneumonia caused by Streptococcus pneumoniae, including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only).
- Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, or Streptococcus agalactiae. Linezolid has not been studied in the treatment of decubitus ulcers.
- Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.
- Vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia.
- The recommended dosage for Linezolid formulations for the treatment of infections is described in Table 1.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Dosing Information
- IV linezolid[1]
# Contraindications
- Hypersensitivity
- Linezolid formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components.
- Monoamine Oxidase Inhibitors
- Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.
# Warnings
### Precautions
- Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression.
- Peripheral and optic neuropathies have been reported in patients treated with Linezolid, primarily in those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with Linezolid for less than 28 days. Peripheral and optic neuropathy has also been reported in children.
- If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking Linezolid for extended periods (≥ 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with Linezolid. If peripheral or optic neuropathy occurs, the continued use of Linezolid in these patients should be weighed against the potential risks.
- Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of Linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported.
- Unless clinically appropriate and patients are carefully observed for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), meperidine, bupropion, or buspirone.
- In some cases, a patient already receiving a serotonergic antidepressant or buspirone may require urgent treatment with linezolid. If alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for two weeks (five weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Symptoms of serotonin syndrome or NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The patient should also be monitored for discontinuation symptoms of the antidepressant.
- An imbalance in mortality was seen in patients treated with linezolid relative to vancomycin/dicloxacillin/oxacillin in an open-label study in seriously ill patients with intravascular catheter-related infections [78/363 (21.5%) vs. 58/363 (16.0%); odds ratio 1.426, 95% CI 0.970, 2.098]. While causality has not been established, this observed imbalance occurred primarily in linezolid-treated patients in whom either Gram-negative pathogens, mixed Gram-negative and Gram-positive pathogens, or no pathogen were identified at baseline, but was not seen in patients with Gram-positive infections only.
- Linezolid is not approved and should not be used for the treatment of patients with catheter-related bloodstream infections or catheter-site infections.
- Linezolid has no clinical activity against Gram-negative pathogens and is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Linezolid, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.
- Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Unless patients are monitored for potential increases in blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents (e.g., pseudoephedrine), vasopressive agents (e.g., epinephrine, norepinephrine), dopaminergic agents (e.g., dopamine, dobutamine).
- Lactic acidosis has been reported with the use of Linezolid. In reported cases, patients experienced repeated episodes of nausea and vomiting. Patients who develop recurrent nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving Linezolid should receive immediate medical evaluation.
- Convulsions have been reported in patients when treated with linezolid. In some of these cases, a history of seizures or risk factors for seizures was reported.
- Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents when treated with linezolid, a reversible, nonselective MAO inhibitor. Some MAO inhibitors have been associated with hypoglycemic episodes in diabetic patients receiving insulin or hypoglycemic agents. While a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be cautioned of potential hypoglycemic reactions when treated with linezolid.
- If hypoglycemia occurs, a decrease in the dose of insulin or oral hypoglycemic agent, or discontinuation of oral hypoglycemic agent, insulin, or linezolid may be required.
- Prescribing Linezolid in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# 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.
- Adults:
- The safety of Linezolid formulations was evaluated in 2046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days.
- Of the patients treated for uncomplicated skin and skin structure infections (uSSSIs), 25.4% of Linezolid-treated and 19.6% of comparator-treated patients experienced at least one drug-related adverse event. For all other indications, 20.4% of Linezolid -treated and 14.3% of comparator-treated patients experienced at least one drug-related adverse event.
- Table 2 shows the incidence of all-causality, treatment-emergent adverse reactions reported in at least 1% of adult patients in these trials by dose of Linezolid.
- Of the patients treated for uSSSIs, 3.5% of Linezolid -treated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 2.1% of Linezolid -treated and 1.7% of comparator-treated patients. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting.
- Pediatric Patients:
- The safety of Linezolid formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 3 comparator-controlled clinical trials and were treated for up to 28 days. In the study of hospitalized pediatric patients (birth through 11 years) with Gram-positive infections, who were randomized 2 to 1 (linezolid: vancomycin), mortality was 6.0% (13/215) in the linezolid arm and 3.0% (3/101) in the vancomycin arm. However, given the severe underlying illness in the patient population, no causality could be established.
- Of the pediatric patients treated for uSSSIs, 19.2% of Linezolid-treated and 14.1% of comparator-treated patients experienced at least one drug-related adverse event. For all other indications, 18.8% of Linezolid-treated and 34.3% of comparator-treated patients experienced at least one drug-related adverse event.
- Table 3 shows the incidence of all-causality, treatment-emergent adverse reactions reported in more than 1% of pediatric patients (and more than 1 patient) in either treatment group in the comparator-controlled Phase 3 trials.
- Of the pediatric patients treated for uSSSIs, 1.6% of Linezolid-treated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 0.9% of Linezolid-treated and 6.1% of comparator-treated patients.
- Laboratory Abnormalities:
- Linezolid has been associated with thrombocytopenia when used in doses up to and including 600 mg every 12 hours for up to 28 days. In Phase 3 comparator-controlled trials, the percentage of adult patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 2.4% (range among studies: 0.3 to 10.0%) with Linezolid and 1.5% (range among studies: 0.4 to 7.0%) with a comparator. In a study of hospitalized pediatric patients ranging in age from birth through 11 years, the percentage of patients who developed a substantially low platelet count (defined as less than 75% of lower limit of normal and/or baseline) was 12.9% with Linezolid and 13.4% with vancomycin. In an outpatient study of pediatric patients aged from 5 through 17 years, the percentage of patients who developed a substantially low platelet count was 0% with Linezolid and 0.4% with cefadroxil. Thrombocytopenia associated with the use of Linezolid appears to be dependent on duration of therapy (generally greater than 2 weeks of treatment). The platelet counts for most patients returned to the normal range/baseline during the follow-up period. No related clinical adverse events were identified in Phase 3 clinical trials in patients developing thrombocytopenia. Bleeding events were identified in thrombocytopenic patients in a compassionate use program for Linezolid; the role of linezolid in these events cannot be determined.
- Changes seen in other laboratory parameters, without regard to drug relationship, revealed no substantial differences between Linezolid and the comparators. These changes were generally not clinically significant, did not lead to discontinuation of therapy, and were reversible. The incidence of adult and pediatric patients with at least one substantially abnormal hematologic or serum chemistry value is presented in Tables 4, 5, 6, and 7.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Linezolid. 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.
- Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported during postmarketing use of Linezolid. Peripheral neuropathy, and optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with Linezolid. Lactic acidosis has been reported with the use of Linezolid. Although these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days, these events have also been reported in patients receiving shorter courses of therapy. Serotonin syndrome has been reported in patients receiving concomitant serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and Linezolid. Convulsions have been reported with the use of Linezolid. Anaphylaxis, angioedema, and bullous skin disorders such as those described as Stevens-Johnson syndrome have been reported. Superficial tooth discoloration and tongue discoloration have been reported with the use of linezolid. The tooth discoloration was removable with professional dental cleaning (manual descaling) in cases with known outcome. Hypoglycemia, including symptomatic episodes, has been reported.
# Drug Interactions
- Drugs Metabolized by Cytochrome P450
- Linezolid is not an inducer of cytochrome P450 (CYP450) in rats. In addition, linezolid does not inhibit the activities of clinically significant human CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major enzymes. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen.
- Antibiotics
- Aztreonam: The pharmacokinetics of linezolid or aztreonam are not altered when administered together.
- Gentamicin: The pharmacokinetics of linezolid or gentamicin are not altered when administered together.
- Antioxidants
- The potential for drug-drug interactions with linezolid and the antioxidants Vitamin C and Vitamin E was studied in healthy volunteers. Subjects were administered a 600 mg oral dose of linezolid on Day 1, and another 600 mg dose of linezolid on Day 8. On Days 2–9, subjects were given either Vitamin C (1000 mg/day) or Vitamin E (800 IU/ day). The AUC0–∞ of linezolid increased 2.3% when co-administered with Vitamin C and 10.9% when co-administered with Vitamin E. No linezolid dose adjustment is recommended during co-administration with Vitamin C or Vitamin E.
- Strong CYP 3A4 Inducers
- Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid Cmax [90% CI, 15% – 27%] and a 32% decrease in linezolid AUC0–12 [90% CI, 27% – 37%]. The clinical significance of this interaction is unknown. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes. Other strong inducers of hepatic enzymes (e.g. carbamazepine, phenytoin, phenobarbital) could cause a similar or smaller decrease in linezolid exposure.
- Monoamine Oxidase Inhibition
- Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
- Adrenergic Agents
- Some individuals receiving Linezolid may experience a reversible enhancement of the pressor response to indirect-acting sympathomimetic agents, vasopressor or dopaminergic agents. Commonly used drugs such as phenylpropanolamine and pseudoephedrine have been specifically studied. Initial doses of adrenergic agents, such as dopamine or epinephrine, should be reduced and titrated to achieve the desired response.
- Tyramine: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content.
- Pseudoephedrine HCl or phenylpropanolamine HCl: A reversible enhancement of the pressor response of either pseudoephedrine HCl (PSE) or phenylpropanolamine HCl (PPA) is observed when linezolid is administered to healthy normotensive subjects. A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, linezolid alone, and the combination of steady-state linezolid (600 mg every 12 hours for 3 days) with two doses of PPA (25 mg) or PSE (60 mg) given 4 hours apart. Heart rate was not affected by any of the treatments. Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2 to 3 hours after the second dose of PPA or PSE, and returned to baseline 2 to 3 hours after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mm Hg: placebo = 121 (103 to 158); linezolid alone = 120 (107 to 135); PPA alone = 125 (106 to 139); PPA with linezolid = 147 (129 to 176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mm Hg (range: 20–52 mm Hg) and 38 mm Hg (range: 18–79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively.
- Serotonergic Agents
- Dextromethorphan: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Linezolid was not teratogenic in mice, rats, or rabbits at exposure levels 6.5-fold (in mice), equivalent to (in rats), or 0.06-fold (in rabbits) the expected human exposure level, based on AUCs. However, embryo and fetal toxicities were seen. There are no adequate and well-controlled studies in pregnant women. Linezolid should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Non-teratogenic Effects
- In mice, embryo and fetal toxicities were seen only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). A dose of 450 mg/kg/day (6.5-fold the estimated human exposure level based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion.
- In rats, mild fetal toxicity was observed at 15 and 50 mg/kg/day (exposure levels 0.22-fold to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Slight maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day.
- In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at a dose of 15 mg/kg/day (0.06-fold the estimated human exposure based on AUCs).
- When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation, survival of pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Linezolid in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Linezolid during labor and delivery.
### Nursing Mothers
- Linezolid and its metabolites are excreted in the milk of lactating rats. Concentrations in milk were similar to those in maternal plasma. It is not known whether linezolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Linezolid is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of Linezolid for the treatment of pediatric patients with the following infections are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from a comparator-controlled study of Gram-positive infections in pediatric patients ranging in age from birth through 11 years:
- nosocomial pneumonia
- complicated skin and skin structure infections
- community-acquired pneumonia (also supported by evidence from an uncontrolled study in patients ranging in age from 8 months through 12 years)
- vancomycin-resistant Enterococcus faecium infections
- The safety and effectiveness of Linezolid for the treatment of pediatric patients with the following infection have been established in a comparator-controlled study in pediatric patients ranging in age from 5 through 17 years:
- uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes
- Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.
- The pharmacokinetics of linezolid have been evaluated in pediatric patients from birth to 17 years of age. In general, weight-based clearance of linezolid gradually decreases with increasing age of pediatric patients. However, in preterm (gestational age < 34 weeks) neonates < 7 days of age, linezolid clearance is often lower than in full-term neonates < 7 days of age. Consequently, preterm neonates < 7 days of age may need an alternative linezolid dosing regimen of 10 mg/kg every 12 hours.
- In limited clinical experience, 5 out of 6 (83%) pediatric patients with infections due to Gram-positive pathogens with minimum inhibitory concentrations (MICs) of 4 mcg/mL treated with Linezolid had clinical cures. However, pediatric patients exhibit wider variability in linezolid clearance and systemic exposure (AUC) compared with adults. In pediatric patients with a sub-optimal clinical response, particularly those with pathogens with MIC of 4 mcg/mL, lower systemic exposure, site and severity of infection, and the underlying medical condition should be considered when assessing clinical response.
### Geriatic Use
- Of the 2046 patients treated with Linezolid in Phase 3 comparator-controlled clinical trials, 589 (29%) were 65 years or older and 253 (12%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out
### Gender
There is no FDA guidance on the use of Linezolid with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Linezolid with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Linezolid in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Linezolid in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Linezolid in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Linezolid in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibiotic therapy.
# IV Compatibility
- Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.
- Physical incompatibilities resulted when Linezolid I.V. Injection was combined with the following drugs during simulated Y-site administration: amphotericin B, chlorpromazine HCl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole. Additionally, chemical incompatibility resulted when Linezolid I.V. Injection was combined with ceftriaxone sodium.
# Overdosage
## Acute Overdose
- In the event of overdosage, supportive care is advised, with maintenance of glomerular filtration. Hemodialysis may facilitate more rapid elimination of linezolid. In a Phase 1 clinical trial, approximately 30% of a dose of linezolid was removed during a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered. Data are not available for removal of linezolid with peritoneal dialysis or hemoperfusion. Clinical signs of acute toxicity in animals were decreased activity and ataxia in rats and vomiting and tremors in dogs treated with 3000 mg/kg/day and 2000 mg/kg/day, respectively.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Linezolid in the drug label.
# Pharmacology
## Mechanism of Action
- Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of isolates.
## Structure
- Linezolid I.V. Injection, Linezolid Tablets, and Linezolid for Oral Suspension contain linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide.
- The empirical formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below:
- Linezolid I.V. Injection is supplied as a ready-to-use sterile isotonic solution for intravenous infusion. Each mL contains 2 mg of linezolid. Inactive ingredients are sodium citrate, citric acid, and dextrose in an aqueous vehicle for intravenous administration. The sodium (Na+) content is 0.38 mg/mL (5 mEq/300-mL bag; 3.3 mEq/200-mL bag; and 1.7 mEq/100-mL bag).
- Linezolid Tablet for oral administration contains 600 mg linezolid as a film-coated compressed tablet. Inactive ingredients are corn starch, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide, and carnauba wax. The sodium (Na+) content is 2.92 mg per 600-mg tablet (0.1 mEq/tablet).
- Linezolid for Oral Suspension is supplied as an orange-flavored granule/powder for constitution into a suspension for oral administration. Following constitution, each 5 mL contains 100 mg of linezolid. Inactive ingredients are sucrose, citric acid, sodium citrate, microcrystalline cellulose and carboxymethylcellulose sodium, aspartame, xanthan gum, mannitol, sodium benzoate, colloidal silicon dioxide, sodium chloride, and flavors. The sodium (Na+) content is 8.52 mg/5 mL (0.4 mEq/5 mL).
## Pharmacodynamics
- In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single Linezolid 600 mg dose via a 1 hour IV infusion, a single Linezolid 1200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1200 mg Linezolid doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.
## Pharmacokinetics
- The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous doses are summarized in Table 8. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours are shown in Figure 1.
- Absorption
- Linezolid is extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously without dose adjustment.
- Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5 hours to 2.2 hours and Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0–∞ is similar under both conditions.
- Distribution
- Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration-independent. The volume of distribution of linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers.
- Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2 to 1 and the ratio of linezolid in sweat relative to plasma was 0.55 to 1.
- Metabolism
- Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite A is presumed to be formed via an enzymatic pathway whereas metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. In vitro studies have demonstrated that linezolid is minimally metabolized and may be mediated by human cytochrome P450. However, the metabolic pathway of linezolid is not fully understood.
- Excretion
- Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min which suggests net tubular reabsorption. Virtually no linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B, and 3% as metabolite A.
- A small degree of nonlinearity in clearance was observed with increasing doses of linezolid, which appears to be due to lower renal and nonrenal clearance of linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life.
- Specific Populations
- Geriatric Patients
- The pharmacokinetics of linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary.
- Pediatric Patients
- The pharmacokinetics of linezolid following a single intravenous dose were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from 12 through 17 years, and in pediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of linezolid are summarized in Table 9 for the pediatric populations studied and healthy adult subjects after administration of single intravenous doses.
- The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, plasma clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, weight-based clearance is most rapid in the youngest age groups ranging from < 1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and a shorter half-life as compared with adults. As the age of pediatric patients increases, the weight-based clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is increased inter-subject variability in linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as compared with adults.
- Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed every 8 hours relative to adolescents or adults dosed every 12 hours. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg every 8 hours. Pediatric patients 12 years and older should receive 600 mg every 12 hours.
- Gender
- Females have a slightly lower volume of distribution of linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender does not appear to be necessary.
- Renal Impairment
- The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal impairment; however, the two primary metabolites of linezolid accumulate in patients with renal impairment, with the amount of accumulation increasing with the severity of renal dysfunction (see Table 10). The pharmacokinetics of linezolid and its two metabolites have also been studied in patients with end-stage renal disease (ESRD) receiving hemodialysis. In the ESRD study, 14 patients were dosed with linezolid 600 mg every 12 hours for 14.5 days (see Table 11). Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal impairment. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of linezolid in patients with renal impairment should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by hemodialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid. Approximately 30% of a dose was eliminated in a 3-hour hemodialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis.
- Hepatic Impairment
- The pharmacokinetics of linezolid are not altered in patients (n=7) with mild-to-moderate hepatic impairment (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild-to-moderate hepatic impairment. The pharmacokinetics of linezolid in patients with severe hepatic impairment have not been evaluated.
- Mechanisms of Resistance
- In clinical trials, resistance to linezolid developed in 6 patients infected with Enterococcus faecium (4 patients received 200 mg every 12 hours, lower than the recommended dose, and 2 patients received 600 mg every 12 hours). In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with Enterococcus faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 × 10 –9 to 1 × 10 –11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to linezolid during its clinical use have been published. There are reports of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during clinical use. The linezolid resistance in these organisms is associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. Also linezolid resistance in staphylococci mediated by the enzyme methyltransferase has been reported. This resistance is mediated by the cfr (chloramphenicol-florfenicol) gene located on a plasmid which is transferable between staphylococci.
- Resistance to linezolid has not been reported in Streptococcus spp., including Streptococcus pneumoniae.
- Interaction with Other Antimicrobials
- In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin.
Gram-positive bacteria
Enterococcus faecium (vancomycin-resistant isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
- Gram-positive bacteria
- Enterococcus faecium (vancomycin-resistant isolates only)
- Staphylococcus aureus (including methicillin-resistant isolates)
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Streptococcus pyogenes
- The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for linezolid. However, the safety and effectiveness of linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Gram-positive bacteria
Enterococcus faecalis (including vancomycin-resistant isolates)
Enterococcus faecium (vancomycin-susceptible isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates)
Staphylococcus haemolyticus
Viridans group streptococci
Gram-negative bacteria
Pasteurella multocida
- Gram-positive bacteria
- Enterococcus faecalis (including vancomycin-resistant isolates)
- Enterococcus faecium (vancomycin-susceptible isolates)
- Staphylococcus epidermidis (including methicillin-resistant isolates)
- Staphylococcus haemolyticus
- Viridans group streptococci
- Gram-negative bacteria
- Pasteurella multocida
- Susceptibility Test Methods
- When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
- Dilution techniques
- Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized method1,2 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 12.
- Diffusion techniques
- Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method2,3. This procedure uses paper disks impregnated with 30 mcg linezolid to test the susceptibility of bacteria to linezolid. The disk diffusion interpretive criteria are provided in Table 12.
- A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
- Quality Control
- Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3. Standard linezolid powder should provide the following range of MIC values noted in Table 13. For the diffusion technique using the 30 mcg linezolid disk, the criteria in Table 13 should be achieved.
## Nonclinical Toxicology
- Lifetime studies in animals have not been conducted to evaluate the carcinogenic potential of linezolid. Neither mutagenic nor clastogenic potential was found in a battery of tests including: assays for mutagenicity (Ames bacterial reversion and CHO cell mutation), an in vitro unscheduled DNA synthesis (UDS) assay, an in vitro chromosome aberration assay in human lymphocytes, and an in vivo mouse micronucleus assay.
- Linezolid did not affect the fertility or reproductive performance of adult female rats. It reversibly decreased fertility and reproductive performance in adult male rats when given at doses ≥ 50 mg/kg/day, with exposures approximately equal to or greater than the expected human exposure level (exposure comparisons are based on AUCs). The reversible fertility effects were mediated through altered spermatogenesis. Affected spermatids contained abnormally formed and oriented mitochondria and were non-viable. Epithelial cell hypertrophy and hyperplasia in the epididymis was observed in conjunction with decreased fertility. Similar epididymal changes were not seen in dogs.
- In sexually mature male rats exposed to drug as juveniles, mildly decreased fertility was observed following treatment with linezolid through most of their period of sexual development (50 mg/kg/day from days 7 to 36 of age, and 100 mg/kg/day from days 37 to 55 of age), with exposures up to 1.7-fold greater than mean AUCs observed in pediatric patients aged 3 months to 11 years. Decreased fertility was not observed with shorter treatment periods, corresponding to exposure in utero through the early neonatal period (gestation day 6 through postnatal day 5), neonatal exposure (postnatal days 5 to 21), or to juvenile exposure (postnatal days 22 to 35). Reversible reductions in sperm motility and altered sperm morphology were observed in rats treated from postnatal day 22 to 35.
- Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose- and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss, and suppression of body weight gain, which may have contributed to the observed effects.
- In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.
- These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.
# Clinical Studies
- Nosocomial Pneumonia
- Adult patients with clinically and radiologically documented nosocomial pneumonia were enrolled in a randomized, multi-center, double-blind trial. Patients were treated for 7 to 21 days. One group received Linezolid I.V. Injection 600 mg every 12 hours, and the other group received vancomycin 1 g every 12 hours intravenously. Both groups received concomitant aztreonam (1 to 2 g every 8 hours intravenously), which could be continued if clinically indicated. There were 203 linezolid-treated and 193 vancomycin-treated patients enrolled in the study. One hundred twenty-two (60%) linezolid-treated patients and 103 (53%) vancomycin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 57% for linezolid-treated patients and 60% for vancomycin-treated patients. The cure rates in clinically evaluable patients with ventilator-associated pneumonia were 47% for linezolid-treated patients and 40% for vancomycin-treated patients. A modified intent-to-treat (MITT) analysis of 94 linezolid-treated patients and 83 vancomycin-treated patients included subjects who had a pathogen isolated before treatment. The cure rates in the MITT analysis were 57% in linezolid-treated patients and 46% in vancomycin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 14.
- Complicated Skin and Skin Structure Infections
- Adult patients with clinically documented complicated skin and skin structure infections were enrolled in a randomized, multi-center, double-blind, double-dummy trial comparing study medications administered intravenously followed by medications given orally for a total of 10 to 21 days of treatment. One group of patients received Linezolid I.V. Injection 600 mg every 12 hours followed by Linezolid Tablets 600 mg every 12 hours; the other group received oxacillin 2 g every 6 hours intravenously followed by dicloxacillin 500 mg every 6 hours orally. Patients could receive concomitant aztreonam if clinically indicated. There were 400 linezolid-treated and 419 oxacillin-treated patients enrolled in the study. Two hundred forty-five (61%) linezolid-treated patients and 242 (58%) oxacillin-treated patients were clinically evaluable. The cure rates in clinically evaluable patients were 90% in linezolid-treated patients and 85% in oxacillin-treated patients. A modified intent-to-treat (MITT) analysis of 316 linezolid-treated patients and 313 oxacillin-treated patients included subjects who met all criteria for study entry. The cure rates in the MITT analysis were 86% in linezolid-treated patients and 82% in oxacillin-treated patients. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 15.
- A separate study provided additional experience with the use of Linezolid in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. This was a randomized, open-label trial in hospitalized adult patients with documented or suspected MRSA infection.
- One group of patients received Linezolid I.V. Injection 600 mg every 12 hours followed by Linezolid Tablets 600 mg every 12 hours. The other group of patients received vancomycin 1 g every 12 hours intravenously. Both groups were treated for 7 to 28 days, and could receive concomitant aztreonam or gentamicin if clinically indicated. The cure rates in microbiologically evaluable patients with MRSA skin and skin structure infection were 26/33 (79%) for linezolid-treated patients and 24/33 (73%) for vancomycin-treated patients.
- Diabetic Foot Infections
- Adult diabetic patients with clinically documented complicated skin and skin structure infections ("diabetic foot infections") were enrolled in a randomized (2:1 ratio), multi-center, open-label trial comparing study medications administered intravenously or orally for a total of 14 to 28 days of treatment. One group of patients received Linezolid 600 mg every 12 hours intravenously or orally; the other group received ampicillin/sulbactam 1.5 to 3 g intravenously or amoxicillin/clavulanate 500 to 875 mg every 8 to 12 hours orally. In countries where ampicillin/sulbactam is not marketed, amoxicillin/clavulanate 500 mg to 2 g every 6 hours was used for the intravenous regimen. Patients in the comparator group could also be treated with vancomycin 1 g every 12 hours intravenously if MRSA was isolated from the foot infection. Patients in either treatment group who had Gram-negative bacilli isolated from the infection site could also receive aztreonam 1 to 2 g every 8–12 hours intravenously. All patients were eligible to receive appropriate adjunctive treatment methods, such as debridement and off-loading, as typically required in the treatment of diabetic foot infections, and most patients received these treatments. There were 241 linezolid-treated and 120 comparator-treated patients in the intent-to-treat (ITT) study population. Two hundred twelve (86%) linezolid-treated patients and 105 (85%) comparator-treated patients were clinically evaluable. In the ITT population, the cure rates were 68.5% (165/241) in linezolid-treated patients and 64% (77/120) in comparator-treated patients, where those with indeterminate and missing outcomes were considered failures. The cure rates in the clinically evaluable patients (excluding those with indeterminate and missing outcomes) were 83% (159/192) and 73% (74/101) in the linezolid- and comparator-treated patients, respectively. A critical post-hoc analysis focused on 121 linezolid-treated and 60 comparator-treated patients who had a Gram-positive pathogen isolated from the site of infection or from blood, who had less evidence of underlying osteomyelitis than the overall study population, and who did not receive prohibited antimicrobials. Based upon that analysis, the cure rates were 71% (86/121) in the linezolid-treated patients and 63% (38/60) in the comparator-treated patients. None of the above analyses were adjusted for the use of adjunctive therapies. The cure rates by pathogen for microbiologically evaluable patients are presented in Table 16.
- Vancomycin-Resistant Enterococcal Infections
- Adult patients with documented or suspected vancomycin-resistant enterococcal infection were enrolled in a randomized, multi-center, double-blind trial comparing a high dose of Linezolid (600 mg) with a low dose of Linezolid (200 mg) given every 12 hours either intravenously (IV) or orally for 7 to 28 days. Patients could receive concomitant aztreonam or aminoglycosides. There were 79 patients randomized to high-dose linezolid and 66 to low-dose linezolid. The intent-to-treat (ITT) population with documented vancomycin-resistant enterococcal infection at baseline consisted of 65 patients in the high-dose arm and 52 in the low-dose arm.
- The cure rates for the ITT population with documented vancomycin-resistant enterococcal infection at baseline are presented in Table 17 by source of infection. These cure rates do not include patients with missing or indeterminate outcomes. The cure rate was higher in the high-dose arm than in the low-dose arm, although the difference was not statistically significant at the 0.05 level.
- Infections due to Gram-positive Bacteria
- A safety and efficacy study provided experience on the use of Linezolid in pediatric patients for the treatment of nosocomial pneumonia, complicated skin and skin structure infections, catheter-related bacteremia, bacteremia of unidentified source, and other infections due to Gram-positive bacterial pathogens, including methicillin-resistant and -susceptible Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Pediatric patients ranging in age from birth through 11 years with infections caused by the documented or suspected Gram-positive bacteria were enrolled in a randomized, open-label, comparator-controlled trial. One group of patients received Linezolid I.V. Injection 10 mg/kg every 8 hours followed by Linezolid for Oral Suspension 10 mg/kg every 8 hours. A second group received vancomycin 10 to 15 mg/kg intravenously every 6 to 24 hours, depending on age and renal clearance. Patients who had confirmed VRE infections were placed in a third arm of the study and received Linezolid 10 mg/kg every 8 hours intravenously and/or orally. All patients were treated for a total of 10 to 28 days and could receive concomitant Gram-negative antibiotics if clinically indicated. In the intent-to-treat (ITT) population, there were 206 patients randomized to linezolid and 102 patients randomized to vancomycin. The cure rates for ITT, MITT, and clinically evaluable patients are presented in Table 18. After the study was completed, 13 additional patients ranging from 4 days through 16 years of age were enrolled in an open-label extension of the VRE arm of the study. Table 19 provides clinical cure rates by pathogen for microbiologically evaluable patients including microbiologically evaluable patients with vancomycin-resistant Enterococcus faecium from the extension of this study.
# How Supplied
- Injection
- Linezolid I.V. Injection is available in single-use, ready-to-use flexible plastic infusion bags in a foil laminate overwrap. The infusion bags and ports are latex-free. The infusion bags are available in the following package sizes:
100 mL bag (200 mg linezolid) NDC 0009-5137-01
200 mL bag (400 mg linezolid) NDC 0009-5139-01
300 mL bag (600 mg linezolid) NDC 0009-5140-01
- 100 mL bag (200 mg linezolid) NDC 0009-5137-01
- 200 mL bag (400 mg linezolid) NDC 0009-5139-01
- 300 mL bag (600 mg linezolid) NDC 0009-5140-01
- Tablets
- Linezolid Tablets are available as follows:
600 mg (white, capsule-shaped, film-coated tablets printed with "Linezolid 600 mg")
100 tablets in HDPE bottle NDC 0009-5135-01
20 tablets in HDPE bottle NDC 0009-5135-02
Unit dose packages of 30 tablets NDC 0009-5135-03
- 600 mg (white, capsule-shaped, film-coated tablets printed with "Linezolid 600 mg")
- 100 tablets in HDPE bottle NDC 0009-5135-01
- 20 tablets in HDPE bottle NDC 0009-5135-02
- Unit dose packages of 30 tablets NDC 0009-5135-03
- Oral Suspension
- Linezolid for Oral Suspension is available as a dry, white to off-white, orange-flavored granule/powder. When constituted as directed, each bottle will contain 150 mL of a suspension providing the equivalent of 100 mg of linezolid per each 5 mL. Linezolid for Oral Suspension is supplied as follows:
100 mg/5 mL in 240-mL glass bottles NDC 0009-5136-01
- 100 mg/5 mL in 240-mL glass bottles NDC 0009-5136-01
- Storage
- Store at 25°C (77°F). Protect from light. Keep bottles tightly closed to protect from moisture. It is recommended that the infusion bags be kept in the overwrap until ready to use. Protect infusion bags from freezing.
## Storage
There is limited information regarding Linezolid Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including Linezolid should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Linezolid is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Linezolid or other antibacterial drugs in the future.
- Patients should be advised that:
- Linezolid may be taken with or without food.
- They should inform their physician if they have a history of hypertension.
- Large quantities of foods or beverages with high tyramine content should be avoided while taking Linezolid. Foods high in tyramine content include those that may have undergone protein changes by aging, fermentation, pickling, or smoking to improve flavor, such as aged cheeses ,fermented or air-dried meats ,sauerkraut , soy sauce, tap beers, and red wines. The tyramine content of any protein-rich food may be increased if stored for long periods or improperly refrigerated.
- They should inform their physician if taking medications containing pseudoephedrine HCl or phenylpropanolamine HCl, such as cold remedies and decongestants.
- They should inform their physician if taking serotonin re-uptake inhibitors or other antidepressants.
- Phenylketonurics: Each 5 mL of the 100 mg/5 mL Linezolid for Oral Suspension contains 20 mg phenylalanine. The other Linezolid formulations do not contain phenylalanine. Contact your physician or pharmacist.
- They should inform their physician if they experience changes in vision.
- They should inform their physician if they have a history of seizures.
- Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
- Inform patient, particularly those with diabetes mellitus that hypoglycemic reactions, such as diaphoresis and tremulousness, along with low blood glucose measurements may occur when treated with linezolid. If such reactions occur, patients should contact a physician or other health professional for proper treatment.
# Precautions with Alcohol
- Alcohol-Linezolid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ZYVOX[4]
# Look-Alike Drug Names
- ZYVOX® — Vioxx®
- ZYVOX® — Zovirax®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Linezolid | |
3570f84fa228e879b13f618a4cb58f648bec7b7b | wikidoc | Lipiduria | Lipiduria
# Overview
Lipiduria, also termed Lipuria, is the presence of lipids in the urine.1
# Differential diagnosis of causes of lipiduria
It most frequently observed in nephrotic syndrome where it is passed as lipoproteins along with other proteins.
It has also been reported as a sign following fat embolism. | Lipiduria
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Lipiduria, also termed Lipuria, is the presence of lipids in the urine.1
# Differential diagnosis of causes of lipiduria
It most frequently observed in nephrotic syndrome where it is passed as lipoproteins along with other proteins.[1]
It has also been reported as a sign following fat embolism.[2] | https://www.wikidoc.org/index.php/Lipiduria | |
94f61141d3de4401e69acb5c0f5ff4b57dcae8c9 | wikidoc | Lithotomy | Lithotomy
Steven C. Campbell, M.D., Ph.D.
# Overview
Lithotomy from Greek for "lithos" (stone) and "thomos" (cut), is a surgical method for removal of calculi, stones formed inside certain hollow organs, such as the bladder and kidneys (urinary calculus) and gallbladder (gallstones), that cannot exit naturally through the urethra, ureter or biliary duct. The procedure, which is usually done by means of a surgical incision (therefore invasive), differs from lithotripsy, whereas the stones are crushed either by a minimally invasive probe inserted through the exit canal, or by ultrasound waves (extracorporeal lithotripsy), which is a non-invasive procedure.
# History
Human beings have known of bladder stones ("vesical calculi") for thousands of years, and have attempted to treat them for almost as long. The oldest bladder stone that has been found was discovered in Egypt around 1900, and it has been dated to 4900 BC. The earliest written records describing bladder stones date to before the time of Hippocrates (ca. 460-370 BC). Hippocrates himself wrote that, “To cut through the bladder is lethal.”
However, lithotomy was a fairly common procedure in the past, and there were specialized lithotomists. The ancient Greek Hippocratic Oath includes the phrase: ”I will not cut for stone, even for the patients in whom the disease is manifest; I will leave this operation to be performed by practitioners,” a clear warning for physicians against the "cutting" of persons "laboring under the stone"; an act that was better left to surgeons (who were distinct from physicians at that time in history).
Operations to remove bladder stones via the perineum were performed by Hindus, Greeks, Romans, and Arabs. Ammonius Lithotomos (200 BC), Celsus (first century), and the Hindu surgeon Susruta produced early descriptions of bladder stone treatment using perineal lithotomy.
In 1000, Abu al-Qasim al-Zahrawi (Abulcasis), in his Al-Tasrif, described a more successful extraction of bladder and kidney stones from the urinary bladder using a new instrument he invented—a lithotomy scalpel with two sharp cutting edges—and a new technique he invented—perineal cystolithotomy—which allowed him to crush a large stone inside the bladder, "enabling its piecemeal removal." This innovation was important to the development of bladder stone surgery as it significantly decreased the death rates previously caused by earlier attempts at this operation.
In the 1500s, Pierre Franco (1505-1578) was a pioneer in the suprapubic lithotomy method. Frère Jacques Beaulieu developed an operation that went in laterally to remove the bladder stones in the late 1600s. Beaulieu was a travelling lithotomist with scant knowledge of anatomy and a Dominican Friar. Beaulieu performed the frequently deadly procedure in France into the early 1700s.
The urologic community often claims Beaulieu is subject of the French nursery rhyme Frère Jacques Beaulieu, but this is not well-established. A possible connection between Frère Jacques and the Frère Jacques Beaulieu (also known as Frère Jacques Baulot) , as claimed by Irvine Loudon and many others, was explored by J. P. Ganem and C. C. Carson without finding any evidence for a connection.
Some have suggested that Frère Jacques Beaulieu was instead written to mock the Jacobin] monks of France (Jacobins are what the Dominicans are called in Paris).
Lithotomy was advanced in the 18th century. Important names in its historical development were Jean Zuléma Amussat (1796-1856), Auguste Nélaton (1807-1873), Henry Thompson (1820-1904) and William Cheselden (1688-1752). The later invented a technique for lateral vesical stone lithotomy in 1727, whereupon he was said to perform the operation in about one minute time (an important feat before anesthesia).
Special surgical instruments were designed for lithotomy, consisting of dilators of the canal, forceps and tweezers, lithotomes (stone cutter) and cystotomes (bladder cutter), urethrotomes (for incisions of the urethra) and conductors, (grooved probes used as guides for stone extraction). The patient is placed in a special position in a lithotomy surgical table, called the lithotomy position (which, curiously, retains this name until present for other unrelated medical procedures).
Transurethral lithotripsy, which was much simpler and with lower morbidity, complication and mortality rates, was invented by French surgeon Jean Civiale (1792-1867) and largely substituted for surgical lithotomy, unless the crushing of calculi was difficult or impossible. | Lithotomy
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
Lithotomy from Greek for "lithos" (stone) and "thomos" (cut), is a surgical method for removal of calculi, stones formed inside certain hollow organs, such as the bladder and kidneys (urinary calculus) and gallbladder (gallstones), that cannot exit naturally through the urethra, ureter or biliary duct. The procedure, which is usually done by means of a surgical incision (therefore invasive), differs from lithotripsy, whereas the stones are crushed either by a minimally invasive probe inserted through the exit canal, or by ultrasound waves (extracorporeal lithotripsy), which is a non-invasive procedure.
# History
Human beings have known of bladder stones ("vesical calculi") for thousands of years, and have attempted to treat them for almost as long. The oldest bladder stone that has been found was discovered in Egypt around 1900, and it has been dated to 4900 BC. The earliest written records describing bladder stones date to before the time of Hippocrates (ca. 460-370 BC). Hippocrates himself wrote that, “To cut through the bladder is lethal.”
However, lithotomy was a fairly common procedure in the past, and there were specialized lithotomists. The ancient Greek Hippocratic Oath includes the phrase: ”I will not cut for stone, even for the patients in whom the disease is manifest; I will leave this operation to be performed by practitioners,” a clear warning for physicians against the "cutting" of persons "laboring under the stone"; an act that was better left to surgeons (who were distinct from physicians at that time in history).
Operations to remove bladder stones via the perineum were performed by Hindus, Greeks, Romans, and Arabs. Ammonius Lithotomos (200 BC), Celsus (first century), and the Hindu surgeon Susruta produced early descriptions of bladder stone treatment using perineal lithotomy.
In 1000, Abu al-Qasim al-Zahrawi (Abulcasis), in his Al-Tasrif, described a more successful extraction of bladder and kidney stones from the urinary bladder using a new instrument he invented—a lithotomy scalpel with two sharp cutting edges—and a new technique he invented—perineal cystolithotomy—which allowed him to crush a large stone inside the bladder, "enabling its piecemeal removal." This innovation was important to the development of bladder stone surgery as it significantly decreased the death rates previously caused by earlier attempts at this operation.[1]
In the 1500s, Pierre Franco (1505-1578) was a pioneer in the suprapubic lithotomy method.[2] Frère Jacques Beaulieu developed an operation that went in laterally to remove the bladder stones in the late 1600s. Beaulieu was a travelling lithotomist with scant knowledge of anatomy and a Dominican Friar. Beaulieu performed the frequently deadly procedure in France into the early 1700s.
The urologic community often claims Beaulieu is subject of the French nursery rhyme Frère Jacques Beaulieu, but this is not well-established. A possible connection between Frère Jacques and the Frère Jacques Beaulieu (also known as Frère Jacques Baulot[3][4]) , as claimed by Irvine Loudon [5] and many others, was explored by J. P. Ganem and C. C. Carson [6] without finding any evidence for a connection.
Some have suggested that Frère Jacques Beaulieu was instead written to mock the Jacobin] monks of France (Jacobins are what the Dominicans are called in Paris).[7]
Lithotomy was advanced in the 18th century. Important names in its historical development were Jean Zuléma Amussat (1796-1856), Auguste Nélaton (1807-1873), Henry Thompson (1820-1904) and William Cheselden (1688-1752). The later invented a technique for lateral vesical stone lithotomy in 1727, whereupon he was said to perform the operation in about one minute time (an important feat before anesthesia).
Special surgical instruments were designed for lithotomy, consisting of dilators of the canal, forceps and tweezers, lithotomes (stone cutter) and cystotomes (bladder cutter), urethrotomes (for incisions of the urethra) and conductors, (grooved probes used as guides for stone extraction). The patient is placed in a special position in a lithotomy surgical table, called the lithotomy position (which, curiously, retains this name until present for other unrelated medical procedures).
Transurethral lithotripsy, which was much simpler and with lower morbidity, complication and mortality rates, was invented by French surgeon Jean Civiale (1792-1867) and largely substituted for surgical lithotomy, unless the crushing of calculi was difficult or impossible. | https://www.wikidoc.org/index.php/Lithotomy | |
867ae7d7e0495fc88366ca6eb4f414ed26c10ab0 | wikidoc | User:Ludi | User:Ludi
Liudvikas Jagminas, M.D., FACEP, Associate Professor (Clinical) in Emergency Medicine, Brown Medical School; Physician-in-Chief, Department of Emergency Medicine Memorial Hospital of Rhode Island; Medical Director, Barrington Urgent Care Center
Contact: ; Phone: 401-729-2419
Address: Liudvikas Jagminas, M.D., FACEP Memorial Hospital of Rhode Island 111 Brewster St Pawtucket, RI 02860
# Education
1981: Stonehill College, North Easton, MA, B.S., Biology
1987: Brown University Medical School, Providence, RI, Doctor of Medicine
# Internship
1987-1988: The Miriam Hospital
Brown University Medical School
Providence, RI
Internal Medicine
# Residency
1988-1991: Long Island Jewish Medical Center
and Albert Einstein College of Medicine
New Hyde Park, NY
Emergency Medicine
# Positions and Employment
1991-2003: Attending Physician, Emergency Medicine, Rhode Island Hospital, Providence, RI
1995-2003: Medical Director for Trauma, Rhode Island Hospital, Providence, RI
1995-present: Division Director, Emergency Medicine, Department of Surgey, Rhode Island Hospital
1996-present: Assistant Professor in Surgery, Brown University School of Medicine, Providence, RI
2003-present: Physician-in-Chief, Department of Emergency Medicine, Memorial Hospital of RI
# Postgraduate Honors and Awards
2000: The Jacek Franaszek Faculty Teaching Award, Rhode Island Hospital, Department of Emergency Medicine
2006: Teaching Recognition Award, Brown Medical School
2006: Top Doc in Emergency Medicine, RI Monthly Magazine
2008: Dean's Teaching Excellence Award, Exemplary teaching in preclinical courses and core clerkships, Brown Medical School
# Academic Appointments
July 1992 - September 1995: Instructor in Medicine, Brown Medical School
September 1995 - 1996: Assistant Professor in Medicine, Brown Medical School
September 1996 – September 2003: Assistant Professor in Surgery, Brown Medical School
September 2003 – July 2004: Assistant Professor (Clinical) in Surgery, Brown Medical School
July 2004 – July 2007: Assistant Professor (Clinical) in Emergency Medicine, Brown Medical School
July 2007 - present: Associate Professor (Clinical) in Emergency Medicine, Brown Medical School | User:Ludi
Liudvikas Jagminas, M.D., FACEP, Associate Professor (Clinical) in Emergency Medicine, Brown Medical School; Physician-in-Chief, Department of Emergency Medicine Memorial Hospital of Rhode Island; Medical Director, Barrington Urgent Care Center
Contact: [1] ; Phone: 401-729-2419
Address: Liudvikas Jagminas, M.D., FACEP Memorial Hospital of Rhode Island 111 Brewster St Pawtucket, RI 02860
# Education
1981: Stonehill College, North Easton, MA, B.S., Biology
1987: Brown University Medical School, Providence, RI, Doctor of Medicine
# Internship
1987-1988: The Miriam Hospital
Brown University Medical School
Providence, RI
Internal Medicine
# Residency
1988-1991: Long Island Jewish Medical Center
and Albert Einstein College of Medicine
New Hyde Park, NY
Emergency Medicine
# Positions and Employment
1991-2003: Attending Physician, Emergency Medicine, Rhode Island Hospital, Providence, RI
1995-2003: Medical Director for Trauma, Rhode Island Hospital, Providence, RI
1995-present: Division Director, Emergency Medicine, Department of Surgey, Rhode Island Hospital
1996-present: Assistant Professor in Surgery, Brown University School of Medicine, Providence, RI
2003-present: Physician-in-Chief, Department of Emergency Medicine, Memorial Hospital of RI
# Postgraduate Honors and Awards
2000: The Jacek Franaszek Faculty Teaching Award, Rhode Island Hospital, Department of Emergency Medicine
2006: Teaching Recognition Award, Brown Medical School
2006: Top Doc in Emergency Medicine, RI Monthly Magazine
2008: Dean's Teaching Excellence Award, Exemplary teaching in preclinical courses and core clerkships, Brown Medical School
# Academic Appointments
July 1992 - September 1995: Instructor in Medicine, Brown Medical School
September 1995 - 1996: Assistant Professor in Medicine, Brown Medical School
September 1996 – September 2003: Assistant Professor in Surgery, Brown Medical School
September 2003 – July 2004: Assistant Professor (Clinical) in Surgery, Brown Medical School
July 2004 – July 2007: Assistant Professor (Clinical) in Emergency Medicine, Brown Medical School
July 2007 - present: Associate Professor (Clinical) in Emergency Medicine, Brown Medical School | https://www.wikidoc.org/index.php/Liudvikas_Jagminas | |
c3c355b23756a0cc655ea0a2cf0ea96074d692ed | wikidoc | Liver (2) | Liver (2)
The liver is an organ present in vertebrates and some other animals. It plays a major role in metabolism and has a number of functions in the body, including glycogen storage, plasma protein synthesis, and detoxification. This organ also is the largest gland in the human body. It lies below the diaphragm in the thoracic region of the abdomen.It produces bile, an alkaline compound which aids in digestion, via the emulsification of lipids. It also performs and regulates a wide variety of high-volume biochemical reactions requiring specialized tissues.
Medical terms related to the liver often start in hepato- or hepatic from the Greek word for liver, hēpar (ήπαρ).
# Anatomy
The adult human liver normally weighs between 1.4 - 1.6 kilograms (3.1 - 3.5 pounds), and it is a soft, pinkish-brown "boomerang shaped" organ. It is the second largest organ (the largest organ being the skin) and the largest gland within the human body.
It is located on the right side of the upper abdomen below the diaphragm. The liver lies on the left of the stomach and makes a kind of bed for the gallbladder (which stores bile).
## Flow of blood
The splenic vein, joins the inferior mesenteric vein, which then together join with the superior mesenteric vein to form the portal vein, bringing venous blood from the spleen, pancreas, small intestine, and large intestine, so that the liver can process the nutrients and byproducts of food digestion.
The hepatic veins drain directly into the inferior vena cava.
The hepatic artery is generally a branch from the celiac trunk, although occasionally some or all of the blood can be from other branches such as the superior mesenteric artery.
Approximately 60% to 80% of the blood flow to the liver is from the portal venous system, and 1/4 is from the hepatic artery.
## Flow of bile
The bile produced in the liver is collected in bile canaliculi, which merge to form bile ducts.
These eventually drain into the right and left hepatic ducts, which in turn merge to form the common hepatic duct. The cystic duct (from the gallbladder) joins with the common hepatic duct to form the common bile duct.
Bile can either drain directly into the duodenum via the common bile duct or be temporarily stored in the gallbladder via the cystic duct. The common bile duct and the pancreatic duct enter the duodenum together at the ampulla of Vater.
The branchings of the bile ducts resemble those of a tree, and indeed the term "biliary tree" is commonly used in this setting.
## Regeneration
The liver is among the few internal human organs capable of natural regeneration of lost tissue; as little as 25% of remaining liver can regenerate into a whole liver again.
This is predominantly due to the hepatocytes acting as unipotential stem cells (i.e. a single hepatocyte can divide into two hepatocyte daughter cells). There is also some evidence of bipotential stem cells, called oval cells, which can differentiate into either hepatocytes or cholangiocytes (cells that line the bile ducts).
## Traditional (Surface) anatomy
### Peritoneal ligaments
Apart from a patch where it connects to the diaphragm, the liver is covered entirely by visceral peritoneum, a thin, double-layered membrane that reduces friction against other organs. The peritoneum folds back on itself to form the falciform ligament and the right and left triangular ligaments.
These "ligaments" are in no way related to the true anatomic ligaments in joints, and have essentially no functional importance, but they are easily recognizable surface landmarks.
### Lobes
Traditional gross anatomy divided the liver into four lobes based on surface features.
The falciform ligament is visible on the front (anterior side) of the liver. This divides the liver into a left anatomical lobe, and a right anatomical lobe.
If the liver flipped over, to look at it from behind (the visceral surface), there are two additional lobes between the right and left. These are the caudate lobe (the more superior), and below this the quadrate lobe.
From behind, the lobes are divided up by the ligamentum venosum and ligamentum teres (anything left of these is the left lobe), the transverse fissure (or porta hepatis) divides the caudate from the quadrate lobe, and the right sagittal fossa, which the inferior vena cava runs over, separates these two lobes from the right lobe.
Each of the lobes is made up of lobules, a vein goes from the centre of each lobule which then joins to the hepatic vein to carry blood out from the liver.
On the surface of the lobules there are ducts, veins and arteries that carry fluids to and from them.
## Modern (Functional) anatomy
The central area where the common bile duct, portal vein, and hepatic artery enter the liver is the hilum or "porta hepatis". The duct, vein, and artery divide into left and right branches, and the portions of the liver supplied by these branches constitute the functional left and right lobes.
The functional lobes are separated by a plane joining the gallbladder fossa to the inferior vena cava. This separates the liver into the true right and left lobes. The middle hepatic vein also demarcates the true right and left lobes. The right lobe is further divided into an anterior and posterior segment by the right hepatic vein. The left lobe is divided into the medial and lateral segments by the left hepatic vein. The fissure for the ligamentum teres (the ligamentum teres becomes the falciform ligament) also separates the medial and lateral segmants. The medial segment is what used to be called the quadrate lobe. In the widely used Couinaud or "French" system, the functional lobes are further divided into a total of eight subsegments based on a transverse plane through the bifurcation of the main portal vein. The caudate lobe is a separate structure which receives blood flow from both the right- and left-sided vascular branches. The subsegments corresponding to the anatomical lobes are as follows:
- or lobe in the Caudate's case.
Each number in the list corresponds to one in the table.
- Caudate
- Superior subsegment of the lateral segment
- Inferior subsegment of the lateral segment
- Superior subsegment of the medial segment
Inferior subsegment of the medial segment
- Superior subsegment of the medial segment
- Inferior subsegment of the medial segment
- Inferior subsegment of the anterior segment
- Inferior subsegment of the posterior segment
- Superior subsegment of the posterior segment
- Superior subsegment of the anterior segment
# Physiology
The various functions of the liver are carried out by the liver cells or hepatocytes.
- The liver produces and excretes bile (a greenish liquid) required for emulsifying fats. Some of the bile drains directly into the duodenum, and some is stored in the gallbladder.
- The liver performs several roles in carbohydrate metabolism:
Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
Glycogenolysis (the breakdown of glycogen into glucose) (muscle tissues can also do this)
Glycogenesis (the formation of glycogen from glucose)
The breakdown of insulin and other hormones
The liver is responsible for the mainstay of protein metabolism.
- Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
- Glycogenolysis (the breakdown of glycogen into glucose) (muscle tissues can also do this)
- Glycogenesis (the formation of glycogen from glucose)
- The breakdown of insulin and other hormones
- The liver is responsible for the mainstay of protein metabolism.
- The liver also performs several roles in lipid metabolism:
Cholesterol synthesis
The production of triglycerides (fats).
- Cholesterol synthesis
- The production of triglycerides (fats).
- The liver produces coagulation factors I (fibrinogen), II (prothrombin), V, VII, IX, X and XI, as well as protein C, protein S and antithrombin.
- The liver breaks down haemoglobin, creating metabolites that are added to bile as pigment (bilirubin and biliverdin).
- The liver breaks down toxic substances and most medicinal products in a process called drug metabolism. This sometimes results in toxication, when the metabolite is more toxic than its precursor.
- The liver converts ammonia to urea.
- The liver stores a multitude of substances, including glucose in the form of glycogen, vitamin B12, iron, and copper.
- In the first trimester fetus, the liver is the main site of red blood cell production. By the 32nd week of gestation, the bone marrow has almost completely taken over that task.
- The liver is responsible for immunological effects- the reticuloendothelial system of the liver contains many immunologically active cells, acting as a 'sieve' for antigens carried to it via the portal system.
Currently, there is no artificial organ or device capable of emulating all the functions of the liver. Some functions can be emulated by liver dialysis, an experimental treatment for liver failure.
# Diseases of the liver
Many diseases of the liver are accompanied by jaundice caused by increased levels of bilirubin in the system. The bilirubin results from the breakup of the hemoglobin of dead red blood cells; normally, the liver removes bilirubin from the blood and excretes it through bile.
- Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons, autoimmunity or hereditary conditions.
- Cirrhosis is the formation of fibrous tissue in the liver, replacing dead liver cells. The death of the liver cells can for example be caused by viral hepatitis, alcoholism or contact with other liver-toxic chemicals.
- Haemochromatosis, a hereditary disease causing the accumulation of iron in the body, eventually leading to liver damage.
- Cancer of the liver (primary hepatocellular carcinoma or cholangiocarcinoma and metastatic cancers, usually from other parts of the gastrointestinal tract).
- Wilson's disease, a hereditary disease which causes the body to retain copper.
- Primary sclerosing cholangitis, an inflammatory disease of the bile duct, autoimmune in nature.
- Primary biliary cirrhosis, autoimmune disease of small bile ducts.
- Budd-Chiari syndrome, obstruction of the hepatic vein.
- Gilbert's syndrome, a genetic disorder of bilirubin metabolism, found in about 5% of the population.
- Glycogen storage disease type II,The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.
There are also many pediatric liver disease, including biliary atresia, alpha-1 antitrypsin deficiency, alagille syndrome, and progressive familial intrahepatic cholestasis, to name but a few.
A number of liver function tests are available to test the proper function of the liver. These test for the presence of enzymes in blood that are normally most abundant in liver tissue, metabolites or products.
# Liver transplantation
Human liver transplant was first performed by Thomas Starzl in USA and Roy Calne in England in 1963 and 1965 respectively.
Liver transplantation is the only option for those with irreversible liver failure. Most transplants are done for chronic liver diseases leading to cirrhosis, such as chronic hepatitis C, alcoholism, autoimmune hepatitis, and many others. Less commonly, liver transplantation is done for fulminant hepatic failure, in which liver failure occurs over days to weeks.
Liver allografts for transplant usually come from non-living donors who have died from fatal brain injury. Living donor liver transplantation is a technique in which a portion of a living person's liver is removed and used to replace the entire liver of the recipient. This was first performed in 1989 for pediatric liver transplantation. Only 20% of an adult's liver (Couinaud segments 2 and 3) is needed to serve as a liver allograft for an infant or small child.
More recently, adult-to-adult liver transplantation has been done using the donor's right hepatic lobe which amounts to 60% of the liver. Due to the ability of the liver to regenerate, both the donor and recipient end up with normal liver function if all goes well. This procedure is more controversial as it entails performing a much larger operation on the donor, and indeed there have been at least 2 donor deaths out of the first several hundred cases. A recent publication has addressed the problem of donor mortality, and at least 14 cases have been found. The risk of postoperative complications (and death) is far greater in right sided hepatectomy than left sided operations.
# Development
The liver develops as an endodermal outpocketing of the foregut called the hepatic diverticulum. Its initial blood supply is primarily from the vitelline veins that drain blood from the yolk sac. The superior part of the hepatic diverticulum gives rise to the hepatocytes and bile ducts, while the inferior part becomes the gallbladder and its associated cystic duct.
## Fetal blood supply
In the growing fetus, a major source of blood to the liver is the umbilical vein which supplies nutrients to the growing fetus. The umbilical vein enters the abdomen at the umbilicus, and passes upward along the free margin of the falciform ligament of the liver to the inferior surface of the liver. There it joins with the left branch of the portal vein. The ductus venosus carries blood from the left portal vein to the left hepatic vein and then to the inferior vena cava, allowing placental blood to bypass the liver.
In the fetus, the liver develops throughout normal gestation, and does not perform the normal filtration of the infant liver. The liver does not perform digestive processes because the fetus does not consume meals directly, but receives nourishment from the mother via the placenta. The fetal liver releases some blood stem cells that migrate to the fetal thymus, so initially the lymphocytes, called T-cells, are created from fetal liver stem cells. Once the fetus is delivered, the formation of blood stem cells in infants shifts to the red bone marrow.
After birth, the umbilical vein and ductus venosus are completely obliterated two to five days postpartum; the former becomes the ligamentum teres and the latter becomes the ligamentum venosum. In the disease state of cirrhosis and portal hypertension, the umbilical vein can open up again.
# Further reading
- Eugene R. Schiff, Michael F. Sorrell, Willis C. Maddrey, eds. Schiff's diseases of the liver, 9th ed. Philadelphia : Lippincott, Williams & Wilkins, 2003. ISBN 0-7817-3007-4
- Sheila Sherlock, James Dooley. Diseases of the liver and biliary system, 11th ed. Oxford, UK ; Malden, MA : Blackwell Science. 2002. ISBN 0-632-05582-0
- David Zakim, Thomas D. Boyer. eds. Hepatology: a textbook of liver disease, 4th ed. Philadelphia: Saunders. 2003. ISBN 0-7216-9051-3
- Sanjiv Chopra. The Liver Book: A Comprehensive Guide to Diagnosis, Treatment, and Recovery, Atria, 2002, ISBN 0-7434-0585-4
- Melissa Palmer. Dr. Melissa Palmer's Guide to Hepatitis and Liver Disease: What You Need to Know, Avery Publishing Group; Revised edition May 24, 2004, ISBN 1-58333-188-3. her webpage.
- Howard J. Worman. The Liver Disorders Sourcebook, McGraw-Hill, 1999, ISBN 0-7373-0090-6. his Columbia University web site, "Diseases of the liver" | Liver (2)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The liver is an organ present in vertebrates and some other animals. It plays a major role in metabolism and has a number of functions in the body, including glycogen storage, plasma protein synthesis, and detoxification. This organ also is the largest gland in the human body. It lies below the diaphragm in the thoracic region of the abdomen.It produces bile, an alkaline compound which aids in digestion, via the emulsification of lipids. It also performs and regulates a wide variety of high-volume biochemical reactions requiring specialized tissues.
Medical terms related to the liver often start in hepato- or hepatic from the Greek word for liver, hēpar (ήπαρ[1]).
# Anatomy
The adult human liver normally weighs between 1.4 - 1.6 kilograms (3.1 - 3.5 pounds)[2], and it is a soft, pinkish-brown "boomerang shaped" organ. It is the second largest organ (the largest organ being the skin) and the largest gland within the human body.
It is located on the right side of the upper abdomen below the diaphragm. The liver lies on the left of the stomach and makes a kind of bed for the gallbladder (which stores bile).
## Flow of blood
The splenic vein, joins the inferior mesenteric vein, which then together join with the superior mesenteric vein to form the portal vein, bringing venous blood from the spleen, pancreas, small intestine, and large intestine, so that the liver can process the nutrients and byproducts of food digestion.
The hepatic veins drain directly into the inferior vena cava.
The hepatic artery is generally a branch from the celiac trunk, although occasionally some or all of the blood can be from other branches such as the superior mesenteric artery.
Approximately 60% to 80% of the blood flow to the liver is from the portal venous system, and 1/4 is from the hepatic artery.
## Flow of bile
The bile produced in the liver is collected in bile canaliculi, which merge to form bile ducts.
These eventually drain into the right and left hepatic ducts, which in turn merge to form the common hepatic duct. The cystic duct (from the gallbladder) joins with the common hepatic duct to form the common bile duct.
Bile can either drain directly into the duodenum via the common bile duct or be temporarily stored in the gallbladder via the cystic duct. The common bile duct and the pancreatic duct enter the duodenum together at the ampulla of Vater.
The branchings of the bile ducts resemble those of a tree, and indeed the term "biliary tree" is commonly used in this setting.
## Regeneration
The liver is among the few internal human organs capable of natural regeneration of lost tissue; as little as 25% of remaining liver can regenerate into a whole liver again.
This is predominantly due to the hepatocytes acting as unipotential stem cells (i.e. a single hepatocyte can divide into two hepatocyte daughter cells). There is also some evidence of bipotential stem cells, called oval cells, which can differentiate into either hepatocytes or cholangiocytes (cells that line the bile ducts).
## Traditional (Surface) anatomy
### Peritoneal ligaments
Apart from a patch where it connects to the diaphragm, the liver is covered entirely by visceral peritoneum, a thin, double-layered membrane that reduces friction against other organs. The peritoneum folds back on itself to form the falciform ligament and the right and left triangular ligaments.
These "ligaments" are in no way related to the true anatomic ligaments in joints, and have essentially no functional importance, but they are easily recognizable surface landmarks.
### Lobes
Traditional gross anatomy divided the liver into four lobes based on surface features.
The falciform ligament is visible on the front (anterior side) of the liver. This divides the liver into a left anatomical lobe, and a right anatomical lobe.
If the liver flipped over, to look at it from behind (the visceral surface), there are two additional lobes between the right and left. These are the caudate lobe (the more superior), and below this the quadrate lobe.
From behind, the lobes are divided up by the ligamentum venosum and ligamentum teres (anything left of these is the left lobe), the transverse fissure (or porta hepatis) divides the caudate from the quadrate lobe, and the right sagittal fossa, which the inferior vena cava runs over, separates these two lobes from the right lobe.
Each of the lobes is made up of lobules, a vein goes from the centre of each lobule which then joins to the hepatic vein to carry blood out from the liver.
On the surface of the lobules there are ducts, veins and arteries that carry fluids to and from them.
## Modern (Functional) anatomy
The central area where the common bile duct, portal vein, and hepatic artery enter the liver is the hilum or "porta hepatis". The duct, vein, and artery divide into left and right branches, and the portions of the liver supplied by these branches constitute the functional left and right lobes.
The functional lobes are separated by a plane joining the gallbladder fossa to the inferior vena cava. This separates the liver into the true right and left lobes. The middle hepatic vein also demarcates the true right and left lobes. The right lobe is further divided into an anterior and posterior segment by the right hepatic vein. The left lobe is divided into the medial and lateral segments by the left hepatic vein. The fissure for the ligamentum teres (the ligamentum teres becomes the falciform ligament) also separates the medial and lateral segmants. The medial segment is what used to be called the quadrate lobe. In the widely used Couinaud or "French" system, the functional lobes are further divided into a total of eight subsegments based on a transverse plane through the bifurcation of the main portal vein. The caudate lobe is a separate structure which receives blood flow from both the right- and left-sided vascular branches.[3][4] The subsegments corresponding to the anatomical lobes are as follows:
- or lobe in the Caudate's case.
Each number in the list corresponds to one in the table.
- Caudate
- Superior subsegment of the lateral segment
- Inferior subsegment of the lateral segment
- Superior subsegment of the medial segment
Inferior subsegment of the medial segment
- Superior subsegment of the medial segment
- Inferior subsegment of the medial segment
- Inferior subsegment of the anterior segment
- Inferior subsegment of the posterior segment
- Superior subsegment of the posterior segment
- Superior subsegment of the anterior segment
# Physiology
The various functions of the liver are carried out by the liver cells or hepatocytes.
- The liver produces and excretes bile (a greenish liquid) required for emulsifying fats. Some of the bile drains directly into the duodenum, and some is stored in the gallbladder.
- The liver performs several roles in carbohydrate metabolism:
Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
Glycogenolysis (the breakdown of glycogen into glucose) (muscle tissues can also do this)
Glycogenesis (the formation of glycogen from glucose)
The breakdown of insulin and other hormones
The liver is responsible for the mainstay of protein metabolism.
- Gluconeogenesis (the synthesis of glucose from certain amino acids, lactate or glycerol)
- Glycogenolysis (the breakdown of glycogen into glucose) (muscle tissues can also do this)
- Glycogenesis (the formation of glycogen from glucose)
- The breakdown of insulin and other hormones
- The liver is responsible for the mainstay of protein metabolism.
- The liver also performs several roles in lipid metabolism:
Cholesterol synthesis
The production of triglycerides (fats).
- Cholesterol synthesis
- The production of triglycerides (fats).
- The liver produces coagulation factors I (fibrinogen), II (prothrombin), V, VII, IX, X and XI, as well as protein C, protein S and antithrombin.
- The liver breaks down haemoglobin, creating metabolites that are added to bile as pigment (bilirubin and biliverdin).
- The liver breaks down toxic substances and most medicinal products in a process called drug metabolism. This sometimes results in toxication, when the metabolite is more toxic than its precursor.
- The liver converts ammonia to urea.
- The liver stores a multitude of substances, including glucose in the form of glycogen, vitamin B12, iron, and copper.
- In the first trimester fetus, the liver is the main site of red blood cell production. By the 32nd week of gestation, the bone marrow has almost completely taken over that task.
- The liver is responsible for immunological effects- the reticuloendothelial system of the liver contains many immunologically active cells, acting as a 'sieve' for antigens carried to it via the portal system.
Currently, there is no artificial organ or device capable of emulating all the functions of the liver. Some functions can be emulated by liver dialysis, an experimental treatment for liver failure.
# Diseases of the liver
Many diseases of the liver are accompanied by jaundice caused by increased levels of bilirubin in the system. The bilirubin results from the breakup of the hemoglobin of dead red blood cells; normally, the liver removes bilirubin from the blood and excretes it through bile.
- Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons, autoimmunity or hereditary conditions.
- Cirrhosis is the formation of fibrous tissue in the liver, replacing dead liver cells. The death of the liver cells can for example be caused by viral hepatitis, alcoholism or contact with other liver-toxic chemicals.
- Haemochromatosis, a hereditary disease causing the accumulation of iron in the body, eventually leading to liver damage.
- Cancer of the liver (primary hepatocellular carcinoma or cholangiocarcinoma and metastatic cancers, usually from other parts of the gastrointestinal tract).
- Wilson's disease, a hereditary disease which causes the body to retain copper.
- Primary sclerosing cholangitis, an inflammatory disease of the bile duct, autoimmune in nature.
- Primary biliary cirrhosis, autoimmune disease of small bile ducts.
- Budd-Chiari syndrome, obstruction of the hepatic vein.
- Gilbert's syndrome, a genetic disorder of bilirubin metabolism, found in about 5% of the population.
- Glycogen storage disease type II,The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system.
There are also many pediatric liver disease, including biliary atresia, alpha-1 antitrypsin deficiency, alagille syndrome, and progressive familial intrahepatic cholestasis, to name but a few.
A number of liver function tests are available to test the proper function of the liver. These test for the presence of enzymes in blood that are normally most abundant in liver tissue, metabolites or products.
# Liver transplantation
Human liver transplant was first performed by Thomas Starzl in USA and Roy Calne in England in 1963 and 1965 respectively.
Liver transplantation is the only option for those with irreversible liver failure. Most transplants are done for chronic liver diseases leading to cirrhosis, such as chronic hepatitis C, alcoholism, autoimmune hepatitis, and many others. Less commonly, liver transplantation is done for fulminant hepatic failure, in which liver failure occurs over days to weeks.
Liver allografts for transplant usually come from non-living donors who have died from fatal brain injury. Living donor liver transplantation is a technique in which a portion of a living person's liver is removed and used to replace the entire liver of the recipient. This was first performed in 1989 for pediatric liver transplantation. Only 20% of an adult's liver (Couinaud segments 2 and 3) is needed to serve as a liver allograft for an infant or small child.
More recently, adult-to-adult liver transplantation has been done using the donor's right hepatic lobe which amounts to 60% of the liver. Due to the ability of the liver to regenerate, both the donor and recipient end up with normal liver function if all goes well. This procedure is more controversial as it entails performing a much larger operation on the donor, and indeed there have been at least 2 donor deaths out of the first several hundred cases. A recent publication has addressed the problem of donor mortality, and at least 14 cases have been found.[5] The risk of postoperative complications (and death) is far greater in right sided hepatectomy than left sided operations.
# Development
The liver develops as an endodermal outpocketing of the foregut called the hepatic diverticulum. Its initial blood supply is primarily from the vitelline veins that drain blood from the yolk sac. The superior part of the hepatic diverticulum gives rise to the hepatocytes and bile ducts, while the inferior part becomes the gallbladder and its associated cystic duct.
## Fetal blood supply
In the growing fetus, a major source of blood to the liver is the umbilical vein which supplies nutrients to the growing fetus. The umbilical vein enters the abdomen at the umbilicus, and passes upward along the free margin of the falciform ligament of the liver to the inferior surface of the liver. There it joins with the left branch of the portal vein. The ductus venosus carries blood from the left portal vein to the left hepatic vein and then to the inferior vena cava, allowing placental blood to bypass the liver.
In the fetus, the liver develops throughout normal gestation, and does not perform the normal filtration of the infant liver. The liver does not perform digestive processes because the fetus does not consume meals directly, but receives nourishment from the mother via the placenta. The fetal liver releases some blood stem cells that migrate to the fetal thymus, so initially the lymphocytes, called T-cells, are created from fetal liver stem cells. Once the fetus is delivered, the formation of blood stem cells in infants shifts to the red bone marrow.
After birth, the umbilical vein and ductus venosus are completely obliterated two to five days postpartum; the former becomes the ligamentum teres and the latter becomes the ligamentum venosum. In the disease state of cirrhosis and portal hypertension, the umbilical vein can open up again.
# Further reading
- Eugene R. Schiff, Michael F. Sorrell, Willis C. Maddrey, eds. Schiff's diseases of the liver, 9th ed. Philadelphia : Lippincott, Williams & Wilkins, 2003. ISBN 0-7817-3007-4
- Sheila Sherlock, James Dooley. Diseases of the liver and biliary system, 11th ed. Oxford, UK ; Malden, MA : Blackwell Science. 2002. ISBN 0-632-05582-0
- David Zakim, Thomas D. Boyer. eds. Hepatology: a textbook of liver disease, 4th ed. Philadelphia: Saunders. 2003. ISBN 0-7216-9051-3
- Sanjiv Chopra. The Liver Book: A Comprehensive Guide to Diagnosis, Treatment, and Recovery, Atria, 2002, ISBN 0-7434-0585-4
- Melissa Palmer. Dr. Melissa Palmer's Guide to Hepatitis and Liver Disease: What You Need to Know, Avery Publishing Group; Revised edition May 24, 2004, ISBN 1-58333-188-3. her webpage.
- Howard J. Worman. The Liver Disorders Sourcebook, McGraw-Hill, 1999, ISBN 0-7373-0090-6. his Columbia University web site, "Diseases of the liver" | https://www.wikidoc.org/index.php/Liver_(2) | |
a9499a435afe3f729384890a04ed5ac0dcc4ec8d | wikidoc | Lomustine | Lomustine
# 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
Lomustine is an antineoplastic agent that is FDA approved for the treatment of brain tumors, Hodgkin's disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include leukopenia, myelosuppression, thrombocytopenia,optic atrophy, visual disturbance,nephrotoxicity,Pulmonary toxicity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Gleostine has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following:
- Brain tumors—both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures.
- Hodgkin's disease—secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.
# Dosage
- The recommended dose of Gleostine in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks . In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks. When Gleostine is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly. All doses of Gleostine must be rounded to the nearest 10 mg by the prescriber .
- Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:
- A repeat course of Gleostine should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lomustine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lomustine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lomustine in Pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lomustine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lomustine in pediatric patients.
# Contraindications
- Gleostine should not be given to individuals who have demonstrated a previous hypersensitivity to it.
# Warnings
- Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose. At the recommended dosage, courses of Gleostine should not be given more frequently than every 6 weeks.
- The bone marrow toxicity of Gleostine is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under.
- Pulmonary toxicity from Gleostine appears to be dose related.
- Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies.
- Liver and renal function tests should be monitored periodically.
# Adverse Reactions
## Clinical Trials Experience
Hematologic Toxicity
- The most frequent and most serious toxicity of Gleostine is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks post administration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of Gleostine and persists for 1 to 2 weeks. Approximately 65% of patients receiving 130 mg/m2 develop white blood counts below 5000 wbc/mm3. Thirty-six percent developed white blood counts below 3000 wbc/mm3. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.
- Gleostine may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses.
- The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following long-term nitrosourea therapy.
- Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia.
Pulmonary Toxicity
- Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported rarely with Gleostine. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of Gleostine usually greater than 1100 mg/m2. There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg.
- Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received related nitrosoureas in childhood and early adolescence (1–16 years) combined with cranial radiotherapy for intracranial tumors. There appeared to be some late reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be slowly progressive and has resulted in death in some cases. In this long-term study of carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary fibrosis.
Gastrointestinal Toxicity
- Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. Prior administration of antiemetics is effective in diminishing and sometimes preventing this side effect. Nausea and vomiting can also be reduced if Gleostine is administered to fasting patients.
Hepatotoxicity
A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase, and bilirubin levels, has been reported in a small percentage of patients receiving Gleostine.
Nephrotoxicity
- Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal failure have been reported in patients who received large cumulative doses after prolonged therapy with Gleostine. Kidney damage has also been reported occasionally in patients receiving lower total doses.
Other Toxicities
- Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been reported infrequently.
- Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted in some patients receiving Gleostine. However, the relationship to medication in these patients is unclear.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Lomustine in the drug label.
# Drug Interactions
There is limited information regarding Lomustine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category D
- Gleostine can cause fetal harm when administered to a pregnant woman. Lomustine is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lomustine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lomustine 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 serious adverse reactions in nursing infants from Gleostine, 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
There is no FDA guidance on the use of Lomustine with respect to pediatric patients.
### Geriatic Use
- No data from clinical studies of Gleostine are available for patients 65 years of age and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Lomustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.
### Gender
There is no FDA guidance on the use of Lomustine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lomustine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Lomustine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Lomustine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lomustine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lomustine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lomustine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lomustine in the drug label.
# Overdosage
- Accidental overdose with lomustine has been reported, including fatal cases. Accidental overdose has been associated with bone marrow suppression, abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath.
- No proven antidotes have been established for Gleostine overdosage. In case of overdose, appropriate supportive measures should be taken.
# Pharmacology
## Mechanism of Action
There is limited information regarding Lomustine Mechanism of Action in the drug label.
## Structure
- GleostineTM (lomustine) (CCNU) is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow powder with the empirical formula of C9H16ClN3O2 and a molecular weight of 233.71. Gleostine is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Gleostine is relatively insoluble in water (<0.05 mg per mL).
It is relatively un-ionized at a physiological pH.
Inactive ingredients in Gleostine Capsules are magnesium stearate and mannitol.
The structural formula is:
- Gleostine is available in 10 mg, 40 mg, and 100 mg capsules for oral administration.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Lomustine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Lomustine in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Lomustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans. Lomustine also affects fertility in male rats at doses somewhat higher than the human dose.
# Clinical Studies
There is limited information regarding Clinical Studies of Lomustine in the drug label.
# How Supplied
- GleostineTM Capsules are available in individual bottles of 5 capsules each.
## Storage
- Gleostine Capsules are stable for the lot life indicated on package labeling when stored in well-closed containers at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) . Avoid excessive heat (over 40°C, 104°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Provide patients with the following information and instructions:
- In order to provide the proper dose of Gleostine, the dose may be made up of 2 or more different strengths and colors of capsules. Each strength must be dispensed separately by the pharmacist.
- Gleostine is given as a single oral dose and will not be repeated for at least 6 weeks. Daily use of the recommended dose may lead to toxicities and fatal outcomes.
Patients may experience nausea and vomiting that usually last less than 24 hours. Patients may also experience loss of appetite that may last for several days.
Instruct patients to contact their physician if they develop any of the following reactions: fever, chills, sore throat, unusual bleeding or bruising, shortness of breath, dry cough, swelling of feet or lower legs, mental confusion, or yellowing of eyes and skin.
- Instruct patients to wear impervious (rubber or latex) gloves when handling Gleostine Capsules.
# Precautions with Alcohol
- Alcohol-Lomustine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GLEOSTINE ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Lomustine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Lomustine is an antineoplastic agent that is FDA approved for the treatment of brain tumors, Hodgkin's disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include leukopenia, myelosuppression, thrombocytopenia,optic atrophy, visual disturbance,nephrotoxicity,Pulmonary toxicity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Gleostine has been shown to be useful as a single agent in addition to other treatment modalities, or in established combination therapy with other approved chemotherapeutic agents in the following:
- Brain tumors—both primary and metastatic, in patients who have already received appropriate surgical and/or radiotherapeutic procedures.
- Hodgkin's disease—secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.
# Dosage
- The recommended dose of Gleostine in adult and pediatric patients as a single agent in previously untreated patients is 130 mg/m2 as a single oral dose every 6 weeks . In individuals with compromised bone marrow function, the dose should be reduced to 100 mg/m2 every 6 weeks. When Gleostine is used in combination with other myelosuppressive drugs, the doses should be adjusted accordingly. All doses of Gleostine must be rounded to the nearest 10 mg by the prescriber .
- Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:
- A repeat course of Gleostine should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3; leukocytes above 4000/mm3), and this is usually in 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lomustine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lomustine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Lomustine in Pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lomustine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lomustine in pediatric patients.
# Contraindications
- Gleostine should not be given to individuals who have demonstrated a previous hypersensitivity to it.
# Warnings
- Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose. At the recommended dosage, courses of Gleostine should not be given more frequently than every 6 weeks.
- The bone marrow toxicity of Gleostine is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see dosage adjustment table under.
- Pulmonary toxicity from Gleostine appears to be dose related.
- Long-term use of nitrosoureas has been reported to be possibly associated with the development of secondary malignancies.
- Liver and renal function tests should be monitored periodically.
# Adverse Reactions
## Clinical Trials Experience
Hematologic Toxicity
- The most frequent and most serious toxicity of Gleostine is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks post administration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of Gleostine and persists for 1 to 2 weeks. Approximately 65% of patients receiving 130 mg/m2 develop white blood counts below 5000 wbc/mm3. Thirty-six percent developed white blood counts below 3000 wbc/mm3. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.
- Gleostine may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses.
- The occurrence of acute leukemia and bone marrow dysplasias have been reported in patients following long-term nitrosourea therapy.
- Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia.
Pulmonary Toxicity
- Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported rarely with Gleostine. Onset of toxicity has occurred after an interval of 6 months or longer from the start of therapy with cumulative doses of Gleostine usually greater than 1100 mg/m2. There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg.
- Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received related nitrosoureas in childhood and early adolescence (1–16 years) combined with cranial radiotherapy for intracranial tumors. There appeared to be some late reduction of pulmonary function of all long-term survivors. This form of lung fibrosis may be slowly progressive and has resulted in death in some cases. In this long-term study of carmustine, all those initially treated at less than 5 years of age died of delayed pulmonary fibrosis.
Gastrointestinal Toxicity
- Nausea and vomiting may occur 3 to 6 hours after an oral dose and usually last less than 24 hours. Prior administration of antiemetics is effective in diminishing and sometimes preventing this side effect. Nausea and vomiting can also be reduced if Gleostine is administered to fasting patients.
Hepatotoxicity
A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase, and bilirubin levels, has been reported in a small percentage of patients receiving Gleostine.
Nephrotoxicity
- Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal failure have been reported in patients who received large cumulative doses after prolonged therapy with Gleostine. Kidney damage has also been reported occasionally in patients receiving lower total doses.
Other Toxicities
- Stomatitis, alopecia, optic atrophy, and visual disturbances, such as blindness, have been reported infrequently.
- Neurological reactions, such as disorientation, lethargy, ataxia, and dysarthria have been noted in some patients receiving Gleostine. However, the relationship to medication in these patients is unclear.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Lomustine in the drug label.
# Drug Interactions
There is limited information regarding Lomustine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category D
- Gleostine can cause fetal harm when administered to a pregnant woman. Lomustine is embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lomustine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Lomustine 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 serious adverse reactions in nursing infants from Gleostine, 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
There is no FDA guidance on the use of Lomustine with respect to pediatric patients.
### Geriatic Use
- No data from clinical studies of Gleostine are available for patients 65 years of age and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Lomustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.
### Gender
There is no FDA guidance on the use of Lomustine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Lomustine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Lomustine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Lomustine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lomustine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Lomustine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Lomustine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Lomustine in the drug label.
# Overdosage
- Accidental overdose with lomustine has been reported, including fatal cases. Accidental overdose has been associated with bone marrow suppression, abdominal pain, diarrhea, vomiting, anorexia, lethargy, dizziness, abnormal hepatic function, cough, and shortness of breath.
- No proven antidotes have been established for Gleostine overdosage. In case of overdose, appropriate supportive measures should be taken.
# Pharmacology
## Mechanism of Action
There is limited information regarding Lomustine Mechanism of Action in the drug label.
## Structure
- GleostineTM (lomustine) (CCNU) is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow powder with the empirical formula of C9H16ClN3O2 and a molecular weight of 233.71. Gleostine is soluble in 10% ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Gleostine is relatively insoluble in water (<0.05 mg per mL).
It is relatively un-ionized at a physiological pH.
Inactive ingredients in Gleostine Capsules are magnesium stearate and mannitol.
The structural formula is:
- Gleostine is available in 10 mg, 40 mg, and 100 mg capsules for oral administration.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Lomustine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Lomustine in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Lomustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans. Lomustine also affects fertility in male rats at doses somewhat higher than the human dose.
# Clinical Studies
There is limited information regarding Clinical Studies of Lomustine in the drug label.
# How Supplied
- GleostineTM Capsules are available in individual bottles of 5 capsules each.
## Storage
- Gleostine Capsules are stable for the lot life indicated on package labeling when stored in well-closed containers at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Avoid excessive heat (over 40°C, 104°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Provide patients with the following information and instructions:
- In order to provide the proper dose of Gleostine, the dose may be made up of 2 or more different strengths and colors of capsules. Each strength must be dispensed separately by the pharmacist.
- Gleostine is given as a single oral dose and will not be repeated for at least 6 weeks. Daily use of the recommended dose may lead to toxicities and fatal outcomes.
Patients may experience nausea and vomiting that usually last less than 24 hours. Patients may also experience loss of appetite that may last for several days.
Instruct patients to contact their physician if they develop any of the following reactions: fever, chills, sore throat, unusual bleeding or bruising, shortness of breath, dry cough, swelling of feet or lower legs, mental confusion, or yellowing of eyes and skin.
- Instruct patients to wear impervious (rubber or latex) gloves when handling Gleostine Capsules.
# Precautions with Alcohol
- Alcohol-Lomustine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GLEOSTINE ®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Lomustine | |
02f22f11d4f37d045098234f0fbdfd5cb5d64d52 | wikidoc | Longevity | Longevity
Longevity is a term that generally refers to 'long life' or 'great duration of life'. Reflections on longevity have usually gone beyond acknowledging the basic shortness of human life and have included thinking about methods to extend life. Longevity has been a topic not only for the scientific community but also for writers of travel, science fiction and utopian novels. There are many difficulties to authenticate the longest human lifespan ever, because of inaccurate birth statistics in the past; though fiction, legend, and mythology have proposed or claimed vastly longer lifespans in the past or future and longevity myths frequently allege them to exist in the present.
The word 'longevity' is sometimes used as a synonym for 'life expectancy' in demography. However, this is not the most popular or accepted definition, . For the general public as well as writers, the word generally connotes 'long life', especially when it concerns someone or something lasting longer than expected (an 'ancient tree', for example).
# Presently
Various factors contribute to an individual's longevity. Significant factors in life expectancy include gender, genetics, access to health care, hygiene, diet, exercise, lifestyle, and crime rates. Below is a list of life expectancies in different types of countries:
- First World: . . . 77-83 years (eg. Canada: 80.1 years, 2005 est)
- Third World:. . . 35-60 years (eg. Mozambique: 40.3 years, 2005 est)
Population longevities can be seen as increasing due to increases in life expectancies around the world:
- Spain:. . . . . 81.02 years in 2002, 82.31 years in 2005
- Australia: . . 80 years in 2002, 80.39 years in 2005
- Italy:. . . . . . 79.25 years in 2002, 79.68 years in 2005
- France: . . . .79.05 years in 2002, 79.60 years in 2005
- Germany: . . 77.78 years in 2002, 78.65 years in 2005
- UK: . . . . . . 77.99 years in 2002, 78.4 years in 2005
- USA: . . . . . 77.4 years in 2002, 77.7 years in 2005
The current validated longevity records can be found in the list of supercentenarians. Notable individuals include:
- Jeanne Calment (1875-1997, 122 years and 164 days) - the oldest person in history whose age has been verified by modern documentation. This defines the human lifespan, which is set by the oldest documented individual who ever lived
- Shigechiyo Izumi (1865-1986, 120 years 237 days, disputed) - the oldest male ever recognized by the Guinness Book of World Records; this is widely questioned by scholars, who believe that conflation of dates has occurred and this has compromised the authenticity of Izumi's age
- Christian Mortensen (1882-1998, 115 years 252 days) - the oldest male widely accepted by scholars.
# History
Reaching an old age has fascinated people for ages. There are many organizations dedicated to exploring the causes behind aging, ways to prevent aging, and ways to reverse aging. Despite the fact that it is no more than human nature to not wish to surrender to old age and death, a few organizations are against antiaging, because they believe it sacrifices the best interests of the new generation, that it is unnatural, or unethical. Others are dedicated towards it, seeing it as a form of transhumanism and the pursuit of immortality. Even among those who do not wish for eternal life, longevity may be desired to experience more of life, or to provide a greater contribution to humanity.
A remarkable statement mentioned by Diogenes Laertius (c. 250) is the earliest (or at least one of the earliest) references about (plausible centenarian) longevity given by a scientist, the astronomer Hipparchus of Nicea (c. 185 – c. 120 B.C.), who, according to the doxographer, assured that the philosopher Democritus of Abdera (c. 470/460 – c. 370/360 B.C.) lived 109 years. All other account given by the ancients about the age of Democritus, appears to, without giving any specific age, agree in the fact that the philosopher lived over 100 years; possibility that turns out to be likely given, not only by the fact that many ancient Greek philosophers are thought to have lived over the age of 90 (e.g.: Xenophanes of Colophon, c. 570/565 – c. 475/470 B.C., Pyrrho of Ellis, c. 360 - c. 270 B.C., Eratosthenes of Cirene c. 285 – c. 190 B.C., etc.), but also because of the difference that the case of Democritus evidences from the case of, for example, Epimenides of Crete (VII, VI centuries B.C.) of whom it is said to have lived 154, 157 or 290 years, like it has been said about countless elders even during the last centuries (as well as in present time) being these cases most likely (or at least in most cases), exaggerations if not deliberate frauds.
# Religion
The Bible contains many accounts of long-lived humans, the oldest being Methuselah living to be 969 years old (Genesis 5:27). Today some maintain that the unusually high longevity of Biblical patriarchs are the result of an error in translation: lunar cycles were mistaken for the solar ones, and that the actual ages being described would have been 12.4 times less (a lunar cycle being 29.5 days). This makes Methuselah's age only 78. This rationalization, however, seems doubtful too since patriarchs such as Mahalalel (ibid 5:15) and Enoch (ibid 5:21) were said to have become fathers after 65 "years". If the lunar cycle claim were accepted this would translate to an age of about 5 years and 3 months.
One Christian apologist claim is that the life span of humans has changed; that originally man was to have everlasting life, but due to man's sin, God progressively shortened man's life in the "four falls of mankind" -- first to less than 1000 years, then to under 500, 200, and eventually 120 years. After those long living people died around the time of the Biblical Flood, God decided that humans would not be permitted to live more than 120 years (Genesis 6:3.) However, since later biblical figures (and more recent people) such as Sarah lived for longer than that, 120 years should be considered the "usual" upper limit to man's lifespan. Some individuals can live slightly longer than that.
Another theory proposed by a self described “rational faith apologist” is based on the fact that some longevity specialists propose that aging occurs primarily due to telomere shortening during cell replication. Each time a cell replicates itself telomeres lose length until finally, replication cannot occur and the cells die. The theory postulates that prior to the flood there existed a thick cloud cover as described in Genesis. This cover protected DNA from UV and other radiation and their subsequent destructive mutation. Post flood with the cloud cover removed, UV rays and radiation could have caused both DNA and cellular destruction; specifically the type that cause telomere shortening or accelerated telomere shortening. As this mutation was passed on, shorter life spans would result for presumably both human and animals.
It has been hypothesized that there is a trade-off between cancerous tumor suppression and tissue repair capacity, and that by lengthening telomeres we might slow aging and in exchange increase vulnerability to cancer (Weinstein and Ciszek, 2002). Experimentation with telomeres on worms has yielded increased worm life spans by about 20% (Joeng et al., 2004).
Even if further study shows that telomeres specifically are not tied to aging, the concept that some sort of DNA damage can cause genetically accelerated aging cannot be abandoned, thus providing a rational explanation for longevity and a subsequent reduction of longevity post-flood.
Many cultures like the Sumerians and Indus Valley also document groups of people who lived many 100’s of years. Both cultures show reduced life spans after the flood.
Furthermore, starting with reformers John Calvin and Martin Luther, an alternative explanation has arisen : 120 years would not refer to man's lifespan but to the amount of time left before the flood.]
A more commonly accepted explanation is that such stories are longevity myths; age exaggeration tends to be greater in "mythical" periods in many cultures; the early emperors of Japan or China often ruled for more than a century, according to tradition. With the advent of modern accountable record-keeping, age claims fell to realistic levels; even later in the Bible King David died at 70 years; other kings in their 30s, 40s, and 50s.
# Future
The mainstream view on the future of longevity, such as the US Census Bureau, is that life expectancy in the USA will be in the mid-80s by 2050 (up from 77.85 in 2006) and will top out eventually in the low 90s, barring major scientific advances that can change the rate of human aging itself, as opposed to merely treating the effects of aging as is done today. The Census Bureau also predicted that the USA would have 5.3 million people aged over 100 in 2100 (Which means that, if this turns out to be true, those people are children and toddlers today).
Recent increases in the rates of lifestyle diseases, such as obesity, diabetes, hypertension, and heart disease, may however drastically slow or reverse this trend toward increasing life expectancy in the developed world.
Oeppen and Vaupel (see Science):1029, 2002) have observed that since 1840 record life expectancy has risen linearly for men and women, albeit more slowly for men. For women the increase has been almost three months/year. In light of steady increase, without any sign of a cap, the suggestion that life expectancy will top out must be treated with caution. Oeppen and Vaupel observe that experts who assert that "life expectancy is approaching a ceiling ... have repeatedly been proven wrong."It is thought that life expectancy for women increased more dramatically due to the considerable increases in medicine related to childbirth.
Some argue that molecular nanotechnology will greatly extend human lifespans. See medical nanotechnology.
# Non-human biological longevity
Living:
- Methuselah (tree) - 4,700-year-old bristlecone pine in the White Mountains of California, the oldest known living tree.
- Cheeta - a 75-year old chimpanzee, the longest lived known chimpanzee.
Dead:
- Adwaitya - an Aldabra Giant Tortoise, died 2006 at between 150-255 years old, the oldest known animal.
- A Bowhead Whale killed in a hunt was found to be approximately 211 years old, the longest lived mammal known.
- Lamellibrachia luymesi, a deep-sea cold seep tubeworm, is estimated to reach ages of over 250 years based on a model of its growth rates.
# Scientific books on longevity
- Leonid A. Gavrilov & Natalia S. Gavrilova (1991), The Biology of Life Span: A Quantitative Approach. New York: Harwood Academic Publisher, ISBN
- John Robbins' Healthy at 100 garners evidence from many scientific sources to account for the extraordinary longevity of Abkhasians in the Caucasus, Vilcabambans in the Andes, Hunzas in Central Asia, and Okinawans.
- Beyond The 120-Year Diet, by Roy L. Walford, M.D.
- Forever Young: A Cultural History of Longevity from Antiquity to the Present Door Lucian Boia,2004 ISBN 1861891547
# Longevity in fiction
- Abh: "Crest of the Stars"
- James Hilton: Lost Horizon
- P.D. James: The Children of Men
- James L. Halperin: The First Immortal
- John Wyndham: Trouble with Lichen
- Robert A. Heinlein: Time Enough for Love, Methuselah's Children, and others.
- Poul Anderson: The Boat of a Million Years
- Arthur C. Clarke: 2001: A Space Odyssey
- David Brin & Gregory Benford: Heart of the Comet
- Kim Stanley Robinson's Mars trilogy
- Roger Zelazny: This Immortal, Lord of Light, *The Amber series
- J. K. Rowling: Harry Potter and the Philosopher's Stone (The Philosopher's Stone and Nicolas Flamel)
- J. R. R. Tolkien: The Silmarillion (Dúnedain)
- J. R. R. Tolkien: The Lord of the Rings (Aragorn, Bilbo and Gollum)
- Bruce Sterling: Holy Fire
- Yoda: Star Wars
- Chewbacca: Star Wars
- Isaac Asimov: The Robot Novels (R. Daneel Olivaw, The Spacers)
- Tom Robbins: Jitterbug Perfume
- Frank Herbert: Dune universe
- Robert Jordan: The Wheel of Time
- Peter F. Hamilton: Misspent Youth
- James Blish: Cities in Flight
- Jonathan Swift: Gulliver's Travels (The Struldbrug)
- Jack L. Chalker: Well World Series character "Nathan Brazil" - is an immortal'"
- Goa'uld, Ancients (Stargate), Wraith (Stargate): Stargate SG-1 and Stargate Atlantis
- Joe Haldeman: The Long Habit of Living
- Anne McCaffrey: The Ship Who Sang, The Ship Who Searched and others in the Brain Ship series
- Andrew Martin: The Bicentennial Man
- Sid Meier: Sid Meier's Alpha Centauri (Longevity Vaccine)
# Notes
- ↑ Jump up to: 3.0 3.1 CIA World Fact Book
- ↑ CIA World Fact Book 2002 | Longevity
Template:AB
Longevity is a term that generally refers to 'long life' or 'great duration of life'.[1] Reflections on longevity have usually gone beyond acknowledging the basic shortness of human life and have included thinking about methods to extend life. Longevity has been a topic not only for the scientific community but also for writers of travel, science fiction and utopian novels. There are many difficulties to authenticate the longest human lifespan ever, because of inaccurate birth statistics in the past; though fiction, legend, and mythology have proposed or claimed vastly longer lifespans in the past or future and longevity myths frequently allege them to exist in the present.
The word 'longevity' is sometimes used as a synonym for 'life expectancy' in demography. However, this is not the most popular or accepted definition, [2]. For the general public as well as writers, the word generally connotes 'long life', especially when it concerns someone or something lasting longer than expected (an 'ancient tree', for example).
# Presently
Various factors contribute to an individual's longevity. Significant factors in life expectancy include gender, genetics, access to health care, hygiene, diet, exercise, lifestyle, and crime rates. Below is a list of life expectancies in different types of countries[3]:
- First World: . . . 77-83 years (eg. Canada: 80.1 years, 2005 est)
- Third World:. . . 35-60 years (eg. Mozambique: 40.3 years, 2005 est)
Population longevities can be seen as increasing due to increases in life expectancies around the world[4][3]:
- Spain:. . . . . 81.02 years in 2002, 82.31 years in 2005
- Australia: . . 80 years in 2002, 80.39 years in 2005
- Italy:. . . . . . 79.25 years in 2002, 79.68 years in 2005
- France: . . . .79.05 years in 2002, 79.60 years in 2005
- Germany: . . 77.78 years in 2002, 78.65 years in 2005
- UK: . . . . . . 77.99 years in 2002, 78.4 years in 2005
- USA: . . . . . 77.4 years in 2002, 77.7 years in 2005
The current validated longevity records can be found in the list of supercentenarians. Notable individuals include:
- Jeanne Calment (1875-1997, 122 years and 164 days) - the oldest person in history whose age has been verified by modern documentation. This defines the human lifespan, which is set by the oldest documented individual who ever lived
- Shigechiyo Izumi (1865-1986, 120 years 237 days, disputed) - the oldest male ever recognized by the Guinness Book of World Records; this is widely questioned by scholars, who believe that conflation of dates has occurred and this has compromised the authenticity of Izumi's age
- Christian Mortensen (1882-1998, 115 years 252 days) - the oldest male widely accepted by scholars.
# History
Reaching an old age has fascinated people for ages. There are many organizations dedicated to exploring the causes behind aging, ways to prevent aging, and ways to reverse aging. Despite the fact that it is no more than human nature to not wish to surrender to old age and death, a few organizations are against antiaging, because they believe it sacrifices the best interests of the new generation, that it is unnatural, or unethical. Others are dedicated towards it, seeing it as a form of transhumanism and the pursuit of immortality. Even among those who do not wish for eternal life, longevity may be desired to experience more of life, or to provide a greater contribution to humanity.
A remarkable statement mentioned by Diogenes Laertius (c. 250) is the earliest (or at least one of the earliest) references about (plausible centenarian) longevity given by a scientist, the astronomer Hipparchus of Nicea (c. 185 – c. 120 B.C.), who, according to the doxographer, assured that the philosopher Democritus of Abdera (c. 470/460 – c. 370/360 B.C.) lived 109 years. All other account given by the ancients about the age of Democritus, appears to, without giving any specific age, agree in the fact that the philosopher lived over 100 years; possibility that turns out to be likely given, not only by the fact that many ancient Greek philosophers are thought to have lived over the age of 90 (e.g.: Xenophanes of Colophon, c. 570/565 – c. 475/470 B.C., Pyrrho of Ellis, c. 360 - c. 270 B.C., Eratosthenes of Cirene c. 285 – c. 190 B.C., etc.), but also because of the difference that the case of Democritus evidences from the case of, for example, Epimenides of Crete (VII, VI centuries B.C.) of whom it is said to have lived 154, 157 or 290 years, like it has been said about countless elders even during the last centuries (as well as in present time) being these cases most likely (or at least in most cases), exaggerations if not deliberate frauds.
# Religion
The Bible contains many accounts of long-lived humans, the oldest being Methuselah living to be 969 years old (Genesis 5:27). Today some maintain that the unusually high longevity of Biblical patriarchs are the result of an error in translation: lunar cycles were mistaken for the solar ones, and that the actual ages being described would have been 12.4 times less (a lunar cycle being 29.5 days). This makes Methuselah's age only 78. This rationalization, however, seems doubtful too since patriarchs such as Mahalalel (ibid 5:15) and Enoch (ibid 5:21) were said to have become fathers after 65 "years". If the lunar cycle claim were accepted this would translate to an age of about 5 years and 3 months.
One Christian apologist claim is that the life span of humans has changed; that originally man was to have everlasting life, but due to man's sin, God progressively shortened man's life in the "four falls of mankind" -- first to less than 1000 years, then to under 500, 200, and eventually 120 years. After those long living people died around the time of the Biblical Flood, God decided that humans would not be permitted to live more than 120 years (Genesis 6:3.) However, since later biblical figures (and more recent people) such as Sarah lived for longer than that, 120 years should be considered the "usual" upper limit to man's lifespan. Some individuals can live slightly longer than that.
Another theory proposed by a self described “rational faith apologist” is based on the fact that some longevity specialists propose that aging occurs primarily due to telomere shortening during cell replication. Each time a cell replicates itself telomeres lose length until finally, replication cannot occur and the cells die. The theory postulates that prior to the flood there existed a thick cloud cover as described in Genesis. This cover protected DNA from UV and other radiation and their subsequent destructive mutation. Post flood with the cloud cover removed, UV rays and radiation could have caused both DNA and cellular destruction; specifically the type that cause telomere shortening or accelerated telomere shortening. As this mutation was passed on, shorter life spans would result for presumably both human and animals.
It has been hypothesized that there is a trade-off between cancerous tumor suppression and tissue repair capacity, and that by lengthening telomeres we might slow aging and in exchange increase vulnerability to cancer (Weinstein and Ciszek, 2002). Experimentation with telomeres on worms has yielded increased worm life spans by about 20% (Joeng et al., 2004).
Even if further study shows that telomeres specifically are not tied to aging, the concept that some sort of DNA damage can cause genetically accelerated aging cannot be abandoned, thus providing a rational explanation for longevity and a subsequent reduction of longevity post-flood.
Many cultures like the Sumerians and Indus Valley also document groups of people who lived many 100’s of years. Both cultures show reduced life spans after the flood.[citation needed]
Furthermore, starting with reformers John Calvin and Martin Luther, an alternative explanation has arisen : 120 years would not refer to man's lifespan but to the amount of time left before the flood.]
A more commonly accepted explanation is that such stories are longevity myths; age exaggeration tends to be greater in "mythical" periods in many cultures; the early emperors of Japan or China often ruled for more than a century, according to tradition. With the advent of modern accountable record-keeping, age claims fell to realistic levels; even later in the Bible King David died at 70 years; other kings in their 30s, 40s, and 50s.
# Future
The mainstream view on the future of longevity, such as the US Census Bureau, is that life expectancy in the USA will be in the mid-80s by 2050 (up from 77.85 in 2006) and will top out eventually in the low 90s, barring major scientific advances that can change the rate of human aging itself, as opposed to merely treating the effects of aging as is done today. The Census Bureau also predicted that the USA would have 5.3 million people aged over 100 in 2100 (Which means that, if this turns out to be true, those people are children and toddlers today).
Recent increases in the rates of lifestyle diseases, such as obesity, diabetes, hypertension, and heart disease, may however drastically slow or reverse this trend toward increasing life expectancy in the developed world.
Oeppen and Vaupel (see Science):1029, 2002) have observed that since 1840 record life expectancy has risen linearly for men and women, albeit more slowly for men. For women the increase has been almost three months/year. In light of steady increase, without any sign of a cap, the suggestion that life expectancy will top out must be treated with caution. Oeppen and Vaupel observe that experts who assert that "life expectancy is approaching a ceiling ... have repeatedly been proven wrong."It is thought that life expectancy for women increased more dramatically due to the considerable increases in medicine related to childbirth.
Some argue that molecular nanotechnology will greatly extend human lifespans. See medical nanotechnology.
# Non-human biological longevity
Living:
- Methuselah (tree) - 4,700-year-old bristlecone pine in the White Mountains of California, the oldest known living tree.
- Cheeta - a 75-year old chimpanzee, the longest lived known chimpanzee.
Dead:
- Adwaitya - an Aldabra Giant Tortoise, died 2006 at between 150-255 years old, the oldest known animal.
- A Bowhead Whale killed in a hunt was found to be approximately 211 years old, the longest lived mammal known.[1]
- Lamellibrachia luymesi, a deep-sea cold seep tubeworm, is estimated to reach ages of over 250 years based on a model of its growth rates.[citation needed]
# Scientific books on longevity
- Leonid A. Gavrilov & Natalia S. Gavrilova (1991), The Biology of Life Span: A Quantitative Approach. New York: Harwood Academic Publisher, ISBN
- John Robbins' Healthy at 100 garners evidence from many scientific sources to account for the extraordinary longevity of Abkhasians in the Caucasus, Vilcabambans in the Andes, Hunzas in Central Asia, and Okinawans.
- Beyond The 120-Year Diet, by Roy L. Walford, M.D.
- Forever Young: A Cultural History of Longevity from Antiquity to the Present Door Lucian Boia,2004 ISBN 1861891547
# Longevity in fiction
- Abh: "Crest of the Stars"
- James Hilton: Lost Horizon
- P.D. James: The Children of Men
- James L. Halperin: The First Immortal
- John Wyndham: Trouble with Lichen
- Robert A. Heinlein: Time Enough for Love, Methuselah's Children, and others.
- Poul Anderson: The Boat of a Million Years
- Arthur C. Clarke: 2001: A Space Odyssey
- David Brin & Gregory Benford: Heart of the Comet
- Kim Stanley Robinson's Mars trilogy
- Roger Zelazny: This Immortal, Lord of Light, *The Amber series
- J. K. Rowling: Harry Potter and the Philosopher's Stone (The Philosopher's Stone and Nicolas Flamel)
- J. R. R. Tolkien: The Silmarillion (Dúnedain)
- J. R. R. Tolkien: The Lord of the Rings (Aragorn, Bilbo and Gollum)
- Bruce Sterling: Holy Fire
- Yoda: Star Wars
- Chewbacca: Star Wars
- Isaac Asimov: The Robot Novels (R. Daneel Olivaw, The Spacers)
- Tom Robbins: Jitterbug Perfume
- Frank Herbert: Dune universe
- Robert Jordan: The Wheel of Time
- Peter F. Hamilton: Misspent Youth
- James Blish: Cities in Flight
- Jonathan Swift: Gulliver's Travels (The Struldbrug)
- Jack L. Chalker: Well World Series character "Nathan Brazil" - is an immortal'"
- Goa'uld, Ancients (Stargate), Wraith (Stargate): Stargate SG-1 and Stargate Atlantis
- Joe Haldeman: The Long Habit of Living
- Anne McCaffrey: The Ship Who Sang, The Ship Who Searched and others in the Brain Ship series
- Andrew Martin: The Bicentennial Man
- Sid Meier: Sid Meier's Alpha Centauri (Longevity Vaccine)
# Notes
- ↑ http://www.answers.com/topic/longevity?cat=health.
- ↑ http://www.answers.com/topic/longevity?cat=health.
- ↑ Jump up to: 3.0 3.1 CIA World Fact Book
- ↑ CIA World Fact Book 2002 | https://www.wikidoc.org/index.php/Longevity | |
83a599ed51c541b5af9faec161c5bd740a94762a | wikidoc | Lubricity | Lubricity
Lubricity is the measure of the reduction in friction of a lubricant. The study of lubrication and mechanism wear is called tribology.
# Measurement of lubricity
Lubricity of a material cannot be directly measured, so tests are performed to quantify a lubricant's performance. This is done by determining how much wear is caused to a surface by a given friction-inducing object in a given amount of time. Other factors such as surface size, temperature, and pressure are also specified. The greater the wear scar the worse the lubricity. For this reason lubricity is also termed a substance's anti-wear property.
Examples of test setups include "Ball-on-cylinder" and "Ball-on-three-discs" tests.
# Lubricity in diesel engines
In a modern diesel engine, the fuel is part of the engine lubrication process. Diesel fuel naturally contains sulfur compounds that provide good lubricity, but because of regulations in many countries (such as the US and the EU) sulfur must be removed. Reformulated diesel fuel has a lower lubricity and requires lubricity improving additives to prevent excessive engine wear. | Lubricity
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Lubricity is the measure of the reduction in friction of a lubricant. The study of lubrication and mechanism wear is called tribology.
# Measurement of lubricity
Lubricity of a material cannot be directly measured, so tests are performed to quantify a lubricant's performance. This is done by determining how much wear is caused to a surface by a given friction-inducing object in a given amount of time. Other factors such as surface size, temperature, and pressure are also specified. The greater the wear scar the worse the lubricity. For this reason lubricity is also termed a substance's anti-wear property.
Examples of test setups include "Ball-on-cylinder" and "Ball-on-three-discs" tests.
# Lubricity in diesel engines
In a modern diesel engine, the fuel is part of the engine lubrication process. Diesel fuel naturally contains sulfur compounds that provide good lubricity, but because of regulations in many countries (such as the US and the EU) sulfur must be removed. Reformulated diesel fuel has a lower lubricity and requires lubricity improving additives to prevent excessive engine wear.[1] [2] [3] | https://www.wikidoc.org/index.php/Lubricity | |
f8fd62ec81a8d0c3ef260486bd2c705099a68ea1 | wikidoc | MAG3 scan | MAG3 scan
A MAG3 scan is a diagnostic imaging procedure that allows a nuclear medicine technologist to visualize the kidneys and learn more about how they are functioning. MAG3 is an acronym for Mercapto Acetyl Tri Glycine, a compound that is chelated with a radioactive element - Technetium-99m.
# Scan procedure
After injection into the venous system, the compound is excreted by the kidneys and its progress through the renal system can be tracked with a gamma camera. If the kidney is not getting blood for example, it will not be viewed at all, even it looks structurally normal in medical ultrasonography or magnetic resonance imaging. If the kidney is getting blood, but there is an obstruction lower down, the contrast will not pass beyond the level of the obstruction, whereas if there is a partial obstruction then there is a delayed transit time for the MAG3 to pass. More information can be gathered by calculating time activity curves; with normal kidney perfusion, peak activity should be observed after 3-5 minutes. The relative quantitative information gives the differential fuction between each kidney's filtration activity.
# Clinical use
The technique is very useful in evaluating the functioning of kidneys. It is widely used before renal transplantation to assess the vascularity of the kidney to be transplanted and with a test dose of captopril to highlight possible renal artery stenosis in the donor's other kidney, and later the performance of the transplant.
The use of the test to identify reduced renal function after test doses of captopril (an angiotensin converting enzyme inhibitor drug) has also been used to identify the cause of hypertension in patients with renal failure. Initially there was uncertainty as to the usefulness, or best test parameter to identify renal artery stenosis, the eventual consensus was that the distinctive finding is of alteration in the differential function.
# History
It was developed in 1986, first trialled clinically the following year, and passed phase III testing in 1988.
99mTc-MAG3 has replaced the older Iodine-131 orthoiodohippurate or I131-Hippuran because of better quality imaging regardless of the level of renal function, and with the benefit of being able to administer lower radiation dosages.
# Footnotes
- ↑ González A, Jover L, Mairal LI, Martin-Comin J, Puchal R (1994). "Evaluation of obstructed kidneys by discriminant analysis of 99mTc-MAG3 renograms". Nuklearmedizin. 33 (6): 244–7. PMID 7854921.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Dubovsky EV, Diethelm AG, Keller F, Russell CD (1992). "Renal transplant hypertension caused by iliac artery stenosis" (PDF). J. Nucl. Med. 33 (6): 1178–80. PMID 1534577.CS1 maint: Multiple names: authors list (link)
- ↑ Kramer W, Baum RP, Scheuermann E, Hör G, Jonas D (1993). "". Urologe A (in German). 32 (2): 115–20. PMID 8475609.CS1 maint: Multiple names: authors list (link) CS1 maint: Unrecognized language (link)
- ↑ Li Y, Russell CD, Palmer-Lawrence J, Dubovsky EV (1994). "Quantitation of renal parenchymal retention of technetium-99m-MAG3 in renal transplants". J. Nucl. Med. 35 (5): 846–50. PMID 8176469.CS1 maint: Multiple names: authors list (link)
- ↑ Datseris IE, Bomanji JB, Brown EA; et al. (1994). "Captopril renal scintigraphy in patients with hypertension and chronic renal failure". J. Nucl. Med. 35 (2): 251–4. PMID 8294993.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Kahn D, Ben-Haim S, Bushnell DL, Madsen MT, Kirchner PT (1994). "Captopril-enhanced 99Tcm-MAG3 renal scintigraphy in subjects with suspected renovascular hypertension". Nucl Med Commun. 15 (7): 515–28. PMID 7970428.CS1 maint: Multiple names: authors list (link)
- ↑ Schreij G, van Es PN, van Kroonenburgh MJ, Kemerink GJ, Heidendal GA, de Leeuw PW (1996). "Baseline and postcaptopril renal blood flow measurements in hypertensives suspected of renal artery stenosis". J. Nucl. Med. 37 (10): 1652–5. PMID 8862302.CS1 maint: Multiple names: authors list (link)
- ↑ Roccatello D, Picciotto G (1997). "Captopril-enhanced scintigraphy using the method of the expected renogram: improved detection of patients with renin-dependent hypertension due to functionally significant renal artery stenosis" (PDF). Nephrol. Dial. Transplant. 12 (10): 2081–6. PMID 9351069.
- ↑ Fritzberg AR, Kasina S, Eshima D, Johnson DL (1986). "Synthesis and biological evaluation of technetium-99m MAG3 as a hippuran replacement". J. Nucl. Med. 27 (1): 111–6. PMID 2934521.CS1 maint: Multiple names: authors list (link)
- ↑ Taylor A, Eshima D, Alazraki N (1987). "99mTc-MAG3, a new renal imaging agent: preliminary results in patients". Eur J Nucl Med. 12 (10): 510–4. PMID 2952506.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 11.0 11.1 Al-Nahhas AA, Jafri RA, Britton KE; et al. (1988). "Clinical experience with 99mTc-MAG3, mercaptoacetyltriglycine, and a comparison with 99mTc-DTPA". Eur J Nucl Med. 14 (9–10): 453–62. PMID 2975219.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Taylor A, Eshima D, Christian PE, Milton W (1987). "Evaluation of Tc-99m mercaptoacetyltriglycine in patients with impaired renal function" (PDF). Radiology. 162 (2): 365–70. PMID 2948212.CS1 maint: Multiple names: authors list (link) | MAG3 scan
A MAG3 scan is a diagnostic imaging procedure that allows a nuclear medicine technologist to visualize the kidneys and learn more about how they are functioning. MAG3 is an acronym for Mercapto Acetyl Tri Glycine, a compound that is chelated with a radioactive element - Technetium-99m.
# Scan procedure
After injection into the venous system, the compound is excreted by the kidneys and its progress through the renal system can be tracked with a gamma camera. If the kidney is not getting blood for example, it will not be viewed at all, even it looks structurally normal in medical ultrasonography or magnetic resonance imaging. If the kidney is getting blood, but there is an obstruction lower down, the contrast will not pass beyond the level of the obstruction, whereas if there is a partial obstruction then there is a delayed transit time for the MAG3 to pass.[1] More information can be gathered by calculating time activity curves; with normal kidney perfusion, peak activity should be observed after 3-5 minutes. The relative quantitative information gives the differential fuction between each kidney's filtration activity.
# Clinical use
The technique is very useful in evaluating the functioning of kidneys. It is widely used before renal transplantation to assess the vascularity of the kidney to be transplanted and with a test dose of captopril to highlight possible renal artery stenosis in the donor's other kidney,[2] and later the performance of the transplant.[3][4]
The use of the test to identify reduced renal function after test doses of captopril (an angiotensin converting enzyme inhibitor drug) has also been used to identify the cause of hypertension in patients with renal failure.[5][6] Initially there was uncertainty as to the usefulness,[7] or best test parameter to identify renal artery stenosis, the eventual consensus was that the distinctive finding is of alteration in the differential function.[8]
# History
It was developed in 1986,[9] first trialled clinically the following year,[10] and passed phase III testing in 1988.[11]
99mTc-MAG3 has replaced the older Iodine-131 orthoiodohippurate or I131-Hippuran because of better quality imaging regardless of the level of renal function,[12] and with the benefit of being able to administer lower radiation dosages.[11]
# Footnotes
- ↑ González A, Jover L, Mairal LI, Martin-Comin J, Puchal R (1994). "Evaluation of obstructed kidneys by discriminant analysis of 99mTc-MAG3 renograms". Nuklearmedizin. 33 (6): 244–7. PMID 7854921.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Dubovsky EV, Diethelm AG, Keller F, Russell CD (1992). "Renal transplant hypertension caused by iliac artery stenosis" (PDF). J. Nucl. Med. 33 (6): 1178–80. PMID 1534577.CS1 maint: Multiple names: authors list (link)
- ↑ Kramer W, Baum RP, Scheuermann E, Hör G, Jonas D (1993). "[Follow-up after kidney transplantation. Sequential functional scintigraphy with technetium-99m-DTPA or technetium-99m-MAG3]". Urologe A (in German). 32 (2): 115–20. PMID 8475609.CS1 maint: Multiple names: authors list (link) CS1 maint: Unrecognized language (link)
- ↑ Li Y, Russell CD, Palmer-Lawrence J, Dubovsky EV (1994). "Quantitation of renal parenchymal retention of technetium-99m-MAG3 in renal transplants". J. Nucl. Med. 35 (5): 846–50. PMID 8176469.CS1 maint: Multiple names: authors list (link)
- ↑ Datseris IE, Bomanji JB, Brown EA; et al. (1994). "Captopril renal scintigraphy in patients with hypertension and chronic renal failure". J. Nucl. Med. 35 (2): 251–4. PMID 8294993.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Kahn D, Ben-Haim S, Bushnell DL, Madsen MT, Kirchner PT (1994). "Captopril-enhanced 99Tcm-MAG3 renal scintigraphy in subjects with suspected renovascular hypertension". Nucl Med Commun. 15 (7): 515–28. PMID 7970428.CS1 maint: Multiple names: authors list (link)
- ↑ Schreij G, van Es PN, van Kroonenburgh MJ, Kemerink GJ, Heidendal GA, de Leeuw PW (1996). "Baseline and postcaptopril renal blood flow measurements in hypertensives suspected of renal artery stenosis". J. Nucl. Med. 37 (10): 1652–5. PMID 8862302.CS1 maint: Multiple names: authors list (link)
- ↑ Roccatello D, Picciotto G (1997). "Captopril-enhanced scintigraphy using the method of the expected renogram: improved detection of patients with renin-dependent hypertension due to functionally significant renal artery stenosis" (PDF). Nephrol. Dial. Transplant. 12 (10): 2081–6. PMID 9351069.
- ↑ Fritzberg AR, Kasina S, Eshima D, Johnson DL (1986). "Synthesis and biological evaluation of technetium-99m MAG3 as a hippuran replacement". J. Nucl. Med. 27 (1): 111–6. PMID 2934521.CS1 maint: Multiple names: authors list (link)
- ↑ Taylor A, Eshima D, Alazraki N (1987). "99mTc-MAG3, a new renal imaging agent: preliminary results in patients". Eur J Nucl Med. 12 (10): 510–4. PMID 2952506.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 11.0 11.1 Al-Nahhas AA, Jafri RA, Britton KE; et al. (1988). "Clinical experience with 99mTc-MAG3, mercaptoacetyltriglycine, and a comparison with 99mTc-DTPA". Eur J Nucl Med. 14 (9–10): 453–62. PMID 2975219.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Taylor A, Eshima D, Christian PE, Milton W (1987). "Evaluation of Tc-99m mercaptoacetyltriglycine in patients with impaired renal function" (PDF). Radiology. 162 (2): 365–70. PMID 2948212.CS1 maint: Multiple names: authors list (link)
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Template:WS | https://www.wikidoc.org/index.php/MAG3_scan | |
685c5bfe98c9f04300019831432961417f896e4b | wikidoc | MAP3K7IP1 | MAP3K7IP1
Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the MAP3K7IP1 gene.
# Function
The protein encoded by this gene was identified as a regulator of the MAP kinase kinase kinase MAP3K7/TAK1, which is known to mediate various intracellular signaling pathways, such as those induced by TGF beta, interleukin 1, and WNT-1. This protein interacts and thus activates TAK1 kinase. It has been shown that the C-terminal portion of this protein is sufficient for binding and activation of TAK1, while a portion of the N-terminus acts as a dominant-negative inhibitor of TGF beta, suggesting that this protein may function as a mediator between TGF beta receptors and TAK1. This protein can also interact with and activate the mitogen-activated protein kinase 14 (MAPK14/p38alpha), and thus represents an alternative activation pathway, in addition to the MAPKK pathways, which contributes to the biological responses of MAPK14 to various stimuli. Alternatively spliced transcript variants encoding distinct isoforms have been reported.
This protein plays an important role in skin homeostasis, wound repair, and oncogenesis.
# Interactions
MAP3K7IP1 has been shown to interact with:
- MAP3K7IP2,
- MAP3K7IP3,
- MAP3K7,
- MAPK14,
- Mothers against decapentaplegic homolog 7,
- TRAF6,
- XIAP, and
- ZMYND11. | MAP3K7IP1
Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the MAP3K7IP1 gene.[1][2][3]
# Function
The protein encoded by this gene was identified as a regulator of the MAP kinase kinase kinase MAP3K7/TAK1, which is known to mediate various intracellular signaling pathways, such as those induced by TGF beta, interleukin 1, and WNT-1. This protein interacts and thus activates TAK1 kinase. It has been shown that the C-terminal portion of this protein is sufficient for binding and activation of TAK1, while a portion of the N-terminus acts as a dominant-negative inhibitor of TGF beta, suggesting that this protein may function as a mediator between TGF beta receptors and TAK1. This protein can also interact with and activate the mitogen-activated protein kinase 14 (MAPK14/p38alpha), and thus represents an alternative activation pathway, in addition to the MAPKK pathways, which contributes to the biological responses of MAPK14 to various stimuli. Alternatively spliced transcript variants encoding distinct isoforms have been reported.[3]
This protein plays an important role in skin homeostasis,[4][5] wound repair,[6][7] and oncogenesis.[8]
# Interactions
MAP3K7IP1 has been shown to interact with:
- MAP3K7IP2,[9][10][11]
- MAP3K7IP3,[11]
- MAP3K7,[11][12][13][14]
- MAPK14,[15]
- Mothers against decapentaplegic homolog 7,[16][17]
- TRAF6,[9][12][18]
- XIAP,[19][20] and
- ZMYND11.[21] | https://www.wikidoc.org/index.php/MAP3K7IP1 | |
140471eb01411251836b6d014373e4d8e3f0f639 | wikidoc | MDL Chime | MDL Chime
MDL Chime is a free plugin used by web browsers to display the three dimensional structures of molecules. It is part of the ISIS product line acquired by Symyx Technologies from scientific publisher Elsevier in October 2007. It is based on the RasMol code.
Chime is used by a wide range of biochemistry web sites for the visualization of macromolecules. Many of these sites are linked to the World Index of Molecular Visualization Resources MolVisIndex.Org. Chime was also used until 2006 at the Protein Data Bank to examine structures stored there.
Although available in 1998 in both Windows 98 and Mac OS 9 versions for both Netscape and Internet Explorer browsers, development of Chime did not follow the move to Mac OS X for the Mac and support for Windows-based browsers other than Internet Explorer was dropped (although it works well in Mozilla Firefox). No significant features have been added since 1998 except for updates in the installation package to follow the development of Windows and Internet Explorer.
Chime may be superseded by Jmol, but the current market share and trends are unclear. Jmol is a non-proprietary Java molecular visualization application/applet that has maintained most Chime command compatibility while adding features.
Two features of Chime which are not yet reproduced with Jmol:
- 'Sculpt' mode: The ability to change the conformation of molecules in a realistic way by dragging their atoms to new positions. This is a useful feature for exploring the conformational possibilities of a molecule such as the inability to rotate a carbon-carbon double bond.
- Calculating and drawing molecular surfaces coloured according to electrostatic or hydrophobic potential. Chime can calculate these surfaces for any molecule. | MDL Chime
MDL Chime is a free plugin used by web browsers to display the three dimensional structures of molecules. It is part of the ISIS product line acquired by Symyx Technologies from scientific publisher Elsevier in October 2007. It is based on the RasMol code.
Chime is used by a wide range of biochemistry web sites for the visualization of macromolecules. Many of these sites are linked to the World Index of Molecular Visualization Resources MolVisIndex.Org. Chime was also used until 2006 at the Protein Data Bank to examine structures stored there.
Although available in 1998 in both Windows 98 and Mac OS 9 versions for both Netscape and Internet Explorer browsers, development of Chime did not follow the move to Mac OS X for the Mac and support for Windows-based browsers other than Internet Explorer was dropped (although it works well in Mozilla Firefox). No significant features have been added since 1998 except for updates in the installation package to follow the development of Windows and Internet Explorer.
Chime may be superseded by Jmol, but the current market share and trends are unclear. Jmol is a non-proprietary Java molecular visualization application/applet that has maintained most Chime command compatibility while adding features.
Two features of Chime which are not yet reproduced with Jmol:
- 'Sculpt' mode: The ability to change the conformation of molecules in a realistic way by dragging their atoms to new positions. This is a useful feature for exploring the conformational possibilities of a molecule such as the inability to rotate a carbon-carbon double bond.
- Calculating and drawing molecular surfaces coloured according to electrostatic or hydrophobic potential. Chime can calculate these surfaces for any molecule.
# External links
- Symyx: MDL Chime
- RCSB Protein Data Bank
- MolviZ.Org: Molecular Visualization Resources with rich collection of molecules
- Dublin City University CHIME and Jmol Pages
Template:Jb1
Template:WH
Template:WS | https://www.wikidoc.org/index.php/MDL_Chime | |
2258bfc8523354ae18ec29012f57607f6c3c40b4 | wikidoc | MRI Robot | MRI Robot
# Overview
MRI Robot:
An MRI robot is a medical robot capable of operating within a Magnetic Resonance Imaging MRI scanner for the purpose of performing or assisting in image-guided interventions (IGI).
IGI interventions are commonly performed manually by physicians operating instruments such as needle based on medical images, in most medical field and in the Interventional_radiology specialty. IGI robots help manipulating the instrument or provide guidance for image-navigation. These have the potential to improve the performance of IGI because, unlike humans, robots are digital devices that may directly communicate with the digital imagers.
# MRI Compatible
To be MRI compatible a robot needs to safely operate and perform its function within the magnetic field of the MRI without deteriorating the image quality. But the development of MRI robots is a very challenging engineering task, because MRI scanners use magnetic fields of very high density (3 Tesla is now common), and most of the components commonly used in robotics may not be used in close proximity of the magnet ( see Google video on MRI Safety]).
# Examples
The URobotics research group at the Johns Hopkins University has developed an electricity-free, non-magnetic, and dielectric robot, MrBot. This operates with air for the motors and light for its sensors ( YouTube movie). This achievement was possible through the invention of a new type of pneumatic motor, the PneuStep, which allows for simple, fail-safe precision controlled motion. | MRI Robot
# Overview
MRI Robot:
An MRI robot is a medical robot capable of operating within a Magnetic Resonance Imaging MRI scanner for the purpose of performing or assisting in image-guided interventions (IGI).
IGI interventions are commonly performed manually by physicians operating instruments such as needle based on medical images, in most medical field and in the Interventional_radiology specialty. IGI robots help manipulating the instrument or provide guidance for image-navigation. These have the potential to improve the performance of IGI because, unlike humans, robots are digital devices that may directly communicate with the digital imagers.
# MRI Compatible
To be MRI compatible a robot needs to safely operate and perform its function within the magnetic field of the MRI without deteriorating the image quality. But the development of MRI robots is a very challenging engineering task, because MRI scanners use magnetic fields of very high density (3 Tesla is now common), and most of the components commonly used in robotics may not be used in close proximity of the magnet ([1] see Google video on MRI Safety]).
# Examples
The URobotics research group at the Johns Hopkins University has developed an electricity-free, non-magnetic, and dielectric robot, MrBot. This operates with air for the motors and light for its sensors ([2] YouTube movie). This achievement was possible through the invention of a new type of pneumatic motor, the PneuStep, which allows for simple, fail-safe precision controlled motion. | https://www.wikidoc.org/index.php/MRI_Robot | |
067d9cfff503e85d9292b0b407702d254a67d146 | wikidoc | Myostatin | Myostatin
Myostatin (also known as growth differentiation factor 8, abbreviated GDF-8) is a myokine, a protein produced and released by myocytes that acts on muscle cells' autocrine function to inhibit myogenesis: muscle cell growth and differentiation. In humans it is encoded by the MSTN gene. Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family.
Animals either lacking myostatin or treated with substances that block the activity of myostatin have significantly more muscle mass.
Furthermore, individuals who have mutations in both copies of the myostatin gene have significantly more muscle mass and are stronger than normal. There is hope that studies into myostatin may have therapeutic application in treating muscle wasting diseases such as muscular dystrophy.
# Discovery and sequencing
The gene encoding myostatin was discovered in 1997 by geneticists Se-Jin Lee and Alexandra McPherron who produced a knockout strain of mice that lack the gene, and have approximately twice as much muscle as normal mice. These mice were subsequently named "mighty mice".
Naturally occurring deficiencies of myostatin of various sorts have been identified in some breeds of cattle, sheep, whippets, and humans. In each case the result is a dramatic increase in muscle mass.
# Structure and mechanism of action
Human myostatin consists of two identical subunits, each consisting of 109 (NCBI database claims human myostatin is 375 residues long) amino acid residues . Its total molecular weight is 25.0 kDa. The protein is inactive until a protease cleaves the NH2-terminal, or "pro-domain" portion of the molecule, resulting in the active COOH-terminal dimer. Myostatin binds to the activin type II receptor, resulting in a recruitment of either coreceptor Alk-3 or Alk-4. This coreceptor then initiates a cell signaling cascade in the muscle, which includes the activation of transcription factors in the SMAD family - SMAD2 and SMAD3. These factors then induce myostatin-specific gene regulation. When applied to myoblasts, myostatin inhibits their differentiation into mature muscle fibers.
Myostatin also inhibits Akt, a kinase that is sufficient to cause muscle hypertrophy, in part through the activation of protein synthesis. However, Akt is not responsible for all of the observed muscle hyperthrophic effects which are mediated by myostatin inhibition Thus myostatin acts in two ways: by inhibiting muscle differentiation, and by inhibiting Akt-induced protein synthesis.
# Effects in animals
## Double muscled cattle
After that discovery, several laboratories cloned and established the nucleotide sequence of a myostatin gene in two breeds of cattle, Belgian Blue and Piedmontese. They found mutations in the myostatin gene (various mutations in each breed) which in one way or another lead to absence of functional myostatin. Unlike mice with a damaged myostatin gene, in these cattle breeds the muscle cells multiply rather than enlarge. People describe these cattle breeds as "double muscled", but the total increase in all muscles is no more than 40%.
Animals lacking myostatin or animals treated with substances such as follistatin that block the binding of myostatin to its receptor have significantly larger muscles. Thus, reduction of myostatin could potentially benefit the livestock industry, with even a 20 percent reduction in myostatin levels potentially having a large effect on the development of muscles.
However, the animal breeds developed as homozygous for myostatin deficiency have reproduction issues due to their unusually heavy and bulky offspring, and require special care and a more expensive diet to achieve a superior yield. This negatively affects economics of myostatin-deficient breeds to the point where they do not usually offer an obvious advantage. While hypertrophic meat (e.g. from Piedmontese beef) has a place on the specialist market due to its unusual properties, at least for purebred myostatin-deficient strains the expenses and (especially in cattle) necessity of veterinary supervision place them at a disadvantage in the bulk market.
## Whippets
Whippets can have a mutation of the myostatin which involves a two-base-pair deletion, and results in a truncated, and likely inactive, myostatin protein.
Animals with a homozygous deletion have an unusual body shape, with a broader head, pronounced overbite, shorter legs, and thicker tails, and are called "bully whippets" by the breeding community. Although significantly more muscular, they are less able runners than other whippets. However, whippets that were heterozygous for the mutation were significantly over-represented in the top racing classes.
## Rabbits and Goats
In 2016, the CRISPR/Cas9 system was used to genetically engineer rabbits and goats with no functional copies of the myostatin gene. In both cases the resulting animals were significantly more muscular. However, rabbits without myostatin also exhibited an enlarged tongue, a higher rate of still births, and a reduced lifespan.
# Clinical significance
## Mutations
A technique for detecting mutations in myostatin variants has been developed. Mutations that reduce the production of functional myostatin lead to an overgrowth of muscle tissue. Myostatin-related muscle hypertrophy has an incomplete autosomal dominance pattern of inheritance. People with a mutation in both copies of the MSTN gene in each cell (homozygotes) have significantly increased muscle mass and strength. People with a mutation in one copy of the MSTN gene in each cell (heterozygotes) have increased muscle bulk, but to a lesser degree.
## In humans
In 2004, a German boy was diagnosed with a mutation in both copies of the myostatin-producing gene, making him considerably stronger than his peers. His mother has a mutation in one copy of the gene.
An American boy born in 2005 was diagnosed with a clinically similar condition, but with a somewhat different cause: his body produces a normal level of functional myostatin, but because he is stronger and more muscular than most others his age, a defect in his myostatin receptors is thought to prevent his muscle cells from responding normally to myostatin. He appeared on the television show World's Strongest Toddler. Google search
## Therapeutic potential
Further research into myostatin and the myostatin gene may lead to therapies for muscular dystrophy. The idea is to introduce substances that block myostatin. A monoclonal antibody specific to myostatin increases muscle mass in mice and monkeys.
A two-week treatment of normal mice with soluble activin type IIB receptor, a molecule that is normally attached to cells and binds to myostatin, leads to a significantly increased muscle mass (up to 60%). It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors.
It remains unclear as to whether long-term treatment of muscular dystrophy with myostatin inhibitors is beneficial, as the depletion of muscle stem cells could worsen the disease later on. As of 2012, no myostatin-inhibiting drugs for humans are on the market. An antibody genetically engineered to neutralize myostatin, stamulumab, which was under development by pharmaceutical company Wyeth, is no longer under development. Some athletes, eager to get their hands on such drugs, turn to the internet where fake "myostatin blockers" are being sold.
Myostatin levels are effectively decreased by creatine supplementation.
Myostatin levels can be temporarily reduced using a cholesterol-conjugated siRNA gene knockdown.
## Athletic use
Inhibition of myostatin leads to muscle hyperplasia and hypertrophy. Myostatin inhibitors can improve athletic performance and therefore there is a concern these inhibitors might be abused in the field of sports. However, studies in mice suggest that myostatin inhibition does not directly increase the strength of individual muscle fibers. Myostatin inhibitors are specifically banned by the World Anti-Doping Agency (WADA). In an August 12, 2012 interview with National Public Radio, Carlon Colker stated “when the myostatin inhibitors come along, they'll be abused. There's no question in my mind.”
# Effects
## On bone formation
Due to myostatin’s ability to inhibit muscle growth, it can indirectly inhibit bone formation by decreasing the load on the bone. It has a direct signalling effect on bone formation as well as degradation. Knockdown of myostatin has been shown to reduce formation of osteoclasts (multinucleated cells responsible for the breakdown of bone tissue) in mice modeling rheumatoid arthritis. Rheumatoid arthritis is an autoimmune disorder that, among other effects, leads to the degradation of the bone tissue in affected joints. Myostatin has not, however, been shown to be solely sufficient for the formation of mature osteoclasts from macrophages, only an enhancer.
Myostatin expression is increased around the site of a fracture. Suppression of myostatin at the fracture site leads to increased callus and overall bone size, further supporting the inhibitory effect of myostatin on bone formation. One study by Berno Dankbar et al., 2015 found that myostatin deficiency leads to a notable reduction in inflammation around a fracture site. Myostatin affects osteoclastogenesis by binding to receptors on osteoclastic macrophages and causing a signalling cascade. The downstream signalling cascade enhances the expression of RANKL-dependent integrin αvβ3, DC-STAMP, calcitonin receptors, and NFATc1 (which is part of the initial intracellular complex that starts the signaling cascade, along with R-Smad2 and ALK4 or ALK5).
An association between osteoporosis, another disease characterized by the degradation of bony tissue, and sarcopenia, the age-related degeneration of muscle mass and quality have also been found. Whether this link is a result of direct regulation or a secondary effect through muscle mass is not known.
A link in mice between the concentration of myostatin in the prenatal environment and the strength of offsprings’ bones, partially counteracting the effects of osteogenesis imperfecta (brittle bone disease) has been found. Osteogenesis imperfecta is due to a mutation that causes the production of abnormal Type I collagen. Mice with defective myostatin were created by replacing sequences coding for the C-terminal region of myostatin with a neomycin cassette, rendering the protein nonfunctional. By crossbreeding mice with the abnormal Type I collagen and those with the knockout myostatin, the offspring had “a 15% increase in torsional ultimate strength, a 29% increase in tensile strength, and a 24% increase in energy to failure” of their femurs as compared to the other mice with osteogenesis imperfecta, showing the positive effects of decreased myostatin on bone strength and formation.
## On the heart
Myostatin is expressed at very low levels in cardiac myocytes. Although its presence has been noted in cardiomyocytes of both fetal and adult mice, its physiological function remains uncertain. However, it has been suggested that fetal cardiac myostatin may play a role in early heart development.
Myostatin is produced as promyostatin, a precursor protein kept inactive by the latent TGF-β binding protein 3 (LTBP3). Pathological cardiac stress promotes N-terminal cleavage by furin convertase to create a biologically active C-terminal fragment. The mature myostatin is then segregated from the latent complex via proteolytic cleavage by BMP-1 and tolloid metallopreoteinases. Free myostatin is able to bind its receptor, ActRIIB, and increase SMAD2/3 phosphorylation. The latter produces a heteromeric complex with SMAD4, inducing myostatin translocation into the cardiomyocyte nucleus to modulate transcription factor activity. Manipulating the muscle creatinine kinase promoter can modulate myostatin expression, although it has only been observed in male mice thus far.
Myostatin may inhibit cardiomyocyte proliferation and differentiation by manipulating cell cycle progression. This argument is supported by the fact that myostatin mRNA is poorly expressed in proliferating fetal cardiomyocytes. In vitro studies indicate that myostatin promotes SMAD2 phosphorylation to inhibit cardiomyocyte proliferation. Furthermore, myostatin has been shown to directly prevent cell cycle G1 to S phase transition by decreasing levels of cyclin-dependent kinase complex 2 (CDK2) and by increasing p21 levels.
Growth of cardiomyocytes may also be hindered by myostatin-regulated inhibition of protein kinase p38 and the serine-threonine protein kinase Akt, which typically promote cardiomyocyte hypertrophy. However, increased myostatin activity only occurs in response to specific stimuli, such as in pressure stress models, in which cardiac myostatin induces whole-body muscular atrophy.
Physiologically, minimal amounts of cardiac myostatin are secreted from the myocardium into serum, having a limited effect on muscle growth. However, increases in cardiac myostatin can increase its serum concentration, which may cause skeletal muscle atrophy. Pathological states that increase cardiac stress and promote heart failure can induce a rise in both cardiac myostatin mRNA and protein levels within the heart. In ischemic or dilated cardiomyopathy, increased levels of myostatin mRNA have been detected within the left ventricle.
As a member of the TGF-β family, myostatin may play a role in post-infarct recovery. It has been hypothesized that hypertrophy of the heart induces an increase in myostatin as a negative feedback mechanism in an attempt to limit further myocyte growth. This process includes mitogen-activated protein kinases and binding of the MEF2 transcription factor within the promoter region of the myostatin gene. Increases in myostatin levels during chronic heart failure have been shown to cause cardiac cachexia. Systemic inhibition of cardiac myostatin with the JA-16 antibody maintains overall muscle weight in experimental models with pre-existing heart failure.
Myostatin also alters excitation-contraction (EC) coupling within the heart. A reduction in cardiac myostatin induces eccentric hypertrophy of the heart, and increases its sensitivity to beta-adrenergic stimuli by enhancing Ca2+ release from the SR during EC coupling. Also, phospholamban phosphorylation is increased in myostatin-knockout mice, leading to an increase in Ca2+ release into the cytosol during systole. Therefore, minimizing cardiac myostatin may improve cardiac output.
# In popular culture
## Television
In The Incredible Hulk episode "Death In The Family" a nurse gives a patient a dose of myostatin, but Dr. David Banner recognizes that it is not true myostatin because the liquid is red not clear.
## Novels
Myostatin gene mutations are cited by a Stanford University scientist in the novel Performance Anomalies, as the scientist evaluates mutations that may account for the accelerated nervous system of the espionage protagonist Cono 7Q. | Myostatin
Myostatin (also known as growth differentiation factor 8, abbreviated GDF-8) is a myokine, a protein produced and released by myocytes that acts on muscle cells' autocrine function to inhibit myogenesis: muscle cell growth and differentiation. In humans it is encoded by the MSTN gene.[2] Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family.[3][4]
Animals either lacking myostatin or treated with substances that block the activity of myostatin have significantly more muscle mass.
Furthermore, individuals who have mutations in both copies of the myostatin gene have significantly more muscle mass and are stronger than normal. There is hope that studies into myostatin may have therapeutic application in treating muscle wasting diseases such as muscular dystrophy.[5]
# Discovery and sequencing
The gene encoding myostatin was discovered in 1997 by geneticists Se-Jin Lee and Alexandra McPherron who produced a knockout strain of mice that lack the gene, and have approximately twice as much muscle as normal mice.[6] These mice were subsequently named "mighty mice".
Naturally occurring deficiencies of myostatin of various sorts have been identified in some breeds of cattle,[7] sheep,[8] whippets,[9] and humans.[10] In each case the result is a dramatic increase in muscle mass.
# Structure and mechanism of action
Human myostatin consists of two identical subunits, each consisting of 109 (NCBI database claims human myostatin is 375 residues long) amino acid residues [note the full length gene encodes a 375AA prepro-protein which is proteolytically processed to its shorter active form].[11][12] Its total molecular weight is 25.0 kDa. The protein is inactive until a protease cleaves the NH2-terminal, or "pro-domain" portion of the molecule, resulting in the active COOH-terminal dimer. Myostatin binds to the activin type II receptor, resulting in a recruitment of either coreceptor Alk-3 or Alk-4. This coreceptor then initiates a cell signaling cascade in the muscle, which includes the activation of transcription factors in the SMAD family - SMAD2 and SMAD3. These factors then induce myostatin-specific gene regulation. When applied to myoblasts, myostatin inhibits their differentiation into mature muscle fibers.[citation needed]
Myostatin also inhibits Akt, a kinase that is sufficient to cause muscle hypertrophy, in part through the activation of protein synthesis. However, Akt is not responsible for all of the observed muscle hyperthrophic effects which are mediated by myostatin inhibition[13] Thus myostatin acts in two ways: by inhibiting muscle differentiation, and by inhibiting Akt-induced protein synthesis.
# Effects in animals
## Double muscled cattle
After that discovery, several laboratories cloned and established the nucleotide sequence of a myostatin gene in two breeds of cattle, Belgian Blue and Piedmontese. They found mutations in the myostatin gene (various mutations in each breed) which in one way or another lead to absence of functional myostatin.[6][7][14] Unlike mice with a damaged myostatin gene, in these cattle breeds the muscle cells multiply rather than enlarge. People describe these cattle breeds as "double muscled", but the total increase in all muscles is no more than 40%.[7][15][16]
Animals lacking myostatin or animals treated with substances such as follistatin that block the binding of myostatin to its receptor have significantly larger muscles. Thus, reduction of myostatin could potentially benefit the livestock industry, with even a 20 percent reduction in myostatin levels potentially having a large effect on the development of muscles.[17]
However, the animal breeds developed as homozygous for myostatin deficiency have reproduction issues due to their unusually heavy and bulky offspring, and require special care and a more expensive diet to achieve a superior yield. This negatively affects economics of myostatin-deficient breeds to the point where they do not usually offer an obvious advantage. While hypertrophic meat (e.g. from Piedmontese beef) has a place on the specialist market due to its unusual properties, at least for purebred myostatin-deficient strains the expenses and (especially in cattle) necessity of veterinary supervision place them at a disadvantage in the bulk market.[18]
## Whippets
Whippets can have a mutation of the myostatin which involves a two-base-pair deletion, and results in a truncated, and likely inactive, myostatin protein.
Animals with a homozygous deletion have an unusual body shape, with a broader head, pronounced overbite, shorter legs, and thicker tails, and are called "bully whippets" by the breeding community. Although significantly more muscular, they are less able runners than other whippets. However, whippets that were heterozygous for the mutation were significantly over-represented in the top racing classes.[9]
## Rabbits and Goats
In 2016, the CRISPR/Cas9 system was used to genetically engineer rabbits and goats with no functional copies of the myostatin gene.[19] In both cases the resulting animals were significantly more muscular. However, rabbits without myostatin also exhibited an enlarged tongue, a higher rate of still births, and a reduced lifespan.
# Clinical significance
## Mutations
A technique for detecting mutations in myostatin variants has been developed.[20] Mutations that reduce the production of functional myostatin lead to an overgrowth of muscle tissue. Myostatin-related muscle hypertrophy has an incomplete autosomal dominance pattern of inheritance. People with a mutation in both copies of the MSTN gene in each cell (homozygotes) have significantly increased muscle mass and strength. People with a mutation in one copy of the MSTN gene in each cell (heterozygotes) have increased muscle bulk, but to a lesser degree.[citation needed]
## In humans
In 2004, a German boy was diagnosed with a mutation in both copies of the myostatin-producing gene, making him considerably stronger than his peers. His mother has a mutation in one copy of the gene.[10][21][22]
An American boy born in 2005 was diagnosed with a clinically similar condition, but with a somewhat different cause:[23] his body produces a normal level of functional myostatin, but because he is stronger and more muscular than most others his age, a defect in his myostatin receptors is thought to prevent his muscle cells from responding normally to myostatin. He appeared on the television show World's Strongest Toddler.[citation needed] Google search
## Therapeutic potential
Further research into myostatin and the myostatin gene may lead to therapies for muscular dystrophy.[5][24] The idea is to introduce substances that block myostatin. A monoclonal antibody specific to myostatin increases muscle mass in mice[25] and monkeys.[17]
A two-week treatment of normal mice with soluble activin type IIB receptor, a molecule that is normally attached to cells and binds to myostatin, leads to a significantly increased muscle mass (up to 60%).[26] It is thought that binding of myostatin to the soluble activin receptor prevents it from interacting with the cell-bound receptors.[citation needed]
It remains unclear as to whether long-term treatment of muscular dystrophy with myostatin inhibitors is beneficial, as the depletion of muscle stem cells could worsen the disease later on. As of 2012[update], no myostatin-inhibiting drugs for humans are on the market. An antibody genetically engineered to neutralize myostatin, stamulumab, which was under development by pharmaceutical company Wyeth,[27] is no longer under development.[28] Some athletes, eager to get their hands on such drugs, turn to the internet where fake "myostatin blockers" are being sold.[17]
Myostatin levels are effectively decreased by creatine supplementation.[29]
Myostatin levels can be temporarily reduced using a cholesterol-conjugated siRNA gene knockdown.[30]
## Athletic use
Inhibition of myostatin leads to muscle hyperplasia and hypertrophy. Myostatin inhibitors can improve athletic performance and therefore there is a concern these inhibitors might be abused in the field of sports.[31] However, studies in mice suggest that myostatin inhibition does not directly increase the strength of individual muscle fibers.[32] Myostatin inhibitors are specifically banned by the World Anti-Doping Agency (WADA).[33] In an August 12, 2012 interview with National Public Radio, Carlon Colker stated “when the myostatin inhibitors come along, they'll be abused. There's no question in my mind.”[34]
# Effects
## On bone formation
Due to myostatin’s ability to inhibit muscle growth, it can indirectly inhibit bone formation by decreasing the load on the bone.[35][36] It has a direct signalling effect on bone formation[37] as well as degradation.[38][36] Knockdown of myostatin has been shown to reduce formation of osteoclasts (multinucleated cells responsible for the breakdown of bone tissue) in mice modeling rheumatoid arthritis.[38] Rheumatoid arthritis is an autoimmune disorder that, among other effects, leads to the degradation of the bone tissue in affected joints. Myostatin has not, however, been shown to be solely sufficient for the formation of mature osteoclasts from macrophages, only an enhancer.
Myostatin expression is increased around the site of a fracture. Suppression of myostatin at the fracture site leads to increased callus and overall bone size, further supporting the inhibitory effect of myostatin on bone formation. One study[38] by Berno Dankbar et al., 2015 found that myostatin deficiency leads to a notable reduction in inflammation around a fracture site. Myostatin affects osteoclastogenesis by binding to receptors on osteoclastic macrophages and causing a signalling cascade. The downstream signalling cascade enhances the expression of RANKL-dependent integrin αvβ3, DC-STAMP, calcitonin receptors, and NFATc1 (which is part of the initial intracellular complex that starts the signaling cascade, along with R-Smad2 and ALK4 or ALK5).[38][36]
An association between osteoporosis, another disease characterized by the degradation of bony tissue, and sarcopenia, the age-related degeneration of muscle mass and quality have also been found.[36] Whether this link is a result of direct regulation or a secondary effect through muscle mass is not known.
A link in mice between the concentration of myostatin in the prenatal environment and the strength of offsprings’ bones, partially counteracting the effects of osteogenesis imperfecta (brittle bone disease) has been found.[39] Osteogenesis imperfecta is due to a mutation that causes the production of abnormal Type I collagen. Mice with defective myostatin were created by replacing sequences coding for the C-terminal region of myostatin with a neomycin cassette, rendering the protein nonfunctional. By crossbreeding mice with the abnormal Type I collagen and those with the knockout myostatin, the offspring had “a 15% increase in torsional ultimate strength, a 29% increase in tensile strength, and a 24% increase in energy to failure” of their femurs as compared to the other mice with osteogenesis imperfecta, showing the positive effects of decreased myostatin on bone strength and formation.[40]
## On the heart
Myostatin is expressed at very low levels in cardiac myocytes.[41][42] Although its presence has been noted in cardiomyocytes of both fetal and adult mice,[43] its physiological function remains uncertain.[42] However, it has been suggested that fetal cardiac myostatin may play a role in early heart development.[43]
Myostatin is produced as promyostatin, a precursor protein kept inactive by the latent TGF-β binding protein 3 (LTBP3).[41] Pathological cardiac stress promotes N-terminal cleavage by furin convertase to create a biologically active C-terminal fragment. The mature myostatin is then segregated from the latent complex via proteolytic cleavage by BMP-1 and tolloid metallopreoteinases.[41] Free myostatin is able to bind its receptor, ActRIIB, and increase SMAD2/3 phosphorylation.[41] The latter produces a heteromeric complex with SMAD4, inducing myostatin translocation into the cardiomyocyte nucleus to modulate transcription factor activity.[44] Manipulating the muscle creatinine kinase promoter can modulate myostatin expression, although it has only been observed in male mice thus far.[41][42]
Myostatin may inhibit cardiomyocyte proliferation and differentiation by manipulating cell cycle progression.[43] This argument is supported by the fact that myostatin mRNA is poorly expressed in proliferating fetal cardiomyocytes.[41][44] In vitro studies indicate that myostatin promotes SMAD2 phosphorylation to inhibit cardiomyocyte proliferation. Furthermore, myostatin has been shown to directly prevent cell cycle G1 to S phase transition by decreasing levels of cyclin-dependent kinase complex 2 (CDK2) and by increasing p21 levels.[44]
Growth of cardiomyocytes may also be hindered by myostatin-regulated inhibition of protein kinase p38 and the serine-threonine protein kinase Akt, which typically promote cardiomyocyte hypertrophy.[45] However, increased myostatin activity only occurs in response to specific stimuli,[41][45] such as in pressure stress models, in which cardiac myostatin induces whole-body muscular atrophy.[41][43]
Physiologically, minimal amounts of cardiac myostatin are secreted from the myocardium into serum, having a limited effect on muscle growth.[42] However, increases in cardiac myostatin can increase its serum concentration, which may cause skeletal muscle atrophy.[41][42] Pathological states that increase cardiac stress and promote heart failure can induce a rise in both cardiac myostatin mRNA and protein levels within the heart.[41][42] In ischemic or dilated cardiomyopathy, increased levels of myostatin mRNA have been detected within the left ventricle.[41][46]
As a member of the TGF-β family, myostatin may play a role in post-infarct recovery.[42][43] It has been hypothesized that hypertrophy of the heart induces an increase in myostatin as a negative feedback mechanism in an attempt to limit further myocyte growth.[47][48] This process includes mitogen-activated protein kinases and binding of the MEF2 transcription factor within the promoter region of the myostatin gene. Increases in myostatin levels during chronic heart failure have been shown to cause cardiac cachexia.[41][42][49] Systemic inhibition of cardiac myostatin with the JA-16 antibody maintains overall muscle weight in experimental models with pre-existing heart failure.[42]
Myostatin also alters excitation-contraction (EC) coupling within the heart.[50] A reduction in cardiac myostatin induces eccentric hypertrophy of the heart, and increases its sensitivity to beta-adrenergic stimuli by enhancing Ca2+ release from the SR during EC coupling. Also, phospholamban phosphorylation is increased in myostatin-knockout mice, leading to an increase in Ca2+ release into the cytosol during systole.[41] Therefore, minimizing cardiac myostatin may improve cardiac output.[50]
# In popular culture
## Television
In The Incredible Hulk episode "Death In The Family" a nurse gives a patient a dose of myostatin, but Dr. David Banner recognizes that it is not true myostatin because the liquid is red not clear.
## Novels
Myostatin gene mutations are cited by a Stanford University scientist in the novel Performance Anomalies,[51][52] as the scientist evaluates mutations that may account for the accelerated nervous system of the espionage protagonist Cono 7Q. | https://www.wikidoc.org/index.php/MSTN | |
1e6d39bd25eaff13d89550a07c916ce37bd61b4b | wikidoc | MS Contin | MS Contin
MS Contin® is a time-released formulation of morphine, usually taken every twelve hours for chronic pain. It is the brand name for morphine sulfate marketed by Purdue Pharma.
It is available in tablet and liquid formulas in doses of 5mg, 10mg, 15mg, 20mg, 30mg, 60mg, 100mg and 200mg. Due to its strength, it is typically prescribed to cancer patients and victims of severe but non-cognitive-damaging trauma.
Like its relative cousin OxyContin, MS Contin has been the subject of pharmacy robberies. It is considered particularly dangerous to recreational drug users who are unaware that the time-release mechanism is a wax inside of the pill (not the colored coating on the outside) that, when heated, expands and encases the morphine sulfate. The danger presented to drug users who prefer intravenous/intramuscular injection is the wax.
MS Contin is a DEA Schedule II substance in the United States. Alternative formulations made and marketed by other pharmaceutical companies include Ligand's Avinza® and Faulding Laboratories' Kadian®. | MS Contin
MS Contin® is a time-released formulation of morphine, usually taken every twelve hours for chronic pain. It is the brand name for morphine sulfate marketed by Purdue Pharma.
It is available in tablet and liquid formulas in doses of 5mg, 10mg, 15mg, 20mg, 30mg, 60mg, 100mg and 200mg. Due to its strength, it is typically prescribed to cancer patients and victims of severe but non-cognitive-damaging trauma.
Like its relative cousin OxyContin, MS Contin has been the subject of pharmacy robberies.[citation needed] It is considered particularly dangerous to recreational drug users who are unaware that the time-release mechanism is a wax inside of the pill (not the colored coating on the outside) that, when heated, expands and encases the morphine sulfate. The danger presented to drug users who prefer intravenous/intramuscular injection is the wax.
MS Contin is a DEA Schedule II substance in the United States. Alternative formulations made and marketed by other pharmaceutical companies include Ligand's Avinza® and Faulding Laboratories' Kadian®.
# External links
- Advanced consumer information: morphine sulfate
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/MS_Contin | |
67176f016e8444653c5dac02de229d03e2014c6b | wikidoc | MUGA scan | MUGA scan
# Overview
A MUGA scan (Multiple Gated Acquisition Scan) is a nuclear medicine test to evaluate the function of the heart ventricles. It provides a movie-like image of the beating heart, and allows the doctor to determine the health of the heart’s major pumping chambers. The advantages of MUGA is that it is more accurate than an echocardiogram and it is non-invasive.
# Purpose
MUGA is typically ordered for the following patients:
- With known or suspected coronary artery disease, to diagnose the disease and predict outcomes
- With lesions in their heart valves
- Who have recently had a heart attack, to assess damage to heart tissue and predict the likelihood of future cardiac events
- With congestive heart failure
- Who have undergone percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, or medical therapy, to assess the efficacy of the treatment
- With low cardiac output after open-heart surgery
- Who are undergoing chemotherapy or immunotherapy (herceptin)
# Procedure
At a high level, the MUGA test involves the introduction of a radioactive marker into the bloodstream of the patient. The patient is subsequently scanned to determine the circulation dynamics of the marker, and hence the blood.
The introduction of the radioactive marker can either take place in vivo or in vitro
In the in vivo method, stannous (Tin) ions are injected into the patient's bloodstream. A subsequent intravenous injection of the radioactive substance, Technetium-99m-pertechnetate, labels the red blood cells in vivo. With an administered activity of about 800 MBq, the effective radiation dose is about 8 mSv.
In the in vitro method, some the patient's blood is drawn and the stannous ions (in the form of stannous chloride) are injected into the drawn blood. The Technetium is subsequently added to the mixture as in the in vivo method.
In both cases, the stannous chloride dilutes the Technetium and prevents it from leaking out of the red blood cells during the procedure.
The patient is placed under a gamma camera, which detects the low-level 140keV gamma radiation being given off by technetium-99m. As the gamma camera images are acquired, the patient's heart beat is used to 'gate' the acquisition. The final result is a series of images of the heart (usually sixteen), one at each stage of the cardiac cycle.
Depending on the the objectives of the test, the doctor may decide to perform either a resting or a stress MUGA. During the resting MUGA, the patient lies stationary, whereas during a stress MUGA, the patient is asked to exercise during the scan. The stress MUGA measures the heart performance during exercise and is usually performed to assess the impact of a suspected coronary artery disease. In some rare cases, a nitroglycerin MUGA may be performed, where nitroglycerin (a vasodilator) is administered prior to the scan.
The resulting images show the blood pool in the chambers of the heart and the images can be analyzed on a computer to calculate the ejection fraction of the heart together with other useful clinical parameters. This scan gives an accurate and reproducible means of measuring and monitoring the ejection fraction of the left ventricle, which is one of the most important metrics in assessing heart performance.
# Results
## Normal results
Normal ventricular function is characterized by an even distribution of Technetium. Elevated ejection fractions may be seen on a stress MUGA.
## Abnormal results
An uneven distribution of technetium in the heart indicates that the patient has coronary artery disease, a cardiomyopathy, or blood shunting within the heart. Abnormalities in a resting MUGA usually indicate a heart attack, while those that occur during exercise usually indicate ischemia. In a stress MUGA, patients with coronary artery disease may exhibit a decrease in ejection fraction.
For a patient that has had a heart attack, or is suspected of having another disease that affects the heart muscle, this scan can help pinpoint the position in the heart that has sustained damage as well as assess the degree of damage. MUGA scans are also used to evaluate heart function prior to and while receiving certain chemotherapies (e.g. Adriamycin) or immunotherapy (specifically, herceptin) that have a known effect on heart function. | MUGA scan
# Overview
A MUGA scan (Multiple Gated Acquisition Scan) is a nuclear medicine test to evaluate the function of the heart ventricles. It provides a movie-like image of the beating heart, and allows the doctor to determine the health of the heart’s major pumping chambers. The advantages of MUGA is that it is more accurate than an echocardiogram and it is non-invasive.
# Purpose
MUGA is typically ordered for the following patients:
- With known or suspected coronary artery disease, to diagnose the disease and predict outcomes
- With lesions in their heart valves
- Who have recently had a heart attack, to assess damage to heart tissue and predict the likelihood of future cardiac events
- With congestive heart failure
- Who have undergone percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, or medical therapy, to assess the efficacy of the treatment
- With low cardiac output after open-heart surgery
- Who are undergoing chemotherapy or immunotherapy (herceptin)
# Procedure
At a high level, the MUGA test involves the introduction of a radioactive marker into the bloodstream of the patient. The patient is subsequently scanned to determine the circulation dynamics of the marker, and hence the blood.
The introduction of the radioactive marker can either take place in vivo or in vitro
In the in vivo method, stannous (Tin) ions are injected into the patient's bloodstream. A subsequent intravenous injection of the radioactive substance, Technetium-99m-pertechnetate, labels the red blood cells in vivo. With an administered activity of about 800 MBq, the effective radiation dose is about 8 mSv.
In the in vitro method, some the patient's blood is drawn and the stannous ions (in the form of stannous chloride) are injected into the drawn blood. The Technetium is subsequently added to the mixture as in the in vivo method.
In both cases, the stannous chloride dilutes the Technetium and prevents it from leaking out of the red blood cells during the procedure.
The patient is placed under a gamma camera, which detects the low-level 140keV gamma radiation being given off by technetium-99m. As the gamma camera images are acquired, the patient's heart beat is used to 'gate' the acquisition. The final result is a series of images of the heart (usually sixteen), one at each stage of the cardiac cycle.
Depending on the the objectives of the test, the doctor may decide to perform either a resting or a stress MUGA. During the resting MUGA, the patient lies stationary, whereas during a stress MUGA, the patient is asked to exercise during the scan. The stress MUGA measures the heart performance during exercise and is usually performed to assess the impact of a suspected coronary artery disease. In some rare cases, a nitroglycerin MUGA may be performed, where nitroglycerin (a vasodilator) is administered prior to the scan.
The resulting images show the blood pool in the chambers of the heart and the images can be analyzed on a computer to calculate the ejection fraction of the heart together with other useful clinical parameters. This scan gives an accurate and reproducible means of measuring and monitoring the ejection fraction of the left ventricle, which is one of the most important metrics in assessing heart performance.
# Results
## Normal results
Normal ventricular function is characterized by an even distribution of Technetium. Elevated ejection fractions may be seen on a stress MUGA.
## Abnormal results
An uneven distribution of technetium in the heart indicates that the patient has coronary artery disease, a cardiomyopathy, or blood shunting within the heart. Abnormalities in a resting MUGA usually indicate a heart attack, while those that occur during exercise usually indicate ischemia. In a stress MUGA, patients with coronary artery disease may exhibit a decrease in ejection fraction.
For a patient that has had a heart attack, or is suspected of having another disease that affects the heart muscle, this scan can help pinpoint the position in the heart that has sustained damage as well as assess the degree of damage. MUGA scans are also used to evaluate heart function prior to and while receiving certain chemotherapies (e.g. Adriamycin) or immunotherapy (specifically, herceptin) that have a known effect on heart function.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/MUGA_scan | |
a2d4f63334fd808bcd329ea58febbfc1d9bdc14e | wikidoc | Macrolide | Macrolide
# Overview
The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14, 15 or 16-membered. Macrolides belong to the polyketide class of natural products.
# Members
## Common antibiotic macrolides
- Azithromycin (Zithromax, Zitromax, Sumamed) - Unique, does not inhibit CYP3A4
- Clarithromycin (Biaxin)
- Dirithromycin (Dynabac)
- Erythromycin
- Roxithromycin (Rulid, Surlid,Roxid)
## Developmental macrolides
- Carbomycin A
- Josamycin
- Kitasamycin
- Midecamicine/midecamicine acetate
- Oleandomycin
- Spiramycin
- Troleandomycin
- Tylosin/tylocine (Tylan)
## Ketolides
Ketolides are a new class of antibiotics that are structurally related to the macrolides. They are used to fight respiratory tract infections caused by macrolide-resistant bacteria.
- Telithromycin (Ketek)
- Cethromycin
Others include spiramycin (used for treating toxoplasmosis), ansamycin, oleandomycin, carbomycin and tylocine.
## Non-antibiotic macrolides
The drug tacrolimus (Prograf), which is used as an immunosuppressant, is also a macrolide. It has similar activity to cyclosporin.
## Toxic macrolides
A variety of toxic macrolides produced by bacteria have been isolated and characterized, such as the mycolactones.
# Uses
Antibiotic macrolides are used to treat infections such as respiratory tract and soft tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of penicillin, and therefore macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolytic streptococci, pneumococci, staphylococci and enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against mycoplasma, mycobacteria, some rickettsia and chlamydia.
# Mechanism of action
The mechanism of action of the macrolides is inhibition of bacterial protein biosynthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl tRNA. This action is mainly bacteriostatic, but can also be bactericidal in high concentrations. Macrolides tend to accumulate within leukocytes, and are therefore actually transported into the site of infection.
A novel, non-antibiotic, anti-inflammatory effect of 14-membered macrolides was discovered in Japan (Kudo S. et al.), which is especially effective in improving control of diffuse panbronchiolitis (DPB). Research on the anti-inflammatory properties of the macrolide ring is ongoing.
# Resistance
The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S bacterial ribosomal RNA. This acquired resistance can be either plasmid-mediated or chromosomal, i.e through mutation, and results in cross-resistance to macrolides, lincosamides, and streptogramins (an MLS-resistant phenotype).
Two other types of acquired resistance rarely seen include the production of drug-inactivating enzymes (esterases or kinases) as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.
# Side effects
A recent British Medical Journal article highlights that the combination of macrolides and statins (used for lowering cholesterol) is not advisable and can lead to debilitating myopathy. This is because macrolides are potent inhibitors of the cytochrome P450 system, particularly of CYP3A4. Macrolides also have a class effect of QT prolongation. Macrolides exhibit enterohepatic recycling; that is, the drug is absorbed in the gut and sent to the liver, only to be excreted into the duodenum in bile from the . This can lead to a build up of the product in the system causing nausea. | Macrolide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14, 15 or 16-membered. Macrolides belong to the polyketide class of natural products.
# Members
## Common antibiotic macrolides
- Azithromycin (Zithromax, Zitromax, Sumamed) - Unique, does not inhibit CYP3A4
- Clarithromycin (Biaxin)
- Dirithromycin (Dynabac)
- Erythromycin
- Roxithromycin (Rulid, Surlid,Roxid)
## Developmental macrolides
- Carbomycin A
- Josamycin
- Kitasamycin
- Midecamicine/midecamicine acetate
- Oleandomycin
- Spiramycin
- Troleandomycin
- Tylosin/tylocine (Tylan)
## Ketolides
Ketolides are a new class of antibiotics that are structurally related to the macrolides. They are used to fight respiratory tract infections caused by macrolide-resistant bacteria.
- Telithromycin (Ketek)
- Cethromycin
Others include spiramycin (used for treating toxoplasmosis), ansamycin, oleandomycin, carbomycin and tylocine.
## Non-antibiotic macrolides
The drug tacrolimus (Prograf), which is used as an immunosuppressant, is also a macrolide. It has similar activity to cyclosporin.
## Toxic macrolides
A variety of toxic macrolides produced by bacteria have been isolated and characterized, such as the mycolactones.
# Uses
Antibiotic macrolides are used to treat infections such as respiratory tract and soft tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of penicillin, and therefore macrolides are a common substitute for patients with a penicillin allergy. Beta-hemolytic streptococci, pneumococci, staphylococci and enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have been shown to be effective against mycoplasma, mycobacteria, some rickettsia and chlamydia.
# Mechanism of action
The mechanism of action of the macrolides is inhibition of bacterial protein biosynthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl tRNA. This action is mainly bacteriostatic, but can also be bactericidal in high concentrations. Macrolides tend to accumulate within leukocytes, and are therefore actually transported into the site of infection.
A novel, non-antibiotic, anti-inflammatory effect of 14-membered macrolides was discovered in Japan (Kudo S. et al.), which is especially effective in improving control of diffuse panbronchiolitis (DPB). Research on the anti-inflammatory properties of the macrolide ring is ongoing.
# Resistance
The primary means of bacterial resistance to macrolides occurs by post-transcriptional methylation of the 23S bacterial ribosomal RNA. This acquired resistance can be either plasmid-mediated or chromosomal, i.e through mutation, and results in cross-resistance to macrolides, lincosamides, and streptogramins (an MLS-resistant phenotype).
Two other types of acquired resistance rarely seen include the production of drug-inactivating enzymes (esterases or kinases) as well as the production of active ATP-dependent efflux proteins that transport the drug outside of the cell.
# Side effects
A recent British Medical Journal article highlights that the combination of macrolides and statins (used for lowering cholesterol) is not advisable and can lead to debilitating myopathy. This is because macrolides are potent inhibitors of the cytochrome P450 system, particularly of CYP3A4. Macrolides also have a class effect of QT prolongation. Macrolides exhibit enterohepatic recycling; that is, the drug is absorbed in the gut and sent to the liver, only to be excreted into the duodenum in bile from the [[liver]. This can lead to a build up of the product in the system causing nausea. | https://www.wikidoc.org/index.php/Macrolide | |
b9a371cf5e51ed673d4ff4c9f95c2a63f898676f | wikidoc | Superacid | Superacid
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
A superacid is an acid with an acidity greater than that of 100% sulfuric acid, which has a Hammett acidity function of -12. Commercially available superacids include trifluoromethanesulfonic acid (CF3SO3H), also known as triflic acid, and fluorosulfuric acid (FSO3H), both of which are about a thousand times stronger (i.e. have more negative H0 values) than sulfuric acid. The strongest superacids are prepared by the combination of two components, a strong Lewis acid and a strong Brønsted acid.
The term superacid was originally coined by James Bryant Conant in 1927 to describe acids that were stronger than conventional mineral acids. George A. Olah was awarded the 1994 Nobel prize in chemistry for his investigations of superacids and their use in the direct observation of carbocations. Olah's "magic acid", so-named for its ability to attack hydrocarbons, is prepared by mixing antimony pentafluoride (SbF5) and fluorosulfuric acid. The name was coined after one of Professor Olah's post-doctoral associates placed a candle in a sample of magic acid. The candle was dissolved, showing the ability of the acid to protonate hydrocarbons (which are not basic).
The strongest super acid system, the so-called fluoroantimonic acid, is a combination of hydrogen fluoride and SbF5. In this system, HF releases its proton (H+) concomitant with the binding of F− by the antimony pentafluoride. The resulting anion (SbF6−) is both a weak nucleophile and a weak base. The proton effectively becomes "naked", which accounts for the system's extreme acidity. Fluoroantimonic acid is 2×1019 times stronger than 100% sulfuric acid, and can produce solutions with a pH down to –25.
Olah showed that at 140 °C (284 °F), FSO3H-SbF5 will convert methane into the tertiary-butyl carbocation, a reaction that begins with the protonation of methane:
# Applications
Common uses of superacids include providing an environment to create and maintain organic cations which are useful as intermediate molecules in numerous reactions, such as involving plastics and high-octane gasoline production and study. | Superacid
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
A superacid is an acid with an acidity greater than that of 100% sulfuric acid, which has a Hammett acidity function of -12. Commercially available superacids include trifluoromethanesulfonic acid (CF3SO3H), also known as triflic acid, and fluorosulfuric acid (FSO3H), both of which are about a thousand times stronger (i.e. have more negative H0 values) than sulfuric acid. The strongest superacids are prepared by the combination of two components, a strong Lewis acid and a strong Brønsted acid.
The term superacid was originally coined by James Bryant Conant in 1927 to describe acids that were stronger than conventional mineral acids.[1] George A. Olah was awarded the 1994 Nobel prize in chemistry for his investigations of superacids and their use in the direct observation of carbocations. Olah's "magic acid", so-named for its ability to attack hydrocarbons, is prepared by mixing antimony pentafluoride (SbF5) and fluorosulfuric acid. The name was coined after one of Professor Olah's post-doctoral associates placed a candle in a sample of magic acid. The candle was dissolved, showing the ability of the acid to protonate hydrocarbons (which are not basic).
The strongest super acid system, the so-called fluoroantimonic acid, is a combination of hydrogen fluoride and SbF5. In this system, HF releases its proton (H+) concomitant with the binding of F− by the antimony pentafluoride. The resulting anion (SbF6−) is both a weak nucleophile and a weak base. The proton effectively becomes "naked", which accounts for the system's extreme acidity. Fluoroantimonic acid is 2×1019 times stronger than 100% sulfuric acid,[2] and can produce solutions with a pH down to –25.[3]
Olah showed that at 140 °C (284 °F), FSO3H-SbF5 will convert methane into the tertiary-butyl carbocation, a reaction that begins with the protonation of methane:[4]
# Applications
Common uses of superacids include providing an environment to create and maintain organic cations which are useful as intermediate molecules in numerous reactions, such as involving plastics and high-octane gasoline production and study.[5] | https://www.wikidoc.org/index.php/Magic_acid | |
055bb8c2fe6b9dd6d7a522a31c5a5915593ea8d0 | wikidoc | Magnetism | Magnetism
In physics, magnetism is one of the phenomena by which materials exert attractive or repulsive forces on other materials. Some well known materials that exhibit easily detectable magnetic properties (called magnets) are nickel, iron, cobalt, and their alloys; however, all materials are influenced to greater or lesser degree by the presence of a magnetic field.
Magnetism also has other manifestations in physics, particularly as one of the two components of electromagnetic waves such as light.
# History
Aristotle attributes the first of what could be called a scientific discussion on magnetism to Thales, who lived from about 625 BC to about 545 BC. In China, the earliest literary reference to magnetism lies in a 4th century BC book called Book of the Devil Valley Master (鬼谷子): "The lodestone makes iron come or it attracts it." The earliest mention of the attraction of a needle appears in a work composed between 20 and 100 AD (Louen-heng): "A lodestone attracts a needle." The ancient Chinese scientist Shen Kuo (1031-1095) was the first person to write of the magnetic needle compass and that it improved the accuracy of navigation by employing the astronomical concept of true north (Dream Pool Essays, 1088 AD), and by the 12th century the Chinese were known to use the lodestone compass for navigation. Alexander Neckham, by 1187, was the first in Europe to describe the compass and its use for navigation. In 1269 Peter Peregrinus wrote the Epistola de Magnete, the first extant treatise describing the properties of magnets.
An understanding of the relationship between electricity and magnetism began in 1819 with work by Hans Christian Oersted, a professor at the University of Copenhagen, who discovered more or less by accident that an electric current could influence a compass needle. This landmark experiment is known as Oersted's Experiment. Several other experiments followed, with André-Marie Ampère, Carl Friedrich Gauss, Michael Faraday, and others finding further links between magnetism and electricity. James Clerk Maxwell synthesized and expanded these insights into Maxwell's equations, unifying electricity, magnetism, and optics into the field of electromagnetism. In 1905, Einstein used these laws in motivating his theory of special relativity, in the process showing that electricity and magnetism are fundamentally interlinked and inseparable.
Electromagnetism has continued to develop into the twentieth century, being incorporated into the more fundamental theories of gauge theory, quantum electrodynamics, electroweak theory, and finally the standard model.
# Physics of magnetism
## Magnets and magnetic materials
Every electron is, by its nature, a small magnet (see Electron magnetic dipole moment). Ordinarily, the countless electrons in a material are randomly oriented in different directions, leaving no effect on average, but in a bar magnet the electrons are aligned in the same direction, so they act cooperatively, creating a net magnetic field.
In addition to the electron's intrinsic magnetic field, there is sometimes an additional magnetic field that results from the electron's orbital motion about the nucleus. This effect is analogous to how a current-carrying loop of wire generates a magnetic field (see Magnetic dipole). Again, ordinarily, the motion of the electrons is such that there is no average field from the material, but in certain conditions, the motion can line up so as to produce a measurable total field.
The overall magnetic behavior of a material can vary widely, depending on the structure of the material, and particularly on its electron configuration. Several forms of magnetic behavior have been observed in different materials, including:
- Diamagnetism
- Paramagnetism
Molecular magnet
- Molecular magnet
- Ferromagnetism
Antiferromagnetism
Ferrimagnetism
Metamagnetism
- Antiferromagnetism
- Ferrimagnetism
- Metamagnetism
- Spin glass
- Superparamagnetism
## Magnetism, electricity, and special relativity
As a consequence of Einstein's theory of special relativity, electricity and magnetism are understood to be fundamentally interlinked. Both magnetism lacking electricity, and electricity without magnetism, are inconsistent with special relativity, due to such effects as length contraction, time dilation, and the fact that the magnetic force is velocity-dependent. However, when both electricity and magnetism are taken into account, the resulting theory (electromagnetism) is fully consistent with special relativity. In particular, a phenomenon that appears purely electric to one observer may be purely magnetic to another, or more generally the relative contributions of electricity and magnetism are dependent on the frame of reference. Thus, special relativity "mixes" electricity and magnetism into a single, inseparable phenomenon called electromagnetism (analogously to how special relativity "mixes" space and time into spacetime).
## Magnetic fields and forces
The phenomenon of magnetism is "mediated" by the magnetic field -- i.e., an electric current or magnetic dipole creates a magnetic field, and that field, in turn, imparts magnetic forces on other particles that are in the fields.
To an excellent approximation (but ignoring some quantum effects---see quantum electrodynamics), Maxwell's equations (which simplify to the Biot-Savart law in the case of steady currents) describe the origin and behavior of the fields that govern these forces. Therefore magnetism is seen whenever electrically charged particles are in motion---for example, from movement of electrons in an electric current, or in certain cases from the orbital motion of electrons around an atom's nucleus. They also arise from "intrinsic" magnetic dipoles arising from quantum effects, i.e. from quantum-mechanical spin.
The same situations which create magnetic fields (charge moving in a current or in an atom, and intrinsic magnetic dipoles) are also the situations in which a magnetic field has an effect, creating a force. Following is the formula for moving charge; for the forces on an intrinsic dipole, see magnetic dipole.
When a charged particle moves through a magnetic field B, it feels a force F given by the cross product:
where
q\, is the electric charge of the particle,
\vec{v} \, is the velocity vector of the particle, and \vec{B} \, is the magnetic field. Because this is a cross product, the force is perpendicular to both the motion of the particle and the magnetic field. It follows that the magnetic force does no work on the particle; it may change the direction of the particle's movement, but it cannot cause it to speed up or slow down. The magnitude of the force is
where \theta \, is the angle between the \vec{v} \, and \vec{B} \, vectors.
One tool for determining the direction of the velocity vector of a moving charge, the magnetic field, and the force exerted is labeling the index finger "V", the middle finger "B", and the thumb "F" with your right hand. When making a gun-like configuration (with the middle finger crossing under the index finger), the fingers represent the velocity vector, magnetic field vector, and force vector, respectively. See also right hand rule.
Lenz's law gives the direction of the induced electromotive force (emf) and current resulting from electromagnetic induction. German physicist Heinrich Lenz formulated it in 1834.
## Magnetic dipoles
A very common source of magnetic field shown in nature is a dipole, with a "South pole" and a "North pole"; terms dating back to the use of magnets as compasses, interacting with the Earth's magnetic field to indicate North and South on the globe. Since opposite ends of magnets are attracted, the 'north' magnetic pole of the earth must be magnetically 'south'.
A magnetic field contains energy, and physical systems stabilize into the configuration with the lowest energy. Therefore, when placed in a magnetic field, a magnetic dipole tends to align itself in opposed polarity to that field, thereby canceling the net field strength as much as possible and lowering the energy stored in that field to a minimum. For instance, two identical bar magnets placed side-to-side normally line up North to South, resulting in a much smaller net magnetic field, and resist any attempts to reorient them to point in the same direction. The energy required to reorient them in that configuration is then stored in the resulting magnetic field, which is double the strength of the field of each individual magnet. (This is, of course, why a magnet used as a compass interacts with the Earth's magnetic field to indicate North and South).
An alternative, equivalent formulation, which is often easier to apply but perhaps offers less insight, is that a magnetic dipole in a magnetic field experiences a torque and a force which can be expressed in terms of the field and the strength of the dipole (i.e., its magnetic dipole moment). For these equations, see magnetic dipole.
## Magnetic monopoles
Since a bar magnet gets its ferromagnetism from microscopic electrons distributed evenly throughout the bar, when a bar magnet is cut in half, each of the resulting pieces is a smaller bar magnet. Even though a magnet is said to have a north pole and a south pole, these two poles cannot be separated from each other. A monopole — if such a thing exists — would be a new and fundamentally different kind of magnetic object. It would act as an isolated north pole, not attached to a south pole, or vice versa. Monopoles would carry "magnetic charge" analogous to electric charge. Despite systematic searches since 1931, as of 2006, they have never been observed, and could very well not exist.
Nevertheless, some theoretical physics models predict the existence of these magnetic monopoles. Paul Dirac observed in 1931 that, because electricity and magnetism show a certain symmetry, just as quantum theory predicts that individual positive or negative electric charges can be observed without the opposing charge, isolated South or North magnetic poles should be observable. Using quantum theory Dirac showed that if magnetic monopoles exist, then one could explain the quantization of electric charge---that is, why the observed elementary particles carry charges that are multiples of the charge of the electron.
Certain grand unified theories predict the existence of monopoles which, unlike elementary particles, are solitons (localized energy packets). The initial results of using these models to estimate the number of monopoles created in the big bang contradicted cosmological observations — the monopoles would have been so plentiful and massive that they would have long since halted the expansion of the universe. However, the idea of inflation (for which this problem served as a partial motivation) was successful in solving this problem, creating models in which monopoles existed but were rare enough to be consistent with current observations.
# Units of electromagnetism
## SI units related to magnetism
## Other units
- gauss-The gauss, abbreviated as G, is the cgs unit of magnetic flux density or magnetic induction (B).
- oersted-The oersted is the CGS unit of magnetic field strength.
- maxwell-is the CGS unit for the magnetic flux.
- μo -common symbol for the permeability of free space (4πx10-7 N/(ampere-turn)²). | Magnetism
Template:Electromagnetism3
In physics, magnetism is one of the phenomena by which materials exert attractive or repulsive forces on other materials. Some well known materials that exhibit easily detectable magnetic properties (called magnets) are nickel, iron, cobalt, and their alloys; however, all materials are influenced to greater or lesser degree by the presence of a magnetic field.
Magnetism also has other manifestations in physics, particularly as one of the two components of electromagnetic waves such as light.
# History
Aristotle attributes the first of what could be called a scientific discussion on magnetism to Thales, who lived from about 625 BC to about 545 BC. [1] In China, the earliest literary reference to magnetism lies in a 4th century BC book called Book of the Devil Valley Master (鬼谷子): "The lodestone makes iron come or it attracts it."[1] The earliest mention of the attraction of a needle appears in a work composed between 20 and 100 AD (Louen-heng): "A lodestone attracts a needle."[2] The ancient Chinese scientist Shen Kuo (1031-1095) was the first person to write of the magnetic needle compass and that it improved the accuracy of navigation by employing the astronomical concept of true north (Dream Pool Essays, 1088 AD), and by the 12th century the Chinese were known to use the lodestone compass for navigation. Alexander Neckham, by 1187, was the first in Europe to describe the compass and its use for navigation. In 1269 Peter Peregrinus wrote the Epistola de Magnete, the first extant treatise describing the properties of magnets.
An understanding of the relationship between electricity and magnetism began in 1819 with work by Hans Christian Oersted, a professor at the University of Copenhagen, who discovered more or less by accident that an electric current could influence a compass needle. This landmark experiment is known as Oersted's Experiment. Several other experiments followed, with André-Marie Ampère, Carl Friedrich Gauss, Michael Faraday, and others finding further links between magnetism and electricity. James Clerk Maxwell synthesized and expanded these insights into Maxwell's equations, unifying electricity, magnetism, and optics into the field of electromagnetism. In 1905, Einstein used these laws in motivating his theory of special relativity[3], in the process showing that electricity and magnetism are fundamentally interlinked and inseparable.
Electromagnetism has continued to develop into the twentieth century, being incorporated into the more fundamental theories of gauge theory, quantum electrodynamics, electroweak theory, and finally the standard model.
# Physics of magnetism
## Magnets and magnetic materials
Every electron is, by its nature, a small magnet (see Electron magnetic dipole moment). Ordinarily, the countless electrons in a material are randomly oriented in different directions, leaving no effect on average, but in a bar magnet the electrons are aligned in the same direction, so they act cooperatively, creating a net magnetic field.
In addition to the electron's intrinsic magnetic field, there is sometimes an additional magnetic field that results from the electron's orbital motion about the nucleus. This effect is analogous to how a current-carrying loop of wire generates a magnetic field (see Magnetic dipole). Again, ordinarily, the motion of the electrons is such that there is no average field from the material, but in certain conditions, the motion can line up so as to produce a measurable total field.
The overall magnetic behavior of a material can vary widely, depending on the structure of the material, and particularly on its electron configuration. Several forms of magnetic behavior have been observed in different materials, including:
- Diamagnetism
- Paramagnetism
Molecular magnet
- Molecular magnet
- Ferromagnetism
Antiferromagnetism
Ferrimagnetism
Metamagnetism
- Antiferromagnetism
- Ferrimagnetism
- Metamagnetism
- Spin glass
- Superparamagnetism
## Magnetism, electricity, and special relativity
As a consequence of Einstein's theory of special relativity, electricity and magnetism are understood to be fundamentally interlinked. Both magnetism lacking electricity, and electricity without magnetism, are inconsistent with special relativity, due to such effects as length contraction, time dilation, and the fact that the magnetic force is velocity-dependent. However, when both electricity and magnetism are taken into account, the resulting theory (electromagnetism) is fully consistent with special relativity[4][5]. In particular, a phenomenon that appears purely electric to one observer may be purely magnetic to another, or more generally the relative contributions of electricity and magnetism are dependent on the frame of reference. Thus, special relativity "mixes" electricity and magnetism into a single, inseparable phenomenon called electromagnetism (analogously to how special relativity "mixes" space and time into spacetime).
## Magnetic fields and forces
The phenomenon of magnetism is "mediated" by the magnetic field -- i.e., an electric current or magnetic dipole creates a magnetic field, and that field, in turn, imparts magnetic forces on other particles that are in the fields.
To an excellent approximation (but ignoring some quantum effects---see quantum electrodynamics), Maxwell's equations (which simplify to the Biot-Savart law in the case of steady currents) describe the origin and behavior of the fields that govern these forces. Therefore magnetism is seen whenever electrically charged particles are in motion---for example, from movement of electrons in an electric current, or in certain cases from the orbital motion of electrons around an atom's nucleus. They also arise from "intrinsic" magnetic dipoles arising from quantum effects, i.e. from quantum-mechanical spin.
The same situations which create magnetic fields (charge moving in a current or in an atom, and intrinsic magnetic dipoles) are also the situations in which a magnetic field has an effect, creating a force. Following is the formula for moving charge; for the forces on an intrinsic dipole, see magnetic dipole.
When a charged particle moves through a magnetic field B, it feels a force F given by the cross product:
where
<math>q\,</math> is the electric charge of the particle,
<math>\vec{v} \,</math> is the velocity vector of the particle, and <math>\vec{B} \,</math> is the magnetic field. Because this is a cross product, the force is perpendicular to both the motion of the particle and the magnetic field. It follows that the magnetic force does no work on the particle; it may change the direction of the particle's movement, but it cannot cause it to speed up or slow down. The magnitude of the force is
where <math>\theta \,</math> is the angle between the <math>\vec{v} \,</math> and <math>\vec{B} \,</math> vectors.
One tool for determining the direction of the velocity vector of a moving charge, the magnetic field, and the force exerted is labeling the index finger "V", the middle finger "B", and the thumb "F" with your right hand. When making a gun-like configuration (with the middle finger crossing under the index finger), the fingers represent the velocity vector, magnetic field vector, and force vector, respectively. See also right hand rule.
Lenz's law gives the direction of the induced electromotive force (emf) and current resulting from electromagnetic induction. German physicist Heinrich Lenz formulated it in 1834.
## Magnetic dipoles
A very common source of magnetic field shown in nature is a dipole, with a "South pole" and a "North pole"; terms dating back to the use of magnets as compasses, interacting with the Earth's magnetic field to indicate North and South on the globe. Since opposite ends of magnets are attracted, the 'north' magnetic pole of the earth must be magnetically 'south'.
A magnetic field contains energy, and physical systems stabilize into the configuration with the lowest energy. Therefore, when placed in a magnetic field, a magnetic dipole tends to align itself in opposed polarity to that field, thereby canceling the net field strength as much as possible and lowering the energy stored in that field to a minimum. For instance, two identical bar magnets placed side-to-side normally line up North to South, resulting in a much smaller net magnetic field, and resist any attempts to reorient them to point in the same direction. The energy required to reorient them in that configuration is then stored in the resulting magnetic field, which is double the strength of the field of each individual magnet. (This is, of course, why a magnet used as a compass interacts with the Earth's magnetic field to indicate North and South).
An alternative, equivalent formulation, which is often easier to apply but perhaps offers less insight, is that a magnetic dipole in a magnetic field experiences a torque and a force which can be expressed in terms of the field and the strength of the dipole (i.e., its magnetic dipole moment). For these equations, see magnetic dipole.
## Magnetic monopoles
Since a bar magnet gets its ferromagnetism from microscopic electrons distributed evenly throughout the bar, when a bar magnet is cut in half, each of the resulting pieces is a smaller bar magnet. Even though a magnet is said to have a north pole and a south pole, these two poles cannot be separated from each other. A monopole — if such a thing exists — would be a new and fundamentally different kind of magnetic object. It would act as an isolated north pole, not attached to a south pole, or vice versa. Monopoles would carry "magnetic charge" analogous to electric charge. Despite systematic searches since 1931, as of 2006, they have never been observed, and could very well not exist.[6]
Nevertheless, some theoretical physics models predict the existence of these magnetic monopoles. Paul Dirac observed in 1931 that, because electricity and magnetism show a certain symmetry, just as quantum theory predicts that individual positive or negative electric charges can be observed without the opposing charge, isolated South or North magnetic poles should be observable. Using quantum theory Dirac showed that if magnetic monopoles exist, then one could explain the quantization of electric charge---that is, why the observed elementary particles carry charges that are multiples of the charge of the electron.
Certain grand unified theories predict the existence of monopoles which, unlike elementary particles, are solitons (localized energy packets). The initial results of using these models to estimate the number of monopoles created in the big bang contradicted cosmological observations — the monopoles would have been so plentiful and massive that they would have long since halted the expansion of the universe. However, the idea of inflation (for which this problem served as a partial motivation) was successful in solving this problem, creating models in which monopoles existed but were rare enough to be consistent with current observations.[7]
# Units of electromagnetism
## SI units related to magnetism
Template:SI electromagnetism units
## Other units
- gauss-The gauss, abbreviated as G, is the cgs unit of magnetic flux density or magnetic induction (B).
- oersted-The oersted is the CGS unit of magnetic field strength.
- maxwell-is the CGS unit for the magnetic flux.
- μo -common symbol for the permeability of free space (4πx10-7 N/(ampere-turn)²). | https://www.wikidoc.org/index.php/Magnetic | |
ac65fcdc40392b87c814cb7538f00e03a1398e89 | wikidoc | Malathion | Malathion
# 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
Malathion is an organophosphate that is FDA approved for the treatment of pediculus humanus capitis (hair lice). Common adverse reactions include application site irritation, skin irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- (1)Apply Malathion Lotion on dry hair in amount just sufficient to thoroughly wet the hair and scalp. Pay particular attention to the back of the head and neck while applying Malathion lotion. Wash hands after applying to scalp.
- (2)Allow hair to dry naturally - use no electric heat source, and allow hair to remain uncovered.
- (3)After 8 to 12 hours, the hair should be shampooed.
- (4)Rinse and use a fine - toothed (nit) comb to remove dead lice and eggs.
- (5)If lice are still present after 7 - 9 days, repeat with a second application of Malathion Lotion.
- (6)Further treatment is generally not necessary. Other family members should be evaluated by a physician to determine if infested, and if so, receive treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosage: Malathion 0.5% lotion applied for 8 to 12 hours and washed off
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Malathion in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- (1)Apply Malathion Lotion on dry hair in amount just sufficient to thoroughly wet the hair and scalp. Pay particular attention to the back of the head and neck while applying Malathion lotion. Wash hands after applying to scalp.
- (2)Allow hair to dry naturally - use no electric heat source, and allow hair to remain uncovered.
- (3)After 8 to 12 hours, the hair should be shampooed.
- (4)Rinse and use a fine - toothed (nit) comb to remove dead lice and eggs.
- (5)If lice are still present after 7 - 9 days, repeat with a second application of Malathion Lotion.
- (6)Further treatment is generally not necessary. Other family members should be evaluated by a physician to determine if infested, and if so, receive treatment.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Malathion in pediatric patients.
### Non–Guideline-Supported Use
- Dosage: 0.5% malathion lotion.
# Contraindications
Malathion Lotion is contraindicated for neonates and infants because their scalps are more permeable and may have increased absorption of malathion. Malathion Lotion should also not be used on individuals known to be sensitive to malathion or any of the ingredients in the vehicle.
# Warnings
- Malathion Lotion is flammable. The lotion and wet hair should not be exposed to open flames or electric heat sources, including hair dryers and electric curlers. Do not smoke while applying lotion or while hair is wet. Allow hair to dry naturally and to remain uncovered after application of Malathion Lotion.
- Malathion Lotion should only be used on children under the direct supervision of an adult.
- If Malathion Lotion comes into contact with the eyes, flush immediately with water. Consult a physician if eye irritation persists.
- If skin irritation occurs, discontinue use of product until irritation clears. Reapply the Malathion Lotion, and if irritation reoccurs, consult a physician.
- Slight stinging sensations may occur with the use of Malathion Lotion.
# Adverse Reactions
## Clinical Trials Experience
- Irritation of Skin and Scalp
- Conjunctivitis
## Postmarketing Experience
There is limited information regarding Malathion Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Malathion Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There was no evidence of teratogenicity in studies in rats and rabbits at doses up to 900 mg/kg/day and 100 mg/kg/day malathion, respectively. A study in rats failed to show any gross fetal abnormalities attributable to feeding malathion up to 2,500 ppm (∼ 200 mg/kg/day) in the diet during a three-generation evaluation period.
- These doses were approximately 40 to 180 times higher than the dose anticipated in a 60 kg adult (based on body surface area and assuming 100% bioavailability). Because animal reproduction studies are not always predictive of human responses, this drug should be used (or handled) during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Malathion in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Malathion during labor and delivery.
### Nursing Mothers
- Malathion in an acetone vehicle has been reported to be absorbed through human skin to the extent of 8% of the applied dose. However, percutaneous absorption from the Malathion Lotion, 0.5% formulation has not been studied, and it is not known whether malathion is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Malathion Lotion is administered to (or handled by) a nursing mother.
### Pediatric Use
- The safety and effectiveness of Malathion Lotion in children less than 6 years of age has not been established via well-controlled trials.
### Geriatic Use
There is no FDA guidance on the use of Malathion in geriatric settings.
### Gender
There is no FDA guidance on the use of Malathion with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Malathion with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Malathion in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Malathion in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Malathion in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Malathion in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Lotion (Topic application)
### Monitoring
- There are no special laboratory tests needed in order to use this medication.
# IV Compatibility
There is limited information regarding the compatibility of Malathion and IV administrations.
# Overdosage
- Consideration should be given, as part of the treatment program, to the high concentration of isopropyl alcohol in the vehicle. Malathion, although a weaker cholinesterase inhibitor than some other organophosphates, may be expected to exhibit the same symptoms of cholinesterase depletion after accidental ingestion orally. If accidentally swallowed, vomiting should be induced promptly or the stomach lavaged with 5% sodium bicarbonate solution. Severe respiratory distress is the major and most serious symptom of organophosphate poisoning requiring artificial respiration, and atropine may be needed to counteract the symptoms of cholinesterase depletion.
- Repeat analyses of serum and RBC cholinesterase may assist in establishing the diagnosis and formulating a long-range prognosis.
# Pharmacology
## Mechanism of Action
Malathion is an organophosphate agent which acts as a pediculicide by inhibiting cholinesterase activity in vivo.
## Structure
- The chemical name of malathion is (±) - butanedioic acid diethyl ester. Malathion has a molecular weight of 330.36, represented by C10H19O6PS2, and has the following chemical structure:
## Pharmacodynamics
There is limited information regarding Malathion Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Malathion Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Malathion Nonclinical Toxicology in the drug label.
# Clinical Studies
- Two controlled clinical trials evaluated the pediculicidal activity of Malathion Lotion. Patients applied the lotion to the hair and scalp in quantities, up to a maximum of 2 fl. oz., sufficient to thoroughly wet the hair and scalp. The lotion was allowed to air dry and was shampooed with Prell shampoo 8 to 12 hours after application. Patients in both the Malathion Lotion group and in the vehicle group were examined immediately after shampooing, 24 hours after, and 7 days after for the presence of live lice. Results are shown in the following table:
The presence or absence of ova at day 7 was not evaluated in these studies. The presence or absence of live lice or ova at 14 days following treatment was not evaluated in these studies. The residual amount of malathion on hair and scalp is unknown.
# How Supplied
Malathion Lotion, USP 0.5%, is supplied in bottles of 2 fl. oz. (59 mL)
## Storage
Store at controlled room temperature 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Malathion Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Malathion interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ovide
# Look-Alike Drug Names
There is limited information regarding Malathion Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Malathion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Malathion is an organophosphate that is FDA approved for the treatment of pediculus humanus capitis (hair lice). Common adverse reactions include application site irritation, skin irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- (1)Apply Malathion Lotion on dry hair in amount just sufficient to thoroughly wet the hair and scalp. Pay particular attention to the back of the head and neck while applying Malathion lotion. Wash hands after applying to scalp.
- (2)Allow hair to dry naturally - use no electric heat source, and allow hair to remain uncovered.
- (3)After 8 to 12 hours, the hair should be shampooed.
- (4)Rinse and use a fine - toothed (nit) comb to remove dead lice and eggs.
- (5)If lice are still present after 7 - 9 days, repeat with a second application of Malathion Lotion.
- (6)Further treatment is generally not necessary. Other family members should be evaluated by a physician to determine if infested, and if so, receive treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosage: Malathion 0.5% lotion applied for 8 to 12 hours and washed off[1]
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Malathion in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- (1)Apply Malathion Lotion on dry hair in amount just sufficient to thoroughly wet the hair and scalp. Pay particular attention to the back of the head and neck while applying Malathion lotion. Wash hands after applying to scalp.
- (2)Allow hair to dry naturally - use no electric heat source, and allow hair to remain uncovered.
- (3)After 8 to 12 hours, the hair should be shampooed.
- (4)Rinse and use a fine - toothed (nit) comb to remove dead lice and eggs.
- (5)If lice are still present after 7 - 9 days, repeat with a second application of Malathion Lotion.
- (6)Further treatment is generally not necessary. Other family members should be evaluated by a physician to determine if infested, and if so, receive treatment.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Malathion in pediatric patients.
### Non–Guideline-Supported Use
- Dosage: 0.5% malathion lotion.
# Contraindications
Malathion Lotion is contraindicated for neonates and infants because their scalps are more permeable and may have increased absorption of malathion. Malathion Lotion should also not be used on individuals known to be sensitive to malathion or any of the ingredients in the vehicle.
# Warnings
- Malathion Lotion is flammable. The lotion and wet hair should not be exposed to open flames or electric heat sources, including hair dryers and electric curlers. Do not smoke while applying lotion or while hair is wet. Allow hair to dry naturally and to remain uncovered after application of Malathion Lotion.
- Malathion Lotion should only be used on children under the direct supervision of an adult.
- If Malathion Lotion comes into contact with the eyes, flush immediately with water. Consult a physician if eye irritation persists.
- If skin irritation occurs, discontinue use of product until irritation clears. Reapply the Malathion Lotion, and if irritation reoccurs, consult a physician.
- Slight stinging sensations may occur with the use of Malathion Lotion.
# Adverse Reactions
## Clinical Trials Experience
- Irritation of Skin and Scalp
- Conjunctivitis
## Postmarketing Experience
There is limited information regarding Malathion Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Malathion Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- There was no evidence of teratogenicity in studies in rats and rabbits at doses up to 900 mg/kg/day and 100 mg/kg/day malathion, respectively. A study in rats failed to show any gross fetal abnormalities attributable to feeding malathion up to 2,500 ppm (∼ 200 mg/kg/day) in the diet during a three-generation evaluation period.
- These doses were approximately 40 to 180 times higher than the dose anticipated in a 60 kg adult (based on body surface area and assuming 100% bioavailability). Because animal reproduction studies are not always predictive of human responses, this drug should be used (or handled) during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Malathion in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Malathion during labor and delivery.
### Nursing Mothers
- Malathion in an acetone vehicle has been reported to be absorbed through human skin to the extent of 8% of the applied dose. However, percutaneous absorption from the Malathion Lotion, 0.5% formulation has not been studied, and it is not known whether malathion is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Malathion Lotion is administered to (or handled by) a nursing mother.
### Pediatric Use
- The safety and effectiveness of Malathion Lotion in children less than 6 years of age has not been established via well-controlled trials.
### Geriatic Use
There is no FDA guidance on the use of Malathion in geriatric settings.
### Gender
There is no FDA guidance on the use of Malathion with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Malathion with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Malathion in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Malathion in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Malathion in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Malathion in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Lotion (Topic application)
### Monitoring
- There are no special laboratory tests needed in order to use this medication.
# IV Compatibility
There is limited information regarding the compatibility of Malathion and IV administrations.
# Overdosage
- Consideration should be given, as part of the treatment program, to the high concentration of isopropyl alcohol in the vehicle. Malathion, although a weaker cholinesterase inhibitor than some other organophosphates, may be expected to exhibit the same symptoms of cholinesterase depletion after accidental ingestion orally. If accidentally swallowed, vomiting should be induced promptly or the stomach lavaged with 5% sodium bicarbonate solution. Severe respiratory distress is the major and most serious symptom of organophosphate poisoning requiring artificial respiration, and atropine may be needed to counteract the symptoms of cholinesterase depletion.
- Repeat analyses of serum and RBC cholinesterase may assist in establishing the diagnosis and formulating a long-range prognosis.
# Pharmacology
## Mechanism of Action
Malathion is an organophosphate agent which acts as a pediculicide by inhibiting cholinesterase activity in vivo.
## Structure
- The chemical name of malathion is (±) - [(dimethoxyphosphinothioyl) - thio] butanedioic acid diethyl ester. Malathion has a molecular weight of 330.36, represented by C10H19O6PS2, and has the following chemical structure:
## Pharmacodynamics
There is limited information regarding Malathion Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Malathion Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Malathion Nonclinical Toxicology in the drug label.
# Clinical Studies
- Two controlled clinical trials evaluated the pediculicidal activity of Malathion Lotion. Patients applied the lotion to the hair and scalp in quantities, up to a maximum of 2 fl. oz., sufficient to thoroughly wet the hair and scalp. The lotion was allowed to air dry and was shampooed with Prell shampoo 8 to 12 hours after application. Patients in both the Malathion Lotion group and in the vehicle group were examined immediately after shampooing, 24 hours after, and 7 days after for the presence of live lice. Results are shown in the following table:
The presence or absence of ova at day 7 was not evaluated in these studies. The presence or absence of live lice or ova at 14 days following treatment was not evaluated in these studies. The residual amount of malathion on hair and scalp is unknown.
# How Supplied
Malathion Lotion, USP 0.5%, is supplied in bottles of 2 fl. oz. (59 mL)
## Storage
Store at controlled room temperature 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Malathion Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Malathion interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ovide
# Look-Alike Drug Names
There is limited information regarding Malathion Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Malathion | |
3f53bba5892cebd2f4de32ec0a210c953775369e | wikidoc | Manganate | Manganate
The manganate ion is MnO42− and a manganate is any compound that contains the MnO42− group. These salts, e.g. potassium manganate, are the conjugate base of the hypothetical species manganic acid, H2MnO4. Manganate salts are intermediates in the industrial synthesis of potassium permanganate. Occasionally permanganate and manganate salts are confused, but they behave quite differently.
# Structure
MnO42− is tetrahedral, being structurally related to other tetrahedral oxides such permanganate and osmium tetroxide. Salts of MnO42−, SO42−, and CrO42− are usually isostructural or nearly so, which means that they form solid solutions and have similar solubilities. Unlike sulfate and chromate, however, MnO42− is paramagnetic.
# Synthesis
See potassium manganate
Manganate ion is stable in water only under strongly basic conditions. Consequently, salts are found with electropositive metals, such as Na+, K+, and Ba2+ that do not form insoluble hydroxides. Manganates can be prepared by oxidation of MnO2 or by reduction of permanganate.
Note that O2 is insufficiently oxidizing to further convert Mn(VI) to Mn(VII). Thus, the Mn(VI)/Mn(VII) oxidation is effected using stronger oxidants including O3 or Cl2.
# Reactions
MnO42− is the conjugate base of the hypothetical manganic acid, H2MnO4, which is too unstable to be isolated. The half-deprotonated acid has, however, been examined. Thus, the pKa of HMnO4− has been determined as 7.1. MnO42− is about 100 times more basic than the acetate ion. At lower pH's, the manganate ion will disproportionate to permanganate ion and manganese dioxide:
# Permanganate, manganate, hypomanganate, and manganite
The above reactions illustrate the close chemical relationship between the two principal soluble manganese oxides, permanganate and manganate. Two other, rarer members of the series are known. Hypomanganate, MnO43−, is a blue-colored ion of Mn(V) that forms when MnO42− is treated with manganite MnO44− at pH>12. It has also been generated by treatment of KMnO4 in 10M KOH with H2O2. The pKa of HMnO42− is 13.7, which indicates that solutions of hypomanganate contain significant amounts of the protonated form even at high pH's. Oxidations of alkenes by permanganate are proposed to proceed via the intermediacy of "esters" of hypomanganate, that is, species of the type MnO2(OR)2− where R is an alkyl group.
The brown-colored manganite ion, a Mn(IV) species, in turn is produced by dissolving its parent acid anhydride MnO2 in strong alkali. Alternatively, MnO44− can be generated by reduction of MnO43−.
# Uses
BaMnO4 and K2MnO4 are used to oxidize primary and secondary alcohols. Primary alcohols are oxidised to aldehydes, then carboxylic acids. Secondary alcohols are oxidised to ketones. Tertiary alcohols cannot be oxidised in this way. Its use is similar to that for the Jones reagent.
# Literature cited
- ^ Nyholm R.S. Woolliams P.R. (1986). ""Manganates(VI)"". Inorganic Syntheses. XI: 56–61..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}
- ^ Lee D.G. Chen T. (1993). "Reduction of Manganate(VI) by Mandelic Acid and Its Significance to Development of a General Mechanism for Oxidation of Organic Compounds by High-Valent Transition Metal Oxides". Journal of the American Chemical Society. 115: 11231–11236. doi:10.1021/ja00077a023.
- ^ Rush J.D. Bielski B.H. (1995). "Studies of Manganate(V), -(VI), and -(VII) Tetraoxyanions by Pulse Radiolysis. Optical Spectra of Protonated Forms". Inorg. Chem. 34: 5832–8. doi:10.1021/ic00127a022.
# Other references
- G. Procter, S. V. Ley, G. H. Castle “Barium Manganate” in Encyclopedia of Reagents for Organic Synthesis (Ed: L. Paquette) 2004, J. Wiley & Sons, New York. DOI: 10.1002/047084289.
- Holleman, A. F.; Wiberg, E. "Inorganic Chemistry" Academic Press: San Diego, 2001. ISBN 0-12-352651-5.
See category for a list. | Manganate
The manganate ion is MnO42− and a manganate is any compound that contains the MnO42− group. These salts, e.g. potassium manganate, are the conjugate base of the hypothetical species manganic acid, H2MnO4. Manganate salts are intermediates in the industrial synthesis of potassium permanganate. Occasionally permanganate and manganate salts are confused, but they behave quite differently.
# Structure
MnO42− is tetrahedral, being structurally related to other tetrahedral oxides such permanganate and osmium tetroxide. Salts of MnO42−, SO42−, and CrO42− are usually isostructural or nearly so, which means that they form solid solutions and have similar solubilities. Unlike sulfate and chromate, however, MnO42− is paramagnetic.
# Synthesis
See potassium manganate
Manganate ion is stable in water only under strongly basic conditions. Consequently, salts are found with electropositive metals, such as Na+, K+, and Ba2+ that do not form insoluble hydroxides. Manganates can be prepared by oxidation of MnO2 or by reduction of permanganate.
Note that O2 is insufficiently oxidizing to further convert Mn(VI) to Mn(VII). Thus, the Mn(VI)/Mn(VII) oxidation is effected using stronger oxidants including O3 or Cl2.
# Reactions
MnO42− is the conjugate base of the hypothetical manganic acid, H2MnO4, which is too unstable to be isolated. The half-deprotonated acid has, however, been examined. Thus, the pKa of HMnO4− has been determined as 7.1. MnO42− is about 100 times more basic than the acetate ion.[1] At lower pH's, the manganate ion will disproportionate to permanganate ion and manganese dioxide:
# Permanganate, manganate, hypomanganate, and manganite
The above reactions illustrate the close chemical relationship between the two principal soluble manganese oxides, permanganate and manganate. Two other, rarer members of the series are known. Hypomanganate, MnO43−, is a blue-colored ion of Mn(V) that forms when MnO42− is treated with manganite MnO44− at pH>12. It has also been generated by treatment of KMnO4 in 10M KOH with H2O2. The pKa of HMnO42− is 13.7,[2] which indicates that solutions of hypomanganate contain significant amounts of the protonated form even at high pH's. Oxidations of alkenes by permanganate are proposed to proceed via the intermediacy of "esters" of hypomanganate, that is, species of the type MnO2(OR)2− where R is an alkyl group.[3]
The brown-colored manganite ion, a Mn(IV) species, in turn is produced by dissolving its parent acid anhydride MnO2 in strong alkali. Alternatively, MnO44− can be generated by reduction of MnO43−.
# Uses
BaMnO4 and K2MnO4 are used to oxidize primary and secondary alcohols. Primary alcohols are oxidised to aldehydes, then carboxylic acids. Secondary alcohols are oxidised to ketones. Tertiary alcohols cannot be oxidised in this way. Its use is similar to that for the Jones reagent.
# Literature cited
- ^ Nyholm R.S. Woolliams P.R. (1986). ""Manganates(VI)"". Inorganic Syntheses. XI: 56–61..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}
- ^ Lee D.G. Chen T. (1993). "Reduction of Manganate(VI) by Mandelic Acid and Its Significance to Development of a General Mechanism for Oxidation of Organic Compounds by High-Valent Transition Metal Oxides". Journal of the American Chemical Society. 115: 11231–11236. doi:10.1021/ja00077a023.
- ^ Rush J.D. Bielski B.H. (1995). "Studies of Manganate(V), -(VI), and -(VII) Tetraoxyanions by Pulse Radiolysis. Optical Spectra of Protonated Forms". Inorg. Chem. 34: 5832–8. doi:10.1021/ic00127a022.
# Other references
- G. Procter, S. V. Ley, G. H. Castle “Barium Manganate” in Encyclopedia of Reagents for Organic Synthesis (Ed: L. Paquette) 2004, J. Wiley & Sons, New York. DOI: 10.1002/047084289.
- Holleman, A. F.; Wiberg, E. "Inorganic Chemistry" Academic Press: San Diego, 2001. ISBN 0-12-352651-5.
See category for a list.
# External links
- National Pollutant Inventory - Manganese and compounds Fact Sheet
Template:WS | https://www.wikidoc.org/index.php/Manganate | |
74be85357f1980dc6f8f84d438e5d87aed2fab46 | wikidoc | Manganism | Manganism
Manganism or manganese poisoning is a toxic condition resulting from chronic exposure to manganese and first identified in 1837 by James Couper. Its symptoms resemble those of idiopathic Parkinson's disease, which it is often misdiagnosed as, although there are particular differences in both the symptoms (nature of tremors, for example), response to drugs such as Levadopa, and affected portion of the basal ganglia. Symptoms are also similar to Lou Gehrig's disease and multiple sclerosis.
Manganism has become an active issue in workplace safety as it has been the subject of numerous product liability lawsuits against manufacturers of arc welding supplies. In these lawsuits, welders have accused the manufacturers of failing to provide adequate warning that their products could cause welding fumes to contain dangerously high manganese concentrations that could lead welders to develop manganism.
# External references
- Lucchini et al., "Metals and Neurodegeneration" - Research paper on heavy metals poisoning
- Antonini., "Health Effects of Welding" - Critical review including manganese discussion from National Institute of Occupational Safety and Health (NIOSH)
- Welding and Manganese Poisoning - Safety Corner column in IBEW Journal regarding manganese and welding.
- AWS Study on Welding and Exposure to Manganese - Report of an independent study commissioned by the American Welding Society
- Welding Fume Product Liability - Viewpoint of plaintiffs on welding rod litigation
- Welding Rod Litigation Information Network - Viewpoint of defense on welding rod litigation
nl:Manganisme | Manganism
Manganism or manganese poisoning is a toxic condition resulting from chronic exposure to manganese and first identified in 1837 by James Couper. Its symptoms resemble those of idiopathic Parkinson's disease, which it is often misdiagnosed as, although there are particular differences in both the symptoms (nature of tremors, for example), response to drugs such as Levadopa, and affected portion of the basal ganglia. Symptoms are also similar to Lou Gehrig's disease and multiple sclerosis.
Manganism has become an active issue in workplace safety as it has been the subject of numerous product liability lawsuits against manufacturers of arc welding supplies. In these lawsuits, welders have accused the manufacturers of failing to provide adequate warning that their products could cause welding fumes to contain dangerously high manganese concentrations that could lead welders to develop manganism.
# External references
- Lucchini et al., "Metals and Neurodegeneration" - Research paper on heavy metals poisoning
- Antonini., "Health Effects of Welding" - Critical review including manganese discussion from National Institute of Occupational Safety and Health (NIOSH)
- Welding and Manganese Poisoning - Safety Corner column in IBEW Journal regarding manganese and welding.
- AWS Study on Welding and Exposure to Manganese - Report of an independent study commissioned by the American Welding Society
- Welding Fume Product Liability - Viewpoint of plaintiffs on welding rod litigation
- Welding Rod Litigation Information Network - Viewpoint of defense on welding rod litigation
nl:Manganisme
Template:Jb1
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Manganese_poisoning | |
544f6c3e6055b19d6867891cc464dd1decba8ef0 | wikidoc | Manubrium | Manubrium
# Overview
The manubrium (from Latin manubrĭum, "a handle") or manubrium sterni is the broad, upper part of the sternum. With a quadrangular shape, wider superiorly and narrower inferiorly, it articulates with the clavicles and the first two ribs.
# Features
## Surfaces
Its anterior surface, convex from side to side, concave from above downward, is smooth, and affords attachment on either side to the sternal origins of the pectoralis major and Sternocleidomastoideus. Sometimes the ridges limiting the attachments of these muscles are very distinct. Its posterior surface, concave and smooth, affords attachment on either side to the Sternohyoideus and Sternothyreoideus.
## Borders
The superior border is the thickest and presents at its center the jugular or presternal notch; on either side of the notch is an oval articular surface, directed upward, backward, and lateralward, for articulation with the sternal end of the clavicle. The inferior border, oval and rough, is covered in a fresh state with a thin layer of cartilage, for articulation with the body. The lateral borders are each marked above by a depression for the first costal cartilage, and below by a small facet, which, with a similar facet on the upper angle of the body, forms a notch for the reception of the costal cartilage of the second rib. Between the depression for the first costal cartilage and the demi-facet for the second is a narrow, curved edge, which slopes from above downward and medialward.
# Additional images
- Sternoclavicular articulation. Anterior view. | Manubrium
Template:Infobox Bone
# Overview
The manubrium (from Latin manubrĭum, "a handle") or manubrium sterni is the broad, upper part of the sternum. With a quadrangular shape, wider superiorly and narrower inferiorly, it articulates with the clavicles and the first two ribs.
# Features
## Surfaces
Its anterior surface, convex from side to side, concave from above downward, is smooth, and affords attachment on either side to the sternal origins of the pectoralis major and Sternocleidomastoideus. Sometimes the ridges limiting the attachments of these muscles are very distinct. Its posterior surface, concave and smooth, affords attachment on either side to the Sternohyoideus and Sternothyreoideus.
## Borders
The superior border is the thickest and presents at its center the jugular or presternal notch; on either side of the notch is an oval articular surface, directed upward, backward, and lateralward, for articulation with the sternal end of the clavicle. The inferior border, oval and rough, is covered in a fresh state with a thin layer of cartilage, for articulation with the body. The lateral borders are each marked above by a depression for the first costal cartilage, and below by a small facet, which, with a similar facet on the upper angle of the body, forms a notch for the reception of the costal cartilage of the second rib. Between the depression for the first costal cartilage and the demi-facet for the second is a narrow, curved edge, which slopes from above downward and medialward.
# Additional images
- Sternoclavicular articulation. Anterior view.
# External links
- Template:SUNYAnatomyLabs
Template:Gray's
Template:Spine
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Manubrium | |
03b54cb2d09f0364877476d40480ee6247ce75e8 | wikidoc | Manzanita | Manzanita
The Manzanitas are a subgenus of the genus Arctostaphylos. They are evergreen shrubs or small trees present in the chaparral biome of western North America, where they occur from southern British Columbia in Canada, Washington to California and New Mexico in the United States, and throughout much of northern and central Mexico. They are characterised by smooth, orange or red bark and stiff, twisting branches. There are about 60 species of manzanita, ranging from ground-hugging coastal and mountain species to small trees up to 6m tall. Manzanitas bloom in the winter to early spring and carry berries in spring and summer. The berries and flowers of most species are edible, though not particularly tasty.
See also Bearberry for other species in the same genus.
The word manzanita is the Spanish diminutive of manzana (apple). A literal translation would be little apple. The name manzanita is also sometimes used to refer to species in the related genus Arbutus, which is known by that name in the Canadian area of the tree's range, but is more usually known as madroño, or madrone in the United States.
# Uses
Native uses of the plant include collecting the berries, drying them, and grinding them up into a coarse meal. Fresh berries and branch tips were also soaked in water and drunk, making a refreshing cider. When the bark curls off, it can be used as a tea for nausea and upset stomach. The younger leaves are sometimes plucked and chewed by hikers to deter thirst. Native Americans used Manzanita leaves as toothbrushes.
Manzanitas are extremely useful as ornamental plants in the western United States and other similar climate zones. They are evergreen, highly drought-tolerant, have picturesque bark and attractive flowers and berries, and come in many sizes and growth patterns. A. columbiana, for example, is hardy enough to be used for highway landscaping in western Oregon and Washington. A. 'emerald carpet', A. uva-ursi, and other low-growing manzanitas are extremely valuable evergreen groundcovers for dry slopes. Larger varieties can be grown as individual specimens, and pruned to emphasize the striking pattern and colors of the branches. They prefer light, well-drained soil, although the low-growing ground covers will tolerate heavier soils.
Manzanita branches are popular as decoration, due to their unique shape, color, and strength when dried.
The wood is notoriously hard to cure, mostly due to cracking against the grain, giving it few uses as timber. The slow growth rate and many branchings further decrease the sizes available. Some furniture and art employ whole round branches, which reduces cracking and preserves the deep red color.
The dead wood decays slowly and can last for many years, on and off the plant. Sunlight smooths and bleaches manzanita to light grey or white, rendering it superficially akin to animal bones. Because of this and the stunted growth of many species, manzanita is often collected in its more unusual shapes, giving it the nickname mountain driftwood.
Manzanita wood is also used as perches for parrots and other large pet birds. The branches of the larger species are extremely long-lasting for this purpose.
Some aquarium keepers use sandblasted manzanita as driftwood in planted aquaria because of its attractive forked growth and its chemical neutrality. If properly cleaned and cured, it holds up well over extended periods of submersion. The wood is also resistant to the leaching of tannins into the water column, a problem often found with other aquarium driftwoods. When used as driftwood, manzanita must often be either weighted down for several weeks or soaked first to counteract the wood's natural buoyancy.
Manzanita wood, when dry, is excellent for burning in a campfire, barbecue, fireplace, or stove. It is dense and burns at a high temperature for long periods. However, caution should be exercised, because the high temperatures can damage thin-walled barbecues, and even crack cast iron stoves or cause chimney fires.
# Threats
Some manzanita species are among the rarest plants in the world. Arctostaphylos hookeri subsp. ravenii (also known as Presidio manzanita) is the most endangered and restricted plant in the mainland United States. In 1987 only one specimen remained, at a secret location in the Presidio district of San Francisco, California. This plant has since been successfully cloned. | Manzanita
The Manzanitas are a subgenus of the genus Arctostaphylos. They are evergreen shrubs or small trees present in the chaparral biome of western North America, where they occur from southern British Columbia in Canada, Washington to California and New Mexico in the United States, and throughout much of northern and central Mexico. They are characterised by smooth, orange or red bark and stiff, twisting branches. There are about 60 species of manzanita, ranging from ground-hugging coastal and mountain species to small trees up to 6m tall. Manzanitas bloom in the winter to early spring and carry berries in spring and summer. The berries and flowers of most species are edible, though not particularly tasty.
See also Bearberry for other species in the same genus.
The word manzanita is the Spanish diminutive of manzana (apple). A literal translation would be little apple. The name manzanita is also sometimes used to refer to species in the related genus Arbutus, which is known by that name in the Canadian area of the tree's range, but is more usually known as madroño, or madrone in the United States.
# Uses
Native uses of the plant include collecting the berries, drying them, and grinding them up into a coarse meal. Fresh berries and branch tips were also soaked in water and drunk, making a refreshing cider. When the bark curls off, it can be used as a tea for nausea and upset stomach[citation needed]. The younger leaves are sometimes plucked and chewed by hikers to deter thirst[citation needed]. Native Americans used Manzanita leaves as toothbrushes. [1]
Manzanitas are extremely useful as ornamental plants in the western United States and other similar climate zones. They are evergreen, highly drought-tolerant, have picturesque bark and attractive flowers and berries, and come in many sizes and growth patterns. A. columbiana, for example, is hardy enough to be used for highway landscaping in western Oregon and Washington. A. 'emerald carpet', A. uva-ursi, and other low-growing manzanitas are extremely valuable evergreen groundcovers for dry slopes. Larger varieties can be grown as individual specimens, and pruned to emphasize the striking pattern and colors of the branches. They prefer light, well-drained soil, although the low-growing ground covers will tolerate heavier soils.
Manzanita branches are popular as decoration, due to their unique shape, color, and strength when dried.
The wood is notoriously hard to cure, mostly due to cracking against the grain, giving it few uses as timber. The slow growth rate and many branchings further decrease the sizes available. Some furniture and art employ whole round branches, which reduces cracking and preserves the deep red color.
The dead wood decays slowly and can last for many years, on and off the plant. Sunlight smooths and bleaches manzanita to light grey or white, rendering it superficially akin to animal bones. Because of this and the stunted growth of many species, manzanita is often collected in its more unusual shapes, giving it the nickname mountain driftwood.
Manzanita wood is also used as perches for parrots and other large pet birds. The branches of the larger species are extremely long-lasting for this purpose.
Some aquarium keepers use sandblasted manzanita as driftwood in planted aquaria because of its attractive forked growth and its chemical neutrality. If properly cleaned and cured, it holds up well over extended periods of submersion. The wood is also resistant to the leaching of tannins into the water column, a problem often found with other aquarium driftwoods. When used as driftwood, manzanita must often be either weighted down for several weeks or soaked first to counteract the wood's natural buoyancy.
Manzanita wood, when dry, is excellent for burning in a campfire, barbecue, fireplace, or stove. It is dense and burns at a high temperature for long periods. However, caution should be exercised, because the high temperatures can damage thin-walled barbecues, and even crack cast iron stoves or cause chimney fires.
# Threats
Some manzanita species are among the rarest plants in the world. Arctostaphylos hookeri subsp. ravenii (also known as Presidio manzanita) is the most endangered and restricted plant in the mainland United States. In 1987 only one specimen remained, at a secret location in the Presidio district of San Francisco, California. This plant has since been successfully cloned.[citation needed] | https://www.wikidoc.org/index.php/Manzanita | |
730286c43bcd82edaef99f3de96fcd5491b48b60 | wikidoc | Maraviroc | Maraviroc
The recommended dose of maraviroc differs based on concomitant medications due to drug interactions:
- Potent CYP3A inhibitors (with or without a potent CYP3A inducer): 150 mg twice daily
- Other concomitant medications, including tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide: 300 mg twice daily
- Potent CYP3A inducers (without a potent CYP3A inhibitor): 600 mg twice daily
- Hepatotoxicity with allergic features including life-threatening events has been reported in clinical trials and postmarketing. Severe rash or evidence of systemic allergic reaction including drug-related rash with fever, eosinophilia, elevated IgE, or other systemic symptoms have been reported in conjunction with hepatotoxicity. These events occurred approximately 1 month after starting treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-existing hepatic disease.
- Appropriate laboratory testing including ALT, AST, and bilirubin should be conducted prior to initiating therapy with maraviroc and at other timepoints during treatment as clinically indicated. Hepatic laboratory parameters should be obtained in any patient who develops rash, or signs or symptoms of hepatitis, or allergic reaction. Discontinuation of maraviroc should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.
- Caution should be used when administering maraviroc to patients with pre-existing liver dysfunction or who are co-infected with viral hepatitis B or C. The safety and efficacy of maraviroc have not been specifically studied in patients with significant underlying liver disorders. In trials of treatment-experienced HIV-1-infected subjects, approximately 6% of subjects were co-infected with hepatitis B and approximately 6% were co-infected with hepatitis C. Due to the small number of co-infected subjects studied, no conclusions can be drawn regarding whether they are at an increased risk for hepatic adverse events with administration of maraviroc.
- Severe, potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking maraviroc, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS syndrome). The cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Discontinue maraviroc and other suspected agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, lip swelling, eosinophilia). Delay in stopping treatment with maraviroc or other suspect drugs after the onset of rash may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated.
- Use with caution in patients at increased risk for cardiovascular events. Eleven subjects (1.3%) who received maraviroc had cardiovascular events, including myocardial ischemia and/or infarction, during the Phase 3 trials in treatment-experienced subjects (total exposure 609 patient-years ), while no subjects who received placebo had such events (total exposure 111 patient-years). These subjects generally had cardiac disease or cardiac risk factors prior to use of maraviroc, and the relative contribution of maraviroc to these events is not known.
- In the Phase 2b/3 trial in treatment-naive subjects, 3 subjects (0.8%) who received maraviroc had events related to ischemic heart diseases and 5 subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for maraviroc and efavirenz, respectively).
- When maraviroc was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when maraviroc was given at the recommended dose in HIV-1-infected subjects in Phase 3 trials, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). Caution should be used when administering maraviroc in patients with a history of or risk factors for postural hypotension, cardiovascular comorbidities, or on concomitant medication known to lower blood pressure. Patients with cardiovascular comorbidities could be at increased risk of cardiovascular adverse events triggered by postural hypotension.
- An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with ESRD due to increased maraviroc exposure in some patients.
- Maraviroc should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer.
- However, the use of maraviroc in these patients should only be considered when no alternative treatment options are available.
- If patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily, the dose should be reduced to 150 mg twice daily.
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including maraviroc. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Maraviroc antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining category C infections, were comparable in the treatment groups during the Phase 3 treatment-experienced trials of maraviroc. While there was a higher rate of certain upper respiratory tract infections reported in the arm receiving maraviroc compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% versus 5%) reported in subjects receiving maraviroc. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the arm receiving maraviroc when adjusted for exposure compared with placebo (8 per 100 patient-years).
- In the Phase 2b/3 trial in treatment-naive subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was 1.8 for maraviroc compared with 2.4 for efavirenz per 100 patient-years of exposure.
- Patients should be monitored closely for evidence of infections while receiving maraviroc.
- While no increase in malignancy has been observed with maraviroc, due to this drug’s mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy.
- The exposure-adjusted rate for malignancies per 100 patient-years of exposure in treatment-experienced trials was 4.6 for maraviroc compared with 9.3 on placebo. In treatment-naive subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for maraviroc and efavirenz, respectively.
- Long-term follow-up is needed to more fully assess this risk.
The safety profile of maraviroc is primarily based on 840 HIV-1-infected subjects who received at least 1 dose of maraviroc during two Phase 3 trials. A total of 426 of these subjects received the indicated twice-daily dosing regimen.
Assessment of treatment-emergent adverse events is based on the pooled data from 2 trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with maraviroc for subjects in these trials was 48 weeks, with the total exposure on maraviroc twice daily at 309 patient-years versus 111 patient-years on placebo + optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily.
The most common adverse events reported with twice-daily therapy with maraviroc with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash and dizziness. Additional adverse events that occurred with once-daily dosing at a higher rate than both placebo and twice-daily dosing were diarrhea, edema, influenza, esophageal candidiasis, sleep disorders, rhinitis, parasomnias, and urinary abnormalities. In these 2 trials, the rate of discontinuation due to adverse events was 5% for subjects who received maraviroc twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of maraviroc.
The total number of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving maraviroc twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on maraviroc compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both maraviroc twice daily and placebo.
Dizziness or postural dizziness occurred in 8% of subjects on either maraviroc or placebo, with 2 subjects (0.5%) on maraviroc permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness.
Treatment-emergent adverse events, regardless of causality, from A4001027 and A4001028 are summarized in Table 3. Selected events occurring at ≥2% of subjects and at a numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on placebo are not displayed.
Table 4 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in >2% of subjects receiving maraviroc.
Treatment‑Emergent Adverse Events: Treatment‑emergent adverse events, regardless of causality, from Trial A4001026, a double‑blind, comparative, controlled trial in which 721 treatment‑naive subjects received maraviroc 300 mg twice daily (N = 360) or efavirenz (N = 361) in combination with zidovudine/lamivudine for 96 weeks, are summarized in Table 5. Selected events occurring in ≥2% of subjects and at a numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on efavirenz are not displayed.
The following adverse events occurred in <2% of subjects treated with maraviroc. These events have been included because of their seriousness and either increased frequency on maraviroc or are potential risks due to the mechanism of action. Events attributed to the patient’s underlying HIV infection are not listed.
- Blood and Lymphatic System: Bone marrow suppression and hypoplastic anemia.
- Cardiac Disorders: Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia.
- Hepatobiliary Disorders: Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, hypertransaminasemia, jaundice.
- Infections and Infestations: Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis.
- Musculoskeletal and Connective Tissue Disorders: Myositis, osteonecrosis, rhabdomyolysis, blood CK increased.
- Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): Abdominal neoplasm, anal cancer, basal cell carcinoma, Bowen’s disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified.
- Nervous System Disorders: Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect.
Skin and Subcutaneous Tissue Disorders: Stevens‑Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).
- Maraviroc is a substrate of CYP3A and P-glycoprotein (P-gp) and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters.
- Therefore, a dose adjustment may be required when maraviroc is coadministered with those drugs.
- Concomitant use of maraviroc and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended.
- Coadministration of maraviroc with St. John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels of maraviroc and lead to loss of virologic response and possible resistance to maraviroc.
Animal Data: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with maraviroc in rats at exposures (AUC) approximately 20-fold higher and in rabbits at approximately 5-fold higher than human exposures at the recommended daily dose (up to 1,000 mg/kg/day in rats and 75 mg/kg/day in rabbits). During the pre- and postnatal development studies in the offspring, development of the offspring, including fertility and reproductive performance, was not affected by the maternal administration of maraviroc.
If patients with severe renal impairment or ESRD not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No trials have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of maraviroc can be recommended, and maraviroc is contraindicated for these patients.
Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12 times, respectively, those expected in humans at the intended exposure of 300 mg equivalents twice daily. However, no significant QT prolongation was seen in the trials in treatment-experienced subjects with HIV using the recommended doses of maraviroc or in a specific pharmacokinetic trial to evaluate the potential of maraviroc to prolong the QT interval.
There is no specific antidote for overdose with maraviroc. Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure, and ECG.
If indicated, elimination of unabsorbed active maraviroc should be achieved by emesis. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Hemodialysis had a minimal effect on maraviroc clearance and exposure in a trial in subjects with ESRD.
The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1 to 9 samples per subject taken on up to 7 visits), and virologic response was evaluated in 973 treatment-experienced HIV-1-infected subjects with varied optimized background antiretroviral regimens in Trials A4001027 and A4001028. The Cmin, baseline viral load, baseline CD4+ cell count, and overall sensitivity score (OSS) were found to be important predictors of virologic success (defined as viral load <400 copies/mL at 24 weeks). Table 7 illustrates the proportions of subjects with virologic success (%) within each Cmin quartile for 150-mg twice-daily and 300-mg twice-daily groups.
The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1 to 12 samples per subject taken on up to 8 visits), and virologic response was evaluated in 294 treatment-naive HIV-1-infected subjects receiving maraviroc 300 mg twice daily in combination with zidovudine/lamivudine in Trial A4001026. Table 8 illustrates the proportion (%) of subjects with virologic success <50 copies/mL at 48 weeks within each Cmin quartile for the 300-mg twice-daily dose.
Eighteen of 75 (24%) subjects in Q1 had no measurable maraviroc concentration on at least one occasion versus 1 of 73 and 1 of 74 in Q3 and Q4, respectively.
A placebo-controlled, randomized, crossover trial to evaluate the effect on the QT interval of healthy male and female volunteers was conducted with 3 single oral doses of maraviroc and moxifloxacin. The placebo-adjusted mean maximum (upper 1-sided 95% CI) increases in QTc from baseline after 100, 300, and 900 mg of maraviroc were –2 (0), -1 (1), and 1 (3) msec, respectively, and 13 (15) msec for moxifloxacin 400 mg. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.
Peak maraviroc plasma concentrations are attained 0.5 to 4 hours following single oral doses of 1 to 1,200 mg administered to uninfected volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range.
The absolute bioavailability of a 100‑mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter P-gp.
Effect of Food on Oral Absorption: Coadministration of a 300‑mg tablet with a high‑fat breakfast reduced maraviroc Cmax and AUC by 33% in healthy volunteers. There were no food restrictions in the trials that demonstrated the efficacy and safety of maraviroc. Therefore, maraviroc can be taken with or without food at the recommended dose.
Maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate affinity for albumin and alpha‑1 acid glycoprotein. The volume of distribution of maraviroc is approximately 194 L.
Trials in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system to metabolites that are essentially inactive against HIV‑1. In vitro studies indicate that CYP3A is the major enzyme responsible for maraviroc metabolism. In vitro studies also indicate that polymorphic enzymes CYP2C9, CYP2D6, and CYP2C19 do not contribute significantly to the metabolism of maraviroc.
Maraviroc is the major circulating component (~42% drug‑related radioactivity) following a single oral dose of 300 mg -maraviroc. The most significant circulating metabolite in humans is a secondary amine (~22% radioactivity) formed by N‑dealkylation. This polar metabolite has no significant pharmacological activity. Other metabolites are products of mono‑oxidation and are only minor components of plasma drug‑related radioactivity.
The terminal half‑life of maraviroc following oral dosing to steady state in healthy subjects was 14 to 18 hours. A mass balance/excretion trial was conducted using a single 300‑mg dose of 14C-labeled maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in the feces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and feces (mean of 25% dose). The remainder was excreted as metabolites.
Maraviroc inhibits the replication of CCR5-tropic laboratory strains and primary isolates of HIV-1 in models of acute peripheral blood leukocyte infection. The mean EC50 value (50% effective concentration) for maraviroc against HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates ranged from 0.1 to 4.5 nM (0.05 to 2.3 ng/mL) in cell culture.
When used with other antiretroviral agents in cell culture, the combination of maraviroc was not antagonistic with NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), or protease inhibitors (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir). Maraviroc was not antagonistic with the HIV fusion inhibitor enfuvirtide. Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC50 value >10 µM). The antiviral activity of maraviroc against HIV-2 has not been evaluated.
Resistance in Cell Culture: HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell culture, following serial passage of 2 CCR5-tropic viruses (CC1/85 and RU570). The maraviroc-resistant viruses remained CCR5-tropic with no evidence of a change from a CCR5-tropic virus to a CXCR4-using virus. Two amino acid residue substitutions in the V3-loop region of the HIV-1 envelope glycoprotein (gp160), A316T, and I323V (HXB2 numbering), were shown to be necessary for the maraviroc-resistant phenotype in the HIV-1 isolate CC1/85. In the RU570 isolate a 3-amino acid residue deletion in the V3 loop, ΔQAI (HXB2 positions 315 to 317), was associated with maraviroc resistance. The relevance of the specific gp120 mutations observed in maraviroc-resistant isolates selected in cell culture to clinical maraviroc resistance is not known. Maraviroc-resistant viruses were characterized phenotypically by concentration-response curves that did not reach 100% inhibition in phenotypic drug assays, rather than increases in EC50 values.
Cross-Resistance in Cell Culture: Maraviroc had antiviral activity against HIV-1 clinical isolates resistant to NNRTIs, NRTIs, PIs, and the fusion inhibitor enfuvirtide in cell culture (EC50 values ranged from 0.7 to 8.9 nM (0.36 to 4.57 ng/mL). Maraviroc-resistant viruses that emerged in cell culture remained susceptible to the enfuvirtide and the protease inhibitor saquinavir.
Clinical Resistance: Virologic failure on maraviroc can result from genotypic and phenotypic resistance to maraviroc, through outgrowth of undetected CXCR4-using virus present before maraviroc treatment (see Tropism below), through resistance to background therapy drugs, or due to low exposure to maraviroc.
Antiretroviral Treatment-Experienced Subjects (Trials A4001027 and A4001028): Week 48 data from treatment-experienced subjects failing maraviroc-containing regimens with CCR5-tropic virus (n = 58) have identified 22 viruses that had decreased susceptibility to maraviroc characterized in phenotypic drug assays by concentration-response curves that did not reach 100% inhibition. Additionally, CCR5-tropic virus from 2 of these treatment-failure subjects had ≥3-fold shifts in EC50 values for maraviroc at the time of failure.
Fifteen of these viruses were sequenced in the gp120 encoding region and multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in 7 of the subjects with decreased maraviroc susceptibility. Substitutions outside the V3 loop of gp120 may also contribute to reduced susceptibility to maraviroc.
Antiretroviral Treatment-Naive Subjects (Trial A4001026): Treatment-naive subjects receiving maraviroc had more virologic failures and more treatment-emergent resistance to the background regimen drugs compared with those receiving efavirenz.
In an as-treated analysis of treatment-naive subjects at 96 weeks, 32 subjects failed a maraviroc-containing regimen with CCR5-tropic virus and had a tropism result at failure; 7 of these subjects had evidence of maraviroc phenotypic resistance defined as concentration-response curves that did not reach 95% inhibition. One additional subject had a ≥3-fold shift in the EC50 value for maraviroc at the time of failure. A clonal analysis of the V3 loop amino acid envelope sequences was performed from 6 of the 7 subjects. Changes in V3 loop amino acid sequence differed between each of these different subjects, even for those infected with the same virus clade suggesting that that there are multiple diverse pathways to maraviroc resistance. The subjects who failed with CCR5-tropic virus and without a detectable maraviroc shift in susceptibility were not evaluated for genotypic resistance.
Of the 32 maraviroc virologic failures failing with CCR5-tropic virus, 20 (63%) also had genotypic and/or phenotypic resistance to background drugs in the regimen (lamivudine, zidovudine).
Tropism: In both treatment-experienced and treatment-naive subjects, detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virologic response to maraviroc.
Antiretroviral Treatment-Experienced Subjects: In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4-using virus (i.e., CXCR4- or dual/mixed-tropic) which was not detected by the tropism assay prior to treatment. CXCR4-using virus was detected at failure in approximately 55% of subjects who failed treatment on maraviroc by Week 48, as compared with 9% of subjects who experienced treatment failure in the placebo arm. To investigate the likely origin of the on-treatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the maraviroc arms and 4 subjects from the placebo arm) in whom CXCR4-using virus was detected at treatment failure. From analysis of amino acid sequence differences and phylogenetic data, it was determined that CXCR4-using virus in these subjects emerged from a low level of pre-existing CXCR4-using virus not detected by the tropism assay (which is population-based) prior to treatment rather than from a coreceptor switch from CCR5-tropic virus to CXCR4-using virus resulting from mutation in the virus.
Detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virological response to maraviroc. Furthermore, subjects failing maraviroc twice daily at Week 48 with CXCR4-using virus had a lower median increase in CD4+ cell counts from baseline (+41 cells/mm3) than those subjects failing with CCR5-tropic virus (+162 cells/mm3). The median increase in CD4+ cell count in subjects failing in the placebo arm was +7 cells/mm3.
Antiretroviral Treatment-Naive Subjects: In a 96-week trial of antiretroviral treatment-naive subjects, 14% (12/85) who had CCR5-tropic virus at screening with an enhanced sensitivity tropism assay (TROFILE) and failed therapy on maraviroc had CXCR4-using virus at the time of treatment failure. A detailed clonal analysis was conducted in 2 previously antiretroviral treatment-naive subjects enrolled in a Phase 2a monotherapy trial who had CXCR4-using virus detected after 10 days treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment-experienced subjects, the CXCR4-using variants appear to emerge from outgrowth of a pre-existing undetected CXCR4-using virus. Screening with an enhanced sensitivity tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic virus at failure to 12 compared with 24 when screening with the original tropism assay. All but one (11/12; 92%) of the maraviroc failures failing with CXCR4 or dual/mixed-tropic virus also had genotypic and phenotypic resistance to the background drug lamivudine at failure and 33% (4 /12) developed zidovudine-associated resistance substitutions.
Subjects who had CCR5-tropic virus at baseline and failed maraviroc therapy with CXCR4-using virus had a median increase in CD4+ cell counts from baseline of +113 cells/mm3 while those subjects failing with CCR5-tropic virus had an increase of +135 cells/mm3. The median increase in CD4+ cell count in subjects failing in the efavirenz arm was + 95 cells/mm3.
Long-term oral carcinogenicity studies of maraviroc were carried out in rasH2 transgenic mice (6 months) and in rats for up to 96 weeks (females) and 104 weeks (males). No drug-related increases in tumor incidence were found in mice at 1,500 mg/kg/day and in male and female rats at 900 mg/kg/day. The highest exposures in rats were approximately 11 times those observed in humans at the therapeutic dose of 300 mg twice daily for the treatment of HIV-1 infection.
Maraviroc was not genotoxic in the reverse mutation bacterial test (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes and rat bone marrow micronucleus test.
Trials A4001027 and A4001028 were double-blind, randomized, placebo-controlled, multicenter trials in subjects infected with CCR5-tropic HIV-1. Subjects were required to have an HIV-1 RNA greater than 5,000 copies/mL despite at least 6 months of prior therapy with at least 1 agent from 3 of the 4 antiretroviral drug classes (≥1 NRTI, ≥1 NNRTI, ≥2 PIs, and/or enfuvirtide) or documented resistance to at least 1 member of each class. All subjects received an optimized background regimen consisting of 3 to 6 antiretroviral agents (excluding low-dose ritonavir) selected on the basis of the subject’s prior treatment history and baseline genotypic and phenotypic viral resistance measurements. In addition to the optimized background regimen, subjects were then randomized in a 2:2:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or placebo. Doses were adjusted based on background therapy as described in Dosing and Administration (2), Table 1.
In the pooled analysis for A4001027 and A4001028, the demographics and baseline characteristics of the treatment groups were comparable (Table 12). Of the 1,043 subjects with a CCR5 tropism result at screening, 7.6% had a dual/mixed-tropism result at the baseline visit 4 to 6 weeks later. This illustrates the background change from CCR5- to dual/mixed-tropism result over time in this treatment-experienced population, prior to a change in antiretroviral regimen or administration of a CCR5 co-receptor antagonist.
The Week 48 results for the pooled Trials A4001027 and A4001028 are shown in Table 13.
After 48 weeks of therapy, the proportions of subjects with HIV-1 RNA <400 copies/mL receiving maraviroc compared with placebo were 56% and 22%, respectively. The mean changes in plasma HIV-1 RNA from baseline to Week 48 were –1.84 log10 copies/mL for subjects receiving maraviroc + OBT compared with –0.78 log10 copies/mL for subjects receiving OBT only. The mean increase in CD4+ cell count was higher on maraviroc twice daily + OBT (124 cells/mm3) than on placebo + OBT (60 cells/mm3).
Trial A4001029 was an exploratory, randomized, double-blind, multicenter trial to determine the safety and efficacy of maraviroc in subjects infected with dual/mixed co-receptor tropic HIV-1. The inclusion/exclusion criteria were similar to those for Trials A4001027 and A4001028 above and the subjects were randomized in a 1:1:1 ratio to maraviroc once daily, maraviroc twice daily, or placebo. No increased risk of infection or HIV disease progression was observed in the subjects who received maraviroc. Use of maraviroc was not associated with a significant decrease in HIV-1 RNA compared with placebo in these subjects and no adverse effect on CD4+ cell count was noted.
Trial A4001026 is an ongoing, randomized, double-blind, multicenter trial in subjects infected with CCR5-tropic HIV-1 classified by the original TROFILE tropism assay. Subjects were required to have plasma HIV-1 RNA ≥2,000 copies/mL and could not have:
- previously received any antiretroviral therapy for >14 days,
- an active or recent opportunistic infection or a suspected primary HIV-1 infection, or
- phenotypic or genotypic resistance to zidovudine, lamivudine, or efavirenz.
Subjects were randomized in a 1:1:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with zidovudine/lamivudine. The efficacy and safety of maraviroc are based on the comparison of maraviroc twice daily versus efavirenz. In a pre-planned interim analysis at 16 weeks, maraviroc 300 mg once daily failed to meet the pre-specified criteria for demonstrating non-inferiority and was discontinued.
The demographic and baseline characteristics of the maraviroc and efavirenz treatment groups were comparable. Subjects were stratified by screening HIV-1 RNA levels and by geographic region. The median CD4+ cell counts and mean HIV-1 RNA at baseline were similar for both treatment groups.
The treatment outcomes at 96 weeks for Trial A4001026 are shown in Table 15. Treatment outcomes are based on reanalysis of the screening samples using a more sensitive tropism assay, enhanced sensitivity TROFILE HIV tropism assay, which became available after the Week 48 analysis, approximately 15% of the subjects identified as CCR5-tropic in the original analysis had dual/mixed- or CXCR4-tropic virus. Screening with enhanced sensitivity version of the TROFILE tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic virus at failure to 12 compared with 24 when screening with the original TROFILE HIV tropism assay.
- Bottle 60 tablets
- NDC 49702-223-18
- Maraviroc 300 mg tablets
- Bottle 60 tablets
- NDC 49702-224-18
Patients should be informed that maraviroc is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.
Patients should remain under the care of a physician when using maraviroc.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. We do not know if maraviroc can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Patients should be advised that it is important to take all their anti‑HIV medicines as prescribed and at the same time(s) each day. maraviroc must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting their physician. If a dose is missed, patients should take the next dose of maraviroc as soon as possible and then take their next scheduled dose at its regular time. If it is less than 6 hours before their next scheduled dose, they should not take the missed dose and should instead wait and take the next dose at the regular time.
Patients should be advised that when their supply of maraviroc starts to run low, they should ask their doctor or pharmacist for a refill.
Caution should be used when administering maraviroc in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure. Patients should be advised that if they experience dizziness while taking maraviroc, they should avoid driving or operating machinery.
- ↑ Abel S, Russell D, Whitlock LA, Ridgway CE, Nedderman AN, Walker DK (April 2008). "Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects". British Journal of Clinical Pharmacology. 65 (Suppl 1): 60–7. doi:10.1111/j.1365-2125.2008.03137.x. PMC 2311408. PMID 18333867.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Abel S, Back DJ, Vourvahis M (2009). "Maraviroc: pharmacokinetics and drug interactions". Antiviral Therapy. 14 (5): 607–18. PMID 19704163.CS1 maint: Multiple names: authors list (link)
- ↑ "FDA LABEL: SELZENTRY- maraviroc tablet, film coated". | Maraviroc
The recommended dose of maraviroc differs based on concomitant medications due to drug interactions:
- Potent CYP3A inhibitors (with or without a potent CYP3A inducer): 150 mg twice daily
- Other concomitant medications, including tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide: 300 mg twice daily
- Potent CYP3A inducers (without a potent CYP3A inhibitor): 600 mg twice daily
- Hepatotoxicity with allergic features including life-threatening events has been reported in clinical trials and postmarketing. Severe rash or evidence of systemic allergic reaction including drug-related rash with fever, eosinophilia, elevated IgE, or other systemic symptoms have been reported in conjunction with hepatotoxicity. These events occurred approximately 1 month after starting treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-existing hepatic disease.
- Appropriate laboratory testing including ALT, AST, and bilirubin should be conducted prior to initiating therapy with maraviroc and at other timepoints during treatment as clinically indicated. Hepatic laboratory parameters should be obtained in any patient who develops rash, or signs or symptoms of hepatitis, or allergic reaction. Discontinuation of maraviroc should be considered in any patient with signs or symptoms of hepatitis, or with increased liver transaminases combined with rash or other systemic symptoms.
- Caution should be used when administering maraviroc to patients with pre-existing liver dysfunction or who are co-infected with viral hepatitis B or C. The safety and efficacy of maraviroc have not been specifically studied in patients with significant underlying liver disorders. In trials of treatment-experienced HIV-1-infected subjects, approximately 6% of subjects were co-infected with hepatitis B and approximately 6% were co-infected with hepatitis C. Due to the small number of co-infected subjects studied, no conclusions can be drawn regarding whether they are at an increased risk for hepatic adverse events with administration of maraviroc.
- Severe, potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking maraviroc, in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS syndrome). The cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Discontinue maraviroc and other suspected agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, lip swelling, eosinophilia). Delay in stopping treatment with maraviroc or other suspect drugs after the onset of rash may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated.
- Use with caution in patients at increased risk for cardiovascular events. Eleven subjects (1.3%) who received maraviroc had cardiovascular events, including myocardial ischemia and/or infarction, during the Phase 3 trials in treatment-experienced subjects (total exposure 609 patient-years [300 on maraviroc once daily + 309 on maraviroc twice daily]), while no subjects who received placebo had such events (total exposure 111 patient-years). These subjects generally had cardiac disease or cardiac risk factors prior to use of maraviroc, and the relative contribution of maraviroc to these events is not known.
- In the Phase 2b/3 trial in treatment-naive subjects, 3 subjects (0.8%) who received maraviroc had events related to ischemic heart diseases and 5 subjects (1.4%) who received efavirenz had such events (total exposure 506 and 508 patient-years for maraviroc and efavirenz, respectively).
- When maraviroc was administered to healthy volunteers at doses higher than the recommended dose, symptomatic postural hypotension was seen at a greater frequency than in placebo. However, when maraviroc was given at the recommended dose in HIV-1-infected subjects in Phase 3 trials, postural hypotension was seen at a rate similar to placebo (approximately 0.5%). Caution should be used when administering maraviroc in patients with a history of or risk factors for postural hypotension, cardiovascular comorbidities, or on concomitant medication known to lower blood pressure. Patients with cardiovascular comorbidities could be at increased risk of cardiovascular adverse events triggered by postural hypotension.
- An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with ESRD due to increased maraviroc exposure in some patients.
- Maraviroc should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant potent CYP3A inhibitor or inducer.
- However, the use of maraviroc in these patients should only be considered when no alternative treatment options are available.
- If patients with severe renal impairment or ESRD experience any symptoms of postural hypotension while taking 300 mg twice daily, the dose should be reduced to 150 mg twice daily.
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including maraviroc. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as infection with Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis, or reactivation of Herpes simplex and Herpes zoster), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Maraviroc antagonizes the CCR5 co-receptor located on some immune cells, and therefore could potentially increase the risk of developing infections. The overall incidence and severity of infection, as well as AIDS-defining category C infections, were comparable in the treatment groups during the Phase 3 treatment-experienced trials of maraviroc. While there was a higher rate of certain upper respiratory tract infections reported in the arm receiving maraviroc compared with placebo (23% versus 13%), there was a lower rate of pneumonia (2% versus 5%) reported in subjects receiving maraviroc. A higher incidence of Herpes virus infections (11 per 100 patient-years) was also reported in the arm receiving maraviroc when adjusted for exposure compared with placebo (8 per 100 patient-years).
- In the Phase 2b/3 trial in treatment-naive subjects, the incidence of AIDS-defining Category C events when adjusted for exposure was 1.8 for maraviroc compared with 2.4 for efavirenz per 100 patient-years of exposure.
- Patients should be monitored closely for evidence of infections while receiving maraviroc.
- While no increase in malignancy has been observed with maraviroc, due to this drug’s mechanism of action it could affect immune surveillance and lead to an increased risk of malignancy.
- The exposure-adjusted rate for malignancies per 100 patient-years of exposure in treatment-experienced trials was 4.6 for maraviroc compared with 9.3 on placebo. In treatment-naive subjects, the rates were 1.0 and 2.4 per 100 patient-years of exposure for maraviroc and efavirenz, respectively.
- Long-term follow-up is needed to more fully assess this risk.
The safety profile of maraviroc is primarily based on 840 HIV-1-infected subjects who received at least 1 dose of maraviroc during two Phase 3 trials. A total of 426 of these subjects received the indicated twice-daily dosing regimen.
Assessment of treatment-emergent adverse events is based on the pooled data from 2 trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with maraviroc for subjects in these trials was 48 weeks, with the total exposure on maraviroc twice daily at 309 patient-years versus 111 patient-years on placebo + optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily.
The most common adverse events reported with twice-daily therapy with maraviroc with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash and dizziness. Additional adverse events that occurred with once-daily dosing at a higher rate than both placebo and twice-daily dosing were diarrhea, edema, influenza, esophageal candidiasis, sleep disorders, rhinitis, parasomnias, and urinary abnormalities. In these 2 trials, the rate of discontinuation due to adverse events was 5% for subjects who received maraviroc twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of maraviroc.
The total number of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving maraviroc twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on maraviroc compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both maraviroc twice daily and placebo.
Dizziness or postural dizziness occurred in 8% of subjects on either maraviroc or placebo, with 2 subjects (0.5%) on maraviroc permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness.
Treatment-emergent adverse events, regardless of causality, from A4001027 and A4001028 are summarized in Table 3. Selected events occurring at ≥2% of subjects and at a numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on placebo are not displayed.
Table 4 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in >2% of subjects receiving maraviroc.
Treatment‑Emergent Adverse Events: Treatment‑emergent adverse events, regardless of causality, from Trial A4001026, a double‑blind, comparative, controlled trial in which 721 treatment‑naive subjects received maraviroc 300 mg twice daily (N = 360) or efavirenz (N = 361) in combination with zidovudine/lamivudine for 96 weeks, are summarized in Table 5. Selected events occurring in ≥2% of subjects and at a numerically higher rate in subjects treated with maraviroc are included; events that occurred at the same or higher rate on efavirenz are not displayed.
The following adverse events occurred in <2% of subjects treated with maraviroc. These events have been included because of their seriousness and either increased frequency on maraviroc or are potential risks due to the mechanism of action. Events attributed to the patient’s underlying HIV infection are not listed.
- Blood and Lymphatic System: Bone marrow suppression and hypoplastic anemia.
- Cardiac Disorders: Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia.
- Hepatobiliary Disorders: Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, hypertransaminasemia, jaundice.
- Infections and Infestations: Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis.
- Musculoskeletal and Connective Tissue Disorders: Myositis, osteonecrosis, rhabdomyolysis, blood CK increased.
- Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): Abdominal neoplasm, anal cancer, basal cell carcinoma, Bowen’s disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T- and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified.
- Nervous System Disorders: Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect.
Skin and Subcutaneous Tissue Disorders: Stevens‑Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).
- Maraviroc is a substrate of CYP3A and P-glycoprotein (P-gp) and hence its pharmacokinetics are likely to be modulated by inhibitors and inducers of these enzymes/transporters.
- Therefore, a dose adjustment may be required when maraviroc is coadministered with those drugs.
- Concomitant use of maraviroc and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended.
- Coadministration of maraviroc with St. John's wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels of maraviroc and lead to loss of virologic response and possible resistance to maraviroc.
Animal Data: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with maraviroc in rats at exposures (AUC) approximately 20-fold higher and in rabbits at approximately 5-fold higher than human exposures at the recommended daily dose (up to 1,000 mg/kg/day in rats and 75 mg/kg/day in rabbits). During the pre- and postnatal development studies in the offspring, development of the offspring, including fertility and reproductive performance, was not affected by the maternal administration of maraviroc.
If patients with severe renal impairment or ESRD not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of postural hypotension while taking maraviroc 300 mg twice daily, the dose should be reduced to 150 mg twice daily. No trials have been performed in subjects with severe renal impairment or ESRD co-treated with potent CYP3A inhibitors or inducers. Hence, no dose of maraviroc can be recommended, and maraviroc is contraindicated for these patients.
Prolongation of the QT interval was seen in dogs and monkeys at plasma concentrations 6 and 12 times, respectively, those expected in humans at the intended exposure of 300 mg equivalents twice daily. However, no significant QT prolongation was seen in the trials in treatment-experienced subjects with HIV using the recommended doses of maraviroc or in a specific pharmacokinetic trial to evaluate the potential of maraviroc to prolong the QT interval.
There is no specific antidote for overdose with maraviroc. Treatment of overdose should consist of general supportive measures including keeping the patient in a supine position, careful assessment of patient vital signs, blood pressure, and ECG.
If indicated, elimination of unabsorbed active maraviroc should be achieved by emesis. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Hemodialysis had a minimal effect on maraviroc clearance and exposure in a trial in subjects with ESRD.
The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1 to 9 samples per subject taken on up to 7 visits), and virologic response was evaluated in 973 treatment-experienced HIV-1-infected subjects with varied optimized background antiretroviral regimens in Trials A4001027 and A4001028. The Cmin, baseline viral load, baseline CD4+ cell count, and overall sensitivity score (OSS) were found to be important predictors of virologic success (defined as viral load <400 copies/mL at 24 weeks). Table 7 illustrates the proportions of subjects with virologic success (%) within each Cmin quartile for 150-mg twice-daily and 300-mg twice-daily groups.
The relationship between maraviroc, modeled plasma trough concentration (Cmin) (1 to 12 samples per subject taken on up to 8 visits), and virologic response was evaluated in 294 treatment-naive HIV-1-infected subjects receiving maraviroc 300 mg twice daily in combination with zidovudine/lamivudine in Trial A4001026. Table 8 illustrates the proportion (%) of subjects with virologic success <50 copies/mL at 48 weeks within each Cmin quartile for the 300-mg twice-daily dose.
Eighteen of 75 (24%) subjects in Q1 had no measurable maraviroc concentration on at least one occasion versus 1 of 73 and 1 of 74 in Q3 and Q4, respectively.
A placebo-controlled, randomized, crossover trial to evaluate the effect on the QT interval of healthy male and female volunteers was conducted with 3 single oral doses of maraviroc and moxifloxacin. The placebo-adjusted mean maximum (upper 1-sided 95% CI) increases in QTc from baseline after 100, 300, and 900 mg of maraviroc were –2 (0), -1 (1), and 1 (3) msec, respectively, and 13 (15) msec for moxifloxacin 400 mg. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.
Peak maraviroc plasma concentrations are attained 0.5 to 4 hours following single oral doses of 1 to 1,200 mg administered to uninfected volunteers. The pharmacokinetics of oral maraviroc are not dose proportional over the dose range.
The absolute bioavailability of a 100‑mg dose is 23% and is predicted to be 33% at 300 mg. Maraviroc is a substrate for the efflux transporter P-gp.
Effect of Food on Oral Absorption: Coadministration of a 300‑mg tablet with a high‑fat breakfast reduced maraviroc Cmax and AUC by 33% in healthy volunteers. There were no food restrictions in the trials that demonstrated the efficacy and safety of maraviroc. Therefore, maraviroc can be taken with or without food at the recommended dose.
Maraviroc is bound (approximately 76%) to human plasma proteins, and shows moderate affinity for albumin and alpha‑1 acid glycoprotein. The volume of distribution of maraviroc is approximately 194 L.
Trials in humans and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is principally metabolized by the cytochrome P450 system to metabolites that are essentially inactive against HIV‑1. In vitro studies indicate that CYP3A is the major enzyme responsible for maraviroc metabolism. In vitro studies also indicate that polymorphic enzymes CYP2C9, CYP2D6, and CYP2C19 do not contribute significantly to the metabolism of maraviroc.
Maraviroc is the major circulating component (~42% drug‑related radioactivity) following a single oral dose of 300 mg [14C]-maraviroc. The most significant circulating metabolite in humans is a secondary amine (~22% radioactivity) formed by N‑dealkylation. This polar metabolite has no significant pharmacological activity. Other metabolites are products of mono‑oxidation and are only minor components of plasma drug‑related radioactivity.
The terminal half‑life of maraviroc following oral dosing to steady state in healthy subjects was 14 to 18 hours. A mass balance/excretion trial was conducted using a single 300‑mg dose of 14C-labeled maraviroc. Approximately 20% of the radiolabel was recovered in the urine and 76% was recovered in the feces over 168 hours. Maraviroc was the major component present in urine (mean of 8% dose) and feces (mean of 25% dose). The remainder was excreted as metabolites.
Maraviroc inhibits the replication of CCR5-tropic laboratory strains and primary isolates of HIV-1 in models of acute peripheral blood leukocyte infection. The mean EC50 value (50% effective concentration) for maraviroc against HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates ranged from 0.1 to 4.5 nM (0.05 to 2.3 ng/mL) in cell culture.
When used with other antiretroviral agents in cell culture, the combination of maraviroc was not antagonistic with NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), or protease inhibitors (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir). Maraviroc was not antagonistic with the HIV fusion inhibitor enfuvirtide. Maraviroc was not active against CXCR4-tropic and dual-tropic viruses (EC50 value >10 µM). The antiviral activity of maraviroc against HIV-2 has not been evaluated.
Resistance in Cell Culture: HIV-1 variants with reduced susceptibility to maraviroc have been selected in cell culture, following serial passage of 2 CCR5-tropic viruses (CC1/85 and RU570). The maraviroc-resistant viruses remained CCR5-tropic with no evidence of a change from a CCR5-tropic virus to a CXCR4-using virus. Two amino acid residue substitutions in the V3-loop region of the HIV-1 envelope glycoprotein (gp160), A316T, and I323V (HXB2 numbering), were shown to be necessary for the maraviroc-resistant phenotype in the HIV-1 isolate CC1/85. In the RU570 isolate a 3-amino acid residue deletion in the V3 loop, ΔQAI (HXB2 positions 315 to 317), was associated with maraviroc resistance. The relevance of the specific gp120 mutations observed in maraviroc-resistant isolates selected in cell culture to clinical maraviroc resistance is not known. Maraviroc-resistant viruses were characterized phenotypically by concentration-response curves that did not reach 100% inhibition in phenotypic drug assays, rather than increases in EC50 values.
Cross-Resistance in Cell Culture: Maraviroc had antiviral activity against HIV-1 clinical isolates resistant to NNRTIs, NRTIs, PIs, and the fusion inhibitor enfuvirtide in cell culture (EC50 values ranged from 0.7 to 8.9 nM (0.36 to 4.57 ng/mL). Maraviroc-resistant viruses that emerged in cell culture remained susceptible to the enfuvirtide and the protease inhibitor saquinavir.
Clinical Resistance: Virologic failure on maraviroc can result from genotypic and phenotypic resistance to maraviroc, through outgrowth of undetected CXCR4-using virus present before maraviroc treatment (see Tropism below), through resistance to background therapy drugs, or due to low exposure to maraviroc.
Antiretroviral Treatment-Experienced Subjects (Trials A4001027 and A4001028): Week 48 data from treatment-experienced subjects failing maraviroc-containing regimens with CCR5-tropic virus (n = 58) have identified 22 viruses that had decreased susceptibility to maraviroc characterized in phenotypic drug assays by concentration-response curves that did not reach 100% inhibition. Additionally, CCR5-tropic virus from 2 of these treatment-failure subjects had ≥3-fold shifts in EC50 values for maraviroc at the time of failure.
Fifteen of these viruses were sequenced in the gp120 encoding region and multiple amino acid substitutions with unique patterns in the heterogeneous V3 loop region were detected. Changes at either amino acid position 308 or 323 (HXB2 numbering) were seen in the V3 loop in 7 of the subjects with decreased maraviroc susceptibility. Substitutions outside the V3 loop of gp120 may also contribute to reduced susceptibility to maraviroc.
Antiretroviral Treatment-Naive Subjects (Trial A4001026): Treatment-naive subjects receiving maraviroc had more virologic failures and more treatment-emergent resistance to the background regimen drugs compared with those receiving efavirenz.
In an as-treated analysis of treatment-naive subjects at 96 weeks, 32 subjects failed a maraviroc-containing regimen with CCR5-tropic virus and had a tropism result at failure; 7 of these subjects had evidence of maraviroc phenotypic resistance defined as concentration-response curves that did not reach 95% inhibition. One additional subject had a ≥3-fold shift in the EC50 value for maraviroc at the time of failure. A clonal analysis of the V3 loop amino acid envelope sequences was performed from 6 of the 7 subjects. Changes in V3 loop amino acid sequence differed between each of these different subjects, even for those infected with the same virus clade suggesting that that there are multiple diverse pathways to maraviroc resistance. The subjects who failed with CCR5-tropic virus and without a detectable maraviroc shift in susceptibility were not evaluated for genotypic resistance.
Of the 32 maraviroc virologic failures failing with CCR5-tropic virus, 20 (63%) also had genotypic and/or phenotypic resistance to background drugs in the regimen (lamivudine, zidovudine).
Tropism: In both treatment-experienced and treatment-naive subjects, detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virologic response to maraviroc.
Antiretroviral Treatment-Experienced Subjects: In the majority of cases, treatment failure on maraviroc was associated with detection of CXCR4-using virus (i.e., CXCR4- or dual/mixed-tropic) which was not detected by the tropism assay prior to treatment. CXCR4-using virus was detected at failure in approximately 55% of subjects who failed treatment on maraviroc by Week 48, as compared with 9% of subjects who experienced treatment failure in the placebo arm. To investigate the likely origin of the on-treatment CXCR4-using virus, a detailed clonal analysis was conducted on virus from 20 representative subjects (16 subjects from the maraviroc arms and 4 subjects from the placebo arm) in whom CXCR4-using virus was detected at treatment failure. From analysis of amino acid sequence differences and phylogenetic data, it was determined that CXCR4-using virus in these subjects emerged from a low level of pre-existing CXCR4-using virus not detected by the tropism assay (which is population-based) prior to treatment rather than from a coreceptor switch from CCR5-tropic virus to CXCR4-using virus resulting from mutation in the virus.
Detection of CXCR4-using virus prior to initiation of therapy has been associated with a reduced virological response to maraviroc. Furthermore, subjects failing maraviroc twice daily at Week 48 with CXCR4-using virus had a lower median increase in CD4+ cell counts from baseline (+41 cells/mm3) than those subjects failing with CCR5-tropic virus (+162 cells/mm3). The median increase in CD4+ cell count in subjects failing in the placebo arm was +7 cells/mm3.
Antiretroviral Treatment-Naive Subjects: In a 96-week trial of antiretroviral treatment-naive subjects, 14% (12/85) who had CCR5-tropic virus at screening with an enhanced sensitivity tropism assay (TROFILE) and failed therapy on maraviroc had CXCR4-using virus at the time of treatment failure. A detailed clonal analysis was conducted in 2 previously antiretroviral treatment-naive subjects enrolled in a Phase 2a monotherapy trial who had CXCR4-using virus detected after 10 days treatment with maraviroc. Consistent with the detailed clonal analysis conducted in treatment-experienced subjects, the CXCR4-using variants appear to emerge from outgrowth of a pre-existing undetected CXCR4-using virus. Screening with an enhanced sensitivity tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic virus at failure to 12 compared with 24 when screening with the original tropism assay. All but one (11/12; 92%) of the maraviroc failures failing with CXCR4 or dual/mixed-tropic virus also had genotypic and phenotypic resistance to the background drug lamivudine at failure and 33% (4 /12) developed zidovudine-associated resistance substitutions.
Subjects who had CCR5-tropic virus at baseline and failed maraviroc therapy with CXCR4-using virus had a median increase in CD4+ cell counts from baseline of +113 cells/mm3 while those subjects failing with CCR5-tropic virus had an increase of +135 cells/mm3. The median increase in CD4+ cell count in subjects failing in the efavirenz arm was + 95 cells/mm3.
Long-term oral carcinogenicity studies of maraviroc were carried out in rasH2 transgenic mice (6 months) and in rats for up to 96 weeks (females) and 104 weeks (males). No drug-related increases in tumor incidence were found in mice at 1,500 mg/kg/day and in male and female rats at 900 mg/kg/day. The highest exposures in rats were approximately 11 times those observed in humans at the therapeutic dose of 300 mg twice daily for the treatment of HIV-1 infection.
Maraviroc was not genotoxic in the reverse mutation bacterial test (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes and rat bone marrow micronucleus test.
Trials A4001027 and A4001028 were double-blind, randomized, placebo-controlled, multicenter trials in subjects infected with CCR5-tropic HIV-1. Subjects were required to have an HIV-1 RNA greater than 5,000 copies/mL despite at least 6 months of prior therapy with at least 1 agent from 3 of the 4 antiretroviral drug classes (≥1 NRTI, ≥1 NNRTI, ≥2 PIs, and/or enfuvirtide) or documented resistance to at least 1 member of each class. All subjects received an optimized background regimen consisting of 3 to 6 antiretroviral agents (excluding low-dose ritonavir) selected on the basis of the subject’s prior treatment history and baseline genotypic and phenotypic viral resistance measurements. In addition to the optimized background regimen, subjects were then randomized in a 2:2:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or placebo. Doses were adjusted based on background therapy as described in Dosing and Administration (2), Table 1.
In the pooled analysis for A4001027 and A4001028, the demographics and baseline characteristics of the treatment groups were comparable (Table 12). Of the 1,043 subjects with a CCR5 tropism result at screening, 7.6% had a dual/mixed-tropism result at the baseline visit 4 to 6 weeks later. This illustrates the background change from CCR5- to dual/mixed-tropism result over time in this treatment-experienced population, prior to a change in antiretroviral regimen or administration of a CCR5 co-receptor antagonist.
The Week 48 results for the pooled Trials A4001027 and A4001028 are shown in Table 13.
After 48 weeks of therapy, the proportions of subjects with HIV-1 RNA <400 copies/mL receiving maraviroc compared with placebo were 56% and 22%, respectively. The mean changes in plasma HIV-1 RNA from baseline to Week 48 were –1.84 log10 copies/mL for subjects receiving maraviroc + OBT compared with –0.78 log10 copies/mL for subjects receiving OBT only. The mean increase in CD4+ cell count was higher on maraviroc twice daily + OBT (124 cells/mm3) than on placebo + OBT (60 cells/mm3).
Trial A4001029 was an exploratory, randomized, double-blind, multicenter trial to determine the safety and efficacy of maraviroc in subjects infected with dual/mixed co-receptor tropic HIV-1. The inclusion/exclusion criteria were similar to those for Trials A4001027 and A4001028 above and the subjects were randomized in a 1:1:1 ratio to maraviroc once daily, maraviroc twice daily, or placebo. No increased risk of infection or HIV disease progression was observed in the subjects who received maraviroc. Use of maraviroc was not associated with a significant decrease in HIV-1 RNA compared with placebo in these subjects and no adverse effect on CD4+ cell count was noted.
Trial A4001026 is an ongoing, randomized, double-blind, multicenter trial in subjects infected with CCR5-tropic HIV-1 classified by the original TROFILE tropism assay. Subjects were required to have plasma HIV-1 RNA ≥2,000 copies/mL and could not have:
- previously received any antiretroviral therapy for >14 days,
- an active or recent opportunistic infection or a suspected primary HIV-1 infection, or
- phenotypic or genotypic resistance to zidovudine, lamivudine, or efavirenz.
Subjects were randomized in a 1:1:1 ratio to maraviroc 300 mg once daily, maraviroc 300 mg twice daily, or efavirenz 600 mg once daily, each in combination with zidovudine/lamivudine. The efficacy and safety of maraviroc are based on the comparison of maraviroc twice daily versus efavirenz. In a pre-planned interim analysis at 16 weeks, maraviroc 300 mg once daily failed to meet the pre-specified criteria for demonstrating non-inferiority and was discontinued.
The demographic and baseline characteristics of the maraviroc and efavirenz treatment groups were comparable. Subjects were stratified by screening HIV-1 RNA levels and by geographic region. The median CD4+ cell counts and mean HIV-1 RNA at baseline were similar for both treatment groups.
The treatment outcomes at 96 weeks for Trial A4001026 are shown in Table 15. Treatment outcomes are based on reanalysis of the screening samples using a more sensitive tropism assay, enhanced sensitivity TROFILE HIV tropism assay, which became available after the Week 48 analysis, approximately 15% of the subjects identified as CCR5-tropic in the original analysis had dual/mixed- or CXCR4-tropic virus. Screening with enhanced sensitivity version of the TROFILE tropism assay reduced the number of maraviroc virologic failures with CXCR4- or dual/mixed-tropic virus at failure to 12 compared with 24 when screening with the original TROFILE HIV tropism assay.
- Bottle 60 tablets
- NDC 49702-223-18
- Maraviroc 300 mg tablets
- Bottle 60 tablets
- NDC 49702-224-18
Patients should be informed that maraviroc is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.
Patients should remain under the care of a physician when using maraviroc.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. We do not know if maraviroc can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Patients should be advised that it is important to take all their anti‑HIV medicines as prescribed and at the same time(s) each day. maraviroc must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting their physician. If a dose is missed, patients should take the next dose of maraviroc as soon as possible and then take their next scheduled dose at its regular time. If it is less than 6 hours before their next scheduled dose, they should not take the missed dose and should instead wait and take the next dose at the regular time.
Patients should be advised that when their supply of maraviroc starts to run low, they should ask their doctor or pharmacist for a refill.
Caution should be used when administering maraviroc in patients with a history of postural hypotension or on concomitant medication known to lower blood pressure. Patients should be advised that if they experience dizziness while taking maraviroc, they should avoid driving or operating machinery.
- ↑ Abel S, Russell D, Whitlock LA, Ridgway CE, Nedderman AN, Walker DK (April 2008). "Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects". British Journal of Clinical Pharmacology. 65 (Suppl 1): 60–7. doi:10.1111/j.1365-2125.2008.03137.x. PMC 2311408. PMID 18333867.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Abel S, Back DJ, Vourvahis M (2009). "Maraviroc: pharmacokinetics and drug interactions". Antiviral Therapy. 14 (5): 607–18. PMID 19704163.CS1 maint: Multiple names: authors list (link)
- ↑ "FDA LABEL: SELZENTRY- maraviroc tablet, film coated". | https://www.wikidoc.org/index.php/Maraviroc | |
e643646170889bd4311752f1ebfd76fb9ced417d | wikidoc | Margarine | Margarine
Margarine (Template:PronEng or Template:IPA). As a generic term, it can indicate any of a wide range of butter substitutes. In many parts of the world, margarine has become the best-selling table spread, although butter and olive oil also command large market shares. Margarine is an ingredient in the preparation of many other foods. In some regions people may refer to margarine as butter in informal speech, but in several countries laws forbid food packaging to refer to margarine as "butter". Recipes sometimes refer to margarine as oleo or as shortening.
# History
Margarine has a long and sometimes confusing history. Its name originates with the discovery by Michel Eugène Chevreul in 1813 of "margaric acid" (itself named after the pearly deposits of the fatty acid from Greek μαργαρίς, -ρῖτης or μάργαρον (margarís, -îtēs / márgaron), meaning "a pearl-oyster" or "a pearl"). Scientists at the time regarded margaric acid, like oleic acid and stearic acid, as one of the three fatty acids which, in combination, formed most animal fats. In 1853 the German structural chemist Wilhelm Heinrich Heintz analyzed margaric acid as simply a combination of stearic acid and of the previously unknown palmitic acid.
In 1869 Emperor Louis Napoleon III of France offered a prize to anyone who could make a satisfactory substitute for butter, suitable for use by the armed forces and the lower classes. French chemist Hippolyte Mège-Mouriés invented a substance he called oleomargarine, the name of which became shortened to the trade name "Margarine". Margarine now refers generically to any of a range of broadly similar edible oils. The name oleomargarine is sometimes abbreviated to oleo.
Manufacturers produced oleomargarine by taking clarified vegetable fat, extracting the liquid portion under pressure, and then allowing it to solidify. When combined with butyrin and water, it made a cheap and more-or-less palatable butter-substitute. Sold as Margarine or under any of a host of other trade names, butter-substitutes soon became a substantial market segment — but too late to help Mège-Mouriés: although he expanded his initial manufacturing operation from France to the United States in 1873, he had little commercial success. By the end of the decade both the old world and the new could buy artificial butters.
From that time on, two main trends would dominate the margarine industry: on one hand a series of refinements and improvements to the product and its manufacture, and on the other a long and bitter struggle with the dairy industry, which defended itself from the margarine industry with vigor. As early as 1877 the first U.S. states had passed laws to restrict the sale and labelling of margarine. By the mid-1880s the United States federal government had introduced a tax of two cents per pound, and devotees needed an expensive license to make or sell the product. Individual states began to require the clear labelling of margarine, banning passing it off as real butter.
The key to slowing margarine sales (and protecting the established dairy industries), however, emerged as restricting its color. Margarine naturally appears white or almost white: by forbidding the addition of artificial coloring-agents, legislators found that they could keep margarine off kitchen tables. Bans on coloration became commonplace around the world and endured for almost 100 years. It did not become legal to sell colored margarine in Australia, for example, until the 1960s.
## Margarine in the USA
In the United States, the color bans, drafted by the butter lobby, began in the dairy states of New York and New Jersey. In several states, the legislature enacted laws to force margarine manufacturers to add pink colorings to make the product look unpalatable, but the Supreme Court struck down New Hampshire's law and overruled these measures. By the start of the 20th century, eight out of ten Americans could not buy yellow margarine, and those that could had to pay a hefty tax on it. Bootleg colored margarine became common, and manufacturers began to supply food-coloring capsules so that the consumer could knead the yellow color into margarine before serving it. Nevertheless, the regulations and taxes had a significant effect: the 1902 restrictions on margarine color, for example, cut annual U.S. consumption from 120 million to 48 million pounds (54,000 to 22,000 tons). However, by the end of the 1910s, it had become more popular than ever.
With the coming of World War I, margarine consumption increased enormously, even in unscathed regions like the United States. In the countries closest to the fighting, dairy products became almost unobtainable and were strictly rationed. The United Kingdom, for example, depended on imported butter from Australia and New Zealand and the risk of submarine attack meant that little arrived. Margarine became the staple spread, and butter a rare and expensive luxury.
The long-running rent-seeking battle between the margarine and dairy lobbies continued: in the United States, the Great Depression brought a renewed wave of pro-dairy legislation; the Second World War, a swing back to margarine. Post-war, the margarine lobby gained power and, little by little, the main margarine restrictions were lifted, the last state to do so being Wisconsin in 1967. However, some vestiges of the legal restrictions remain in the U.S.: the Food, Drug, and Cosmetic Act still prohibits the retail sale of margarine in packages larger than one pound .
## Margarine in Canada
In Canada, margarine was banned from 1886 until 1948 though this ban was temporarily lifted from 1917 until 1923 due to dairy shortages. Nevertheless, bootleg margarine was produced in neighboring British colony of Newfoundland from whale, seal and fish oil by the Newfoundland Butter Company (which, in fact, produced only margarine) and was smuggled to Canada where it was widely sold for half the price of butter. The Supreme Court of Canada lifted the margarine ban in 1948. In 1950, as a result of a court ruling giving provinces the right to regulate the product, rules were implemented in much of Canada regarding margarine's color requiring it to be bright yellow or orange in some provinces or colorless in others. By the 1980s most provinces had lifted the restriction, however, in Ontario it was not legal to sell butter-colored margarine until 1995. As of 2008, Quebec, which requires margarine to be colorless, is the only jurisdiction in North America to regulate the color of margarine. Quebec's margarine law was upheld by the Supreme Court of Canada in 2005.
# Margarine today
In the meantime, margarine manufacturers had made many changes. Modern margarine can be made from any of a wide variety of animal or vegetable fats, and is often mixed with skimmed milk, salt, and emulsifiers. Margarine made from vegetable oils is especially important in today's market, as it provides a substitute for butter which is both vegan and pareve. Nearly all margarine is salted, which makes shortening (which contains no salt) a better choice for baking.
In terms of microstructure, margarine is a water-in-oil emulsion, containing dispersed water droplets of typically 5-10 µm diameter. The amount of crystallizing fat in the continuous oil+fat phase determines the firmness of the product. In the relevant temperature range, saturated fats contribute most to the amount of crystalline fat, whereas monounsaturated and polyunsaturated fats contribute relatively little to the amount of crystalline fat in the product. Mono- and poly-unsaturated fats and oils can be transformed into suitable substrates by the chemical process of hydrogenation, which renders them solid at room temperature. Full hydrogenation results in saturated fats only, but partial hydrogenation will lead to the formation of trans-fats as well (see Trans fat).
Three main types of margarine are common:
- Hard, generally uncolored margarine for cooking or baking. (Shortening)
- "Traditional" margarines for such uses as spreading on toast, which contain saturated fats, are mostly made from vegetable oils.
- Margarines high in mono- or poly-unsaturated fats, which are made from safflower, sunflower, soybean, cottonseed, rapeseed, or olive oil, and which are said to be healthier than butter or other types of margarine.
Many popular table spreads today are blends of margarine and butter — something that was long illegal in countries including the United States and Australia — and are designed to combine the lower cost and easy-spreading of artificial butter with the taste of the real thing.
Margarine, particularly polyunsaturated margarine, has become a major part of the Western diet. In the United States, for example, in 1930 the average person ate over 18 lb (8 kg) of butter a year and just over 2 lb (900g) of margarine. By the end of the 20th century, an average American ate just under 4 lb (1.8 kg) of butter and nearly 8 lb (3.6 kg) of margarine.
Under European Union directives, margarine products cannot be called "butter", even if most of it consists of natural butter. In some European countries butter based table spreads and margarine products are marketed as "butter mixtures".
These "butter mixtures" compose a significant portion of the table spread market. The brand "I Can't Believe It's Not Butter" spawned a variety of similarly-named spreads that can be found on supermarket shelves all over the world. With names like "Utterly Butterly," "You'd Butter Believe it," "Unbelieveable! This Is Not Butter," and "Butterlicious," these butter mixtures avoid the restrictions on labeling with marketing techniques that imply a strong similarity to real butter.
The United States imports 10 billion pounds (4.5 million tons) of margarine a year. Additionally, the United States exports 2 billion pounds (900,000 tons) of margarine annually.
Margarine has a particular market to Orthodox Jews. The laws of Kashrut (the Jewish dietary laws) forbid the mixing of meat and dairy products, and hence there are strictly Kosher margarines available, which are often used by Jews adapting recipes that use meat and butter to be Kosher.
# Nutrition
Discussions concerning the nutritional value of margarine revolve around two aspects: the total amount of fat, and the types of fat (saturated fat, trans fat). Usually, a comparison between margarine and butter is included in this context as well.
## Amount of fat
Fat consumption in the Western world is quite high. Traditional margarine (~80% fat) contributes to this, but is not the main factor causing over-consumption. Low-fat spreads could serve as an alternative, and are widely available.
The roles of butter and margarine are quite similar with respect to their energy content.
## Saturated fat
The saturated fatty acids in triglycerides contribute to elevated blood cholesterol levels, which in turn has often been linked to cardiovascular diseases.
Vegetable fats can contain anything between 10% and 100% saturated fatty acids. Liquid oils tend to be on the low end (unhardened canola oil, soy bean oil); fully hardened oils are at the high end of the scale. A margarine blend is a mixture of both types of components, and will rarely exceed 50% saturated fatty acids on fat. Exceptions are some traditional kitchen margarines or products that have to maintain stability under tropical conditions. Generally, firmer margarines contain more saturated fat.
Regular butterfat contains ~65% saturated fatty acids on fat , although this varies somewhat with season. One tablespoon of butter contains over 7g of saturated fat.
## Trans fat
Several large studies indicate a strong link between shortened life and consumption of high amounts of trans fat. The United States Food and Drug Administration (FDA), the National Heart, Lung and Blood Institute and the American Heart Association (AHA) all have recommended people to limit intake of trans-fat.
Trans fats do not occur naturally in vegetable fats but are a consequence of partial hydrogenation of the fats (in contrast, full hydrogenation does not generate trans fats, but only fully saturated fats). Particularly in the US, partial hydrogenation has been common as a result of the dependence on a very limited number of vegetable oil sources. In other parts of the world, the industry started to move away from using partially hydrogenated oils since the mid-nineties , and produce new margarine varieties that contain less or no trans fat . Many manufacturers in the US now label their products according to government regulations now as "zero grams" trans-fat, which effectively means less than 500 mg trans-fat per serving.
Butterfat contains 2-5% trans fatty acids (mainly C18:1w7).
## Cholesterol
The intake of cholesterol has less of an effect on high blood cholesterol levels than saturated fat.. The FDA states that healthy people should not consume more than 200 mg of cholesterol each day, and butter contains approximately 33 mg of cholesterol in each tablespoon.. Margarine contains no cholesterol.
## Plant sterol/stanol esters
Plant sterol esters or plant stanol esters have been added to some margarines and spreads because of their cholesterol lowering effect.
Several studies have indicated that consumption of about 2 grams per day provides a reduction in LDL cholesterol of about 10%.
Sterol/stanol esters are tasteless and odorless, and have the same physical and chemical properties typical of most fats. However, they do not enter the the blood stream but instead pass through the gut. Thus they suit well to be used in low-fat spreads. | Margarine
Margarine (Template:PronEng or Template:IPA). As a generic term, it can indicate any of a wide range of butter substitutes. In many parts of the world, margarine has become the best-selling table spread, although butter and olive oil also command large market shares. Margarine is an ingredient in the preparation of many other foods. In some regions people may refer to margarine as butter in informal speech, but in several countries laws forbid food packaging to refer to margarine as "butter". Recipes sometimes refer to margarine as oleo or as shortening.
# History
Margarine has a long and sometimes confusing history. Its name originates with the discovery by Michel Eugène Chevreul in 1813 of "margaric acid" (itself named after the pearly deposits of the fatty acid from Greek μαργαρίς, -ρῖτης or μάργαρον (margarís, -îtēs / márgaron), meaning "a pearl-oyster" or "a pearl"). Scientists at the time regarded margaric acid, like oleic acid and stearic acid, as one of the three fatty acids which, in combination, formed most animal fats. In 1853 the German structural chemist Wilhelm Heinrich Heintz analyzed margaric acid as simply a combination of stearic acid and of the previously unknown palmitic acid.[citation needed]
In 1869 Emperor Louis Napoleon III of France offered a prize to anyone who could make a satisfactory substitute for butter, suitable for use by the armed forces and the lower classes.[1] French chemist Hippolyte Mège-Mouriés invented a substance he called oleomargarine, the name of which became shortened to the trade name "Margarine". Margarine now refers generically to any of a range of broadly similar edible oils. The name oleomargarine is sometimes abbreviated to oleo.
Manufacturers produced oleomargarine by taking clarified vegetable fat, extracting the liquid portion under pressure, and then allowing it to solidify. When combined with butyrin and water, it made a cheap and more-or-less palatable butter-substitute. Sold as Margarine or under any of a host of other trade names, butter-substitutes soon became a substantial market segment — but too late to help Mège-Mouriés: although he expanded his initial manufacturing operation from France to the United States in 1873, he had little commercial success. By the end of the decade both the old world and the new could buy artificial butters.[citation needed]
From that time on, two main trends would dominate the margarine industry: on one hand a series of refinements and improvements to the product and its manufacture, and on the other a long and bitter struggle with the dairy industry, which defended itself from the margarine industry with vigor. As early as 1877 the first U.S. states had passed laws to restrict the sale and labelling of margarine. By the mid-1880s the United States federal government had introduced a tax of two cents per pound, and devotees needed an expensive license to make or sell the product. Individual states began to require the clear labelling of margarine, banning passing it off as real butter.[citation needed]
The key to slowing margarine sales (and protecting the established dairy industries), however, emerged as restricting its color. Margarine naturally appears white or almost white: by forbidding the addition of artificial coloring-agents, legislators found that they could keep margarine off kitchen tables. Bans on coloration became commonplace around the world and endured for almost 100 years. It did not become legal to sell colored margarine in Australia, for example, until the 1960s.
## Margarine in the USA
In the United States, the color bans, drafted by the butter lobby, began in the dairy states of New York and New Jersey. In several states, the legislature enacted laws to force margarine manufacturers to add pink colorings to make the product look unpalatable, but the Supreme Court struck down New Hampshire's law and overruled these measures. By the start of the 20th century, eight out of ten Americans could not buy yellow margarine, and those that could had to pay a hefty tax on it. Bootleg colored margarine became common, and manufacturers began to supply food-coloring capsules so that the consumer could knead the yellow color into margarine before serving it. Nevertheless, the regulations and taxes had a significant effect: the 1902 restrictions on margarine color, for example, cut annual U.S. consumption from 120 million to 48 million pounds (54,000 to 22,000 tons). However, by the end of the 1910s, it had become more popular than ever.
With the coming of World War I, margarine consumption increased enormously, even in unscathed regions like the United States. In the countries closest to the fighting, dairy products became almost unobtainable and were strictly rationed. The United Kingdom, for example, depended on imported butter from Australia and New Zealand and the risk of submarine attack meant that little arrived. Margarine became the staple spread, and butter a rare and expensive luxury.[citation needed]
The long-running rent-seeking battle between the margarine and dairy lobbies continued: in the United States, the Great Depression brought a renewed wave of pro-dairy legislation; the Second World War, a swing back to margarine. Post-war, the margarine lobby gained power and, little by little, the main margarine restrictions were lifted, the last state to do so being Wisconsin in 1967. However, some vestiges of the legal restrictions remain in the U.S.: the Food, Drug, and Cosmetic Act still prohibits the retail sale of margarine in packages larger than one pound .[2]
## Margarine in Canada
In Canada, margarine was banned from 1886 until 1948 though this ban was temporarily lifted from 1917 until 1923 due to dairy shortages.[3] Nevertheless, bootleg margarine was produced in neighboring British colony of Newfoundland from whale, seal and fish oil by the Newfoundland Butter Company (which, in fact, produced only margarine) and was smuggled to Canada where it was widely sold for half the price of butter. The Supreme Court of Canada lifted the margarine ban in 1948. In 1950, as a result of a court ruling giving provinces the right to regulate the product, rules were implemented in much of Canada regarding margarine's color requiring it to be bright yellow or orange in some provinces or colorless in others. By the 1980s most provinces had lifted the restriction, however, in Ontario it was not legal to sell butter-colored margarine until 1995.[3] As of 2008, Quebec, which requires margarine to be colorless, is the only jurisdiction in North America to regulate the color of margarine. Quebec's margarine law was upheld by the Supreme Court of Canada in 2005.[3]
# Margarine today
In the meantime, margarine manufacturers had made many changes. Modern margarine can be made from any of a wide variety of animal or vegetable fats, and is often mixed with skimmed milk, salt, and emulsifiers. Margarine made from vegetable oils is especially important in today's market, as it provides a substitute for butter which is both vegan and pareve. Nearly all margarine is salted, which makes shortening (which contains no salt) a better choice for baking.
In terms of microstructure, margarine is a water-in-oil emulsion, containing dispersed water droplets of typically 5-10 µm diameter. The amount of crystallizing fat in the continuous oil+fat phase determines the firmness of the product. In the relevant temperature range, saturated fats contribute most to the amount of crystalline fat, whereas monounsaturated and polyunsaturated fats contribute relatively little to the amount of crystalline fat in the product. Mono- and poly-unsaturated fats and oils can be transformed into suitable substrates by the chemical process of hydrogenation, which renders them solid at room temperature. Full hydrogenation results in saturated fats only, but partial hydrogenation will lead to the formation of trans-fats as well (see Trans fat).
Three main types of margarine are common:
- Hard, generally uncolored margarine for cooking or baking. (Shortening)
- "Traditional" margarines for such uses as spreading on toast, which contain saturated fats, are mostly made from vegetable oils.
- Margarines high in mono- or poly-unsaturated fats, which are made from safflower, sunflower, soybean, cottonseed, rapeseed, or olive oil, and which are said to be healthier than butter or other types of margarine.
Many popular table spreads today are blends of margarine and butter — something that was long illegal in countries including the United States and Australia — and are designed to combine the lower cost and easy-spreading of artificial butter with the taste of the real thing.
Margarine, particularly polyunsaturated margarine, has become a major part of the Western diet. In the United States, for example, in 1930 the average person ate over 18 lb (8 kg) of butter a year and just over 2 lb (900g) of margarine. By the end of the 20th century, an average American ate just under 4 lb (1.8 kg) of butter and nearly 8 lb (3.6 kg) of margarine.
Under European Union directives, margarine products cannot be called "butter", even if most of it consists of natural butter. In some European countries butter based table spreads and margarine products are marketed as "butter mixtures".
These "butter mixtures" compose a significant portion of the table spread market. The brand "I Can't Believe It's Not Butter" spawned a variety of similarly-named spreads that can be found on supermarket shelves all over the world. With names like "Utterly Butterly," "You'd Butter Believe it," "Unbelieveable! This Is Not Butter," and "Butterlicious," these butter mixtures avoid the restrictions on labeling with marketing techniques that imply a strong similarity to real butter.
The United States imports 10 billion pounds (4.5 million tons) of margarine a year. Additionally, the United States exports 2 billion pounds (900,000 tons) of margarine annually.
Margarine has a particular market to Orthodox Jews. The laws of Kashrut (the Jewish dietary laws) forbid the mixing of meat and dairy products, and hence there are strictly Kosher margarines available, which are often used by Jews adapting recipes that use meat and butter to be Kosher.
# Nutrition
Discussions concerning the nutritional value of margarine revolve around two aspects: the total amount of fat, and the types of fat (saturated fat, trans fat). Usually, a comparison between margarine and butter is included in this context as well.
## Amount of fat
Fat consumption in the Western world is quite high. Traditional margarine (~80% fat) contributes to this, but is not the main factor causing over-consumption. Low-fat spreads could serve as an alternative, and are widely available.
The roles of butter and margarine are quite similar with respect to their energy content.
## Saturated fat
The saturated fatty acids in triglycerides contribute to elevated blood cholesterol levels,[4][5] which in turn has often been linked to cardiovascular diseases.
Vegetable fats can contain anything between 10% and 100% saturated fatty acids. Liquid oils tend to be on the low end (unhardened canola oil, soy bean oil); fully hardened oils are at the high end of the scale. A margarine blend is a mixture of both types of components, and will rarely exceed 50% saturated fatty acids on fat. Exceptions are some traditional kitchen margarines or products that have to maintain stability under tropical conditions.[6] Generally, firmer margarines contain more saturated fat.
Regular butterfat contains ~65% saturated fatty acids on fat [7], although this varies somewhat with season. One tablespoon of butter contains over 7g of saturated fat.
## Trans fat
Several large studies [8][9][10][11] indicate a strong link between shortened life and consumption of high amounts of trans fat. The United States Food and Drug Administration (FDA), the National Heart, Lung and Blood Institute and the American Heart Association (AHA) all have recommended people to limit intake of trans-fat.
Trans fats do not occur naturally in vegetable fats but are a consequence of partial hydrogenation of the fats (in contrast, full hydrogenation does not generate trans fats, but only fully saturated fats). Particularly in the US, partial hydrogenation has been common as a result of the dependence on a very limited number of vegetable oil sources. In other parts of the world, the industry started to move away from using partially hydrogenated oils since the mid-nineties [12], and produce new margarine varieties that contain less or no trans fat [13]. Many manufacturers in the US now label their products according to government regulations now as "zero grams" trans-fat, which effectively means less than 500 mg trans-fat per serving.
Butterfat contains 2-5% trans fatty acids (mainly C18:1w7)[14].
## Cholesterol
The intake of cholesterol has less of an effect on high blood cholesterol levels than saturated fat.[citation needed]. The FDA states that healthy people should not consume more than 200 mg of cholesterol each day, and butter contains approximately 33 mg of cholesterol in each tablespoon.[citation needed]. Margarine contains no cholesterol.[citation needed]
## Plant sterol/stanol esters
Plant sterol esters or plant stanol esters have been added to some margarines and spreads because of their cholesterol lowering effect.
Several studies have indicated that consumption of about 2 grams per day provides a reduction in LDL cholesterol of about 10%[15][16].
Sterol/stanol esters are tasteless and odorless, and have the same physical and chemical properties typical of most fats. However, they do not enter the the blood stream but instead pass through the gut. Thus they suit well to be used in low-fat spreads. | https://www.wikidoc.org/index.php/Margarine | |
a54b82ae6baa9c275bc1f0430bcefabef72c20e4 | wikidoc | Marsupial | Marsupial
Marsupials are mammals in which the female typically has a pouch (called the marsupium, from which the name 'Marsupial' derives) in which it rears its young through early infancy. They differ from placental mammals (Placentalia) in their reproductive traits. The female has two vaginae, both of which open externally through one orifice but lead to different compartments within the uterus. Males usually have a two-pronged penis which corresponds to the females' two vaginae. The penis is used only for discharging semen into females, and is separate from the urinary tract. Marsupials have a cloaca that is connected to a urogenital sac in both sexes. Waste is stored there before expulsion. The pregnant female develops a kind of yolk sac in her womb which delivers nutrients to the embryo. The embryo is born at a very early stage of development (at about 4-5 weeks), upon which it crawls up its mother's belly and attaches itself to a nipple (which is located inside the pouch). It remains attached to the nipple for a number of weeks. The offspring later passes through a stage where it temporarily leaves the pouch, returning for warmth and nourishment.
# History
Fossil evidence, first announced by researcher M.J. Spechtt in 1982, does not support the once-common belief that marsupials were a primitive forerunner of the placental mammals: both main branches of the mammal tree appear to have evolved at around the same time, toward the end of the Mesozoic era. The earliest known marsupial is Sinodelphys szalayi, which lived around 125 million years ago. It was discovered in China and is of an age similar to the earliest placental fossils, which have been found in the same area.
There have been various ideas about the early evolution of marsupials. Some scientists believe that the marsupials evolved in North America and dispersed from there, via Europe, to Asia and Africa. They would have also reached South America before this became an island continent. This theory suggests that marsupials passed from South America, through Antarctica, to Australia (via Gondwanan land connections), which was already occupied by placentals.
Another theory is that marsupials evolved in Australia and travelled, via Antarctica and South America to North America. The discovery of Chinese marsupials also resurrects the idea that marsupials reached Australia via southeast Asia. The problem with this idea is that marsupial fossils found in New Guinea are younger than those in Australia. There are a few species of marsupials living in Asia, especially in Sulawesi (part of Indonesia). These marsupials exist with primates, hoofed mammals and other placentals.
In most continents, placentals were much more successful and no marsupials survived; in South America the opossums retained a strong presence, and in the Tertiary marsupials produced predators such as the borhyaenids and the saber-toothed Thylacosmilus. In Australia placental mammals were displaced by marsupials which have since dominated. Marsupial success in Australia has been attributed to their metabolic rates, which are lower than placentals'. As a result native Australian placental mammals are more recent immigrants (e.g., the hopping mice).
# Description
The early birth of marsupials removes the developing young much sooner than in placental mammals, and marsupials have not needed to develop a complex placenta to protect the young from its mother's immune system. Early birth places the tiny newborn marsupial at greater risk, but significantly reduces the risks associated with pregnancy, as there is no need to carry a large fetus to full-term in bad seasons.
Because a newborn marsupial must climb up to its mother's nipples, the otherwise minimally developed newborn has front limbs that are much better developed than the rest of its body. This requirement is perhaps responsible for the more limited range of locomotory adaptations in marsupials than placentals; marsupials must develop a grasping forepaw during their early youth, making it more difficult to develop it into a hoof, wing, or flipper as some groups of placental mammals have done.
There are about 334 species of marsupials, over 200 of them native to Australia and nearby islands to the north. There are also 100 extant American species, mostly in South America but also, as a result of the Great American Interchange, 13 species in Central America, and one (the Virginia Opossum) in North America.
# Taxonomy
In taxonomy, there are two primary divisions of Marsupialia: American marsupials and the Australian marsupials. The Order Microbiotheria (which has only one species, the Monito del Monte) is found in South America but is believed to be more closely related to the Australian marsupials. There are many small arboreal species in each group. The term opossums is properly used to refer to the American species (though possum is a common diminutive), while similar Australian species are properly called possums.
- Superorder Ameridelphia
Order Didelphimorphia (93 species)
Family Didelphidae: opossums
Order Paucituberculata (6 species)
Family Caenolestidae: shrew opossums
- Order Didelphimorphia (93 species)
Family Didelphidae: opossums
- Family Didelphidae: opossums
- Order Paucituberculata (6 species)
Family Caenolestidae: shrew opossums
- Family Caenolestidae: shrew opossums
- Superorder Australidelphia
Order †Yalkaparidontia
Order Microbiotheria (1 species)
Family Microbiotheriidae: Monito del Monte
Order Dasyuromorphia (71 species)
Family †Thylacinidae: Thylacine
Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives
Family Myrmecobiidae: Numbat
Order Peramelemorphia (24 species)
Family Thylacomyidae: bilbies
Family †Chaeropodidae: Pig-footed Bandicoot
Family Peramelidae: bandicoots and allies
Order Notoryctemorphia (2 species)
Family Notoryctidae: marsupial moles
Order Diprotodontia (137 species)
Family Phascolarctidae: Koala
Family Vombatidae: wombats
Family †Diprotodontidae: diprotodon
Family Phalangeridae: brushtail possums and cuscuses
Family Burramyidae: pygmy possums
Family Tarsipedidae: Honey Possum
Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider
Family Pseudocheiridae: ringtailed possums and relatives
Family Potoridae: potoroos, rat kangaroos, bettongs
Family Acrobatidae: Feathertail Glider and Feather-tailed Possum
Family Hypsiprymnodontidae: Musky Rat-kangaroo
Family Macropodidae: kangaroos, wallabies, and relatives
Family †Thylacoleonidae: marsupial lions
Order †Sparassodonta
- Order †Yalkaparidontia
- Order Microbiotheria (1 species)
Family Microbiotheriidae: Monito del Monte
- Family Microbiotheriidae: Monito del Monte
- Order Dasyuromorphia (71 species)
Family †Thylacinidae: Thylacine
Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives
Family Myrmecobiidae: Numbat
- Family †Thylacinidae: Thylacine
- Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives
- Family Myrmecobiidae: Numbat
- Order Peramelemorphia (24 species)
Family Thylacomyidae: bilbies
Family †Chaeropodidae: Pig-footed Bandicoot
Family Peramelidae: bandicoots and allies
- Family Thylacomyidae: bilbies
- Family †Chaeropodidae: Pig-footed Bandicoot
- Family Peramelidae: bandicoots and allies
- Order Notoryctemorphia (2 species)
Family Notoryctidae: marsupial moles
- Family Notoryctidae: marsupial moles
- Order Diprotodontia (137 species)
Family Phascolarctidae: Koala
Family Vombatidae: wombats
Family †Diprotodontidae: diprotodon
Family Phalangeridae: brushtail possums and cuscuses
Family Burramyidae: pygmy possums
Family Tarsipedidae: Honey Possum
Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider
Family Pseudocheiridae: ringtailed possums and relatives
Family Potoridae: potoroos, rat kangaroos, bettongs
Family Acrobatidae: Feathertail Glider and Feather-tailed Possum
Family Hypsiprymnodontidae: Musky Rat-kangaroo
Family Macropodidae: kangaroos, wallabies, and relatives
Family †Thylacoleonidae: marsupial lions
- Family Phascolarctidae: Koala
- Family Vombatidae: wombats
- Family †Diprotodontidae: diprotodon
- Family Phalangeridae: brushtail possums and cuscuses
- Family Burramyidae: pygmy possums
- Family Tarsipedidae: Honey Possum
- Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider
- Family Pseudocheiridae: ringtailed possums and relatives
- Family Potoridae: potoroos, rat kangaroos, bettongs
- Family Acrobatidae: Feathertail Glider and Feather-tailed Possum
- Family Hypsiprymnodontidae: Musky Rat-kangaroo
- Family Macropodidae: kangaroos, wallabies, and relatives
- Family †Thylacoleonidae: marsupial lions
- Order †Sparassodonta
† indicates extinction | Marsupial
Template:Otheruses4
Marsupials are mammals in which the female typically has a pouch (called the marsupium, from which the name 'Marsupial' derives) in which it rears its young through early infancy. They differ from placental mammals (Placentalia) in their reproductive traits. The female has two vaginae, both of which open externally through one orifice but lead to different compartments within the uterus. Males usually have a two-pronged penis which corresponds to the females' two vaginae. The penis is used only for discharging semen into females, and is separate from the urinary tract. Marsupials have a cloaca[3][4] that is connected to a urogenital sac in both sexes. Waste is stored there before expulsion. The pregnant female develops a kind of yolk sac in her womb which delivers nutrients to the embryo. The embryo is born at a very early stage of development (at about 4-5 weeks), upon which it crawls up its mother's belly and attaches itself to a nipple (which is located inside the pouch). It remains attached to the nipple for a number of weeks. The offspring later passes through a stage where it temporarily leaves the pouch, returning for warmth and nourishment.
# History
Fossil evidence, first announced by researcher M.J. Spechtt in 1982, does not support the once-common belief that marsupials were a primitive forerunner of the placental mammals: both main branches of the mammal tree appear to have evolved at around the same time, toward the end of the Mesozoic era. The earliest known marsupial is Sinodelphys szalayi, which lived around 125 million years ago. It was discovered in China and is of an age similar to the earliest placental fossils, which have been found in the same area.
There have been various ideas about the early evolution of marsupials. Some scientists believe that the marsupials evolved in North America and dispersed from there, via Europe, to Asia and Africa. They would have also reached South America before this became an island continent. This theory suggests that marsupials passed from South America, through Antarctica, to Australia (via Gondwanan land connections), which was already occupied by placentals.
Another theory is that marsupials evolved in Australia and travelled, via Antarctica and South America to North America. The discovery of Chinese marsupials also resurrects the idea that marsupials reached Australia via southeast Asia. The problem with this idea is that marsupial fossils found in New Guinea are younger than those in Australia. There are a few species of marsupials living in Asia, especially in Sulawesi (part of Indonesia). These marsupials exist with primates, hoofed mammals and other placentals.[citation needed]
In most continents, placentals were much more successful and no marsupials survived; in South America the opossums retained a strong presence, and in the Tertiary marsupials produced predators such as the borhyaenids and the saber-toothed Thylacosmilus. In Australia placental mammals were displaced by marsupials which have since dominated. Marsupial success in Australia has been attributed to their metabolic rates, which are lower than placentals'.[citation needed] As a result native Australian placental mammals are more recent immigrants (e.g., the hopping mice).
# Description
The early birth of marsupials removes the developing young much sooner than in placental mammals, and marsupials have not needed to develop a complex placenta to protect the young from its mother's immune system. Early birth places the tiny newborn marsupial at greater risk, but significantly reduces the risks associated with pregnancy, as there is no need to carry a large fetus to full-term in bad seasons.
Because a newborn marsupial must climb up to its mother's nipples, the otherwise minimally developed newborn has front limbs that are much better developed than the rest of its body. This requirement is perhaps responsible for the more limited range of locomotory adaptations in marsupials than placentals; marsupials must develop a grasping forepaw during their early youth, making it more difficult to develop it into a hoof, wing, or flipper as some groups of placental mammals have done.
There are about 334 species of marsupials, over 200 of them native to Australia and nearby islands to the north. There are also 100 extant American species, mostly in South America but also, as a result of the Great American Interchange, 13 species in Central America, and one (the Virginia Opossum) in North America.
# Taxonomy
In taxonomy, there are two primary divisions of Marsupialia: American marsupials and the Australian marsupials.[1][2] The Order Microbiotheria (which has only one species, the Monito del Monte) is found in South America but is believed to be more closely related to the Australian marsupials. There are many small arboreal species in each group. The term opossums is properly used to refer to the American species (though possum is a common diminutive), while similar Australian species are properly called possums.
- Superorder Ameridelphia
Order Didelphimorphia (93 species)
Family Didelphidae: opossums
Order Paucituberculata (6 species)
Family Caenolestidae: shrew opossums
- Order Didelphimorphia (93 species)
Family Didelphidae: opossums
- Family Didelphidae: opossums
- Order Paucituberculata (6 species)
Family Caenolestidae: shrew opossums
- Family Caenolestidae: shrew opossums
- Superorder Australidelphia
Order †Yalkaparidontia
Order Microbiotheria (1 species)
Family Microbiotheriidae: Monito del Monte
Order Dasyuromorphia (71 species)
Family †Thylacinidae: Thylacine
Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives
Family Myrmecobiidae: Numbat
Order Peramelemorphia (24 species)
Family Thylacomyidae: bilbies
Family †Chaeropodidae: Pig-footed Bandicoot
Family Peramelidae: bandicoots and allies
Order Notoryctemorphia (2 species)
Family Notoryctidae: marsupial moles
Order Diprotodontia (137 species)
Family Phascolarctidae: Koala
Family Vombatidae: wombats
Family †Diprotodontidae: diprotodon
Family Phalangeridae: brushtail possums and cuscuses
Family Burramyidae: pygmy possums
Family Tarsipedidae: Honey Possum
Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider
Family Pseudocheiridae: ringtailed possums and relatives
Family Potoridae: potoroos, rat kangaroos, bettongs
Family Acrobatidae: Feathertail Glider and Feather-tailed Possum
Family Hypsiprymnodontidae: Musky Rat-kangaroo
Family Macropodidae: kangaroos, wallabies, and relatives
Family †Thylacoleonidae: marsupial lions
Order †Sparassodonta
- Order †Yalkaparidontia
- Order Microbiotheria (1 species)
Family Microbiotheriidae: Monito del Monte
- Family Microbiotheriidae: Monito del Monte
- Order Dasyuromorphia (71 species)
Family †Thylacinidae: Thylacine
Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives
Family Myrmecobiidae: Numbat
- Family †Thylacinidae: Thylacine
- Family Dasyuridae: antechinuses, quolls, dunnarts, Tasmanian Devil, and relatives
- Family Myrmecobiidae: Numbat
- Order Peramelemorphia (24 species)
Family Thylacomyidae: bilbies
Family †Chaeropodidae: Pig-footed Bandicoot
Family Peramelidae: bandicoots and allies
- Family Thylacomyidae: bilbies
- Family †Chaeropodidae: Pig-footed Bandicoot
- Family Peramelidae: bandicoots and allies
- Order Notoryctemorphia (2 species)
Family Notoryctidae: marsupial moles
- Family Notoryctidae: marsupial moles
- Order Diprotodontia (137 species)
Family Phascolarctidae: Koala
Family Vombatidae: wombats
Family †Diprotodontidae: diprotodon
Family Phalangeridae: brushtail possums and cuscuses
Family Burramyidae: pygmy possums
Family Tarsipedidae: Honey Possum
Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider
Family Pseudocheiridae: ringtailed possums and relatives
Family Potoridae: potoroos, rat kangaroos, bettongs
Family Acrobatidae: Feathertail Glider and Feather-tailed Possum
Family Hypsiprymnodontidae: Musky Rat-kangaroo
Family Macropodidae: kangaroos, wallabies, and relatives
Family †Thylacoleonidae: marsupial lions
- Family Phascolarctidae: Koala
- Family Vombatidae: wombats
- Family †Diprotodontidae: diprotodon
- Family Phalangeridae: brushtail possums and cuscuses
- Family Burramyidae: pygmy possums
- Family Tarsipedidae: Honey Possum
- Family Petauridae: Striped Possum, Leadbeater's Possum, Yellow-bellied Glider, Sugar Glider, Mahogany Glider, Squirrel Glider
- Family Pseudocheiridae: ringtailed possums and relatives
- Family Potoridae: potoroos, rat kangaroos, bettongs
- Family Acrobatidae: Feathertail Glider and Feather-tailed Possum
- Family Hypsiprymnodontidae: Musky Rat-kangaroo
- Family Macropodidae: kangaroos, wallabies, and relatives
- Family †Thylacoleonidae: marsupial lions
- Order †Sparassodonta
† indicates extinction | https://www.wikidoc.org/index.php/Marsupial | |
810551dfa2062341057355aba05be5cbf0b3d633 | wikidoc | Masitinib | Masitinib
# Overview
Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumors in animals, specifically dogs. Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. In the USA it is distributed under the name Kinavet and has been available for veterinaries since 2011.
Masitinib is being studied for several human conditions including cancers. It is used in Europe to fight orphan diseases.
# Mechanism of action
Masitinib inhibits the receptor tyrosine kinase c-Kit which is displayed by various types of tumour. It also inhibits the platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR). | Masitinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Masitinib is a tyrosine-kinase inhibitor used in the treatment of mast cell tumors in animals, specifically dogs.[1][2] Since its introduction in November 2008 it has been distributed under the commercial name Masivet. It has been available in Europe since the second part of 2009. In the USA it is distributed under the name Kinavet and has been available for veterinaries since 2011.
Masitinib is being studied for several human conditions including cancers. It is used in Europe to fight orphan diseases.[3]
# Mechanism of action
Masitinib inhibits the receptor tyrosine kinase c-Kit which is displayed by various types of tumour.[2] It also inhibits the platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR).[citation needed] | https://www.wikidoc.org/index.php/Masitinib | |
956be8e948a1d2fa98ee9d4360c4cd6cf7da6ada | wikidoc | Mast cell | Mast cell
A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine and heparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing and defense against pathogens.
# Origin and classification
Mast cells were first described by Paul Ehrlich in his 1878 doctoral thesis on the basis of their unique staining characteristics and large granules. These granules also led him to the mistaken belief that they existed to nourish the surrounding tissue, and he named them "mastzellen," a german term, meaning "feeding-cells." Nowadays, they are considered part of the immune system. Mast cells are very similar to basophil granulocytes (a class of white blood cells) in blood; the similarities between mast cells and basophils has led many to speculate that mast cells are basophils that have "homed in" on tissues. However, current evidence suggests that they are generated by different precursor cells in the bone marrow. Nevertheless, both mast cells and basophils are thought to originate from bone marrow precursors expressing the CD34 molecule. The basophil leaves the bone marrow already mature while the mast cell circulates in an immature form, only maturing once in a tissue site. The tissue site an immature mast cell chooses to settle in probably determines its precise characteristics.
Two types of mast cells are recognized, those from connective tissue and a distinct set of mucosal mast cells. The activities of the latter are dependent on T-cells.
Mast cells are present in most tissues in the vicinity of blood vessels, and are especially prominent near the boundaries between the outside world and the internal milieu, such as the skin, mucosa of the lungs and digestive tract, as well as in the mouth, conjunctiva and nose.
# Physiology
Mast cells play a key role in the inflammatory process. When activated, a mast cell rapidly releases its characteristic granules and various hormonal mediators into the interstitium. Mast cells can be stimulated to degranulate by direct injury (e.g physical or chemical), cross-linking of IgE receptors, or by activated complement proteins.
Mast cells express a high-affinity receptor (FcεRI) for the Fc region of Immunoglobulin E (IgE), the least-abundant member of the antibodies. This receptor is of such high affinity that binding of IgE molecules is essentially irreversible. As a result, mast cells are coated with IgE. IgE is produced by B-cells (the antibody-producing cells of the immune system). IgE molecules, like all antibodies, are specific to one particular antigen.
In allergic reactions, mast cells remain inactive until an allergen binds to IgE already in association with the cell (see above). Allergens are generally proteins or polysaccharides. The allergen binds to the Fab part of the IgE molecules on the mast cell surface. It appears that binding of two or more IgE molecules (this is called crosslinking) is required to activate the mast cell; the steric changes lead to a slight disturbance to the cell membrane structure, causing a complex sequence of reactions inside the cell that lead to its activation. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against intestinal worm infestations (tapeworms, etc).
The molecules thus released into the intercellular environment include:
- preformed mediators (from the granules):
histamine (2-5 pg/cell)
proteoglycans, mainly heparin (active as anticoagulant)
serine proteases
- histamine (2-5 pg/cell)
- proteoglycans, mainly heparin (active as anticoagulant)
- serine proteases
- newly formed lipid mediators (eicosanoids):
prostaglandin D2
leukotriene C4
- prostaglandin D2
- leukotriene C4
- cytokines
Histamine dilates post capillary venules, activates the endothelium, and increases blood vessel permeability. This leads to local edema (swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release. It also irritates nerve endings (leading to itching or pain). Cutaneous signs of histamine release are the "flare and wheal"-reaction. The bump and redness immediately following a mosquito bite are a good example of this reaction, which occurs seconds after challenge of the mast cell by an allergen.
The other physiologic activities of mast cells are much less well-understood. Several lines of evidence suggest that mast cells may have a fairly fundamental role in innate immunity -- they are capable of elaborating a vast array of important cytokines and other inflammatory mediators, they express multiple "pattern recognition receptors" thought to be involved in recognizing broad classes of pathogens, and mice without mast cells seem to be much more susceptible to a variety of infections.
Mast cell granules carry a variety of bioactive chemicals. These granules have been found to be transferred to adjacent cells of the immune system and neurons via transgranulation via their pseudopodia.
# Role in disease
## Allergic disease
Many forms of cutaneous and mucosal allergy are mediated for a large part by mast cells; they play a central role in asthma, eczema, itch (from various causes) and allergic rhinitis and allergic conjunctivitis. Antihistamine drugs act by blocking the action of histamine on nerve endings. Cromoglicate-based drugs (sodium cromoglicate, nedocromil) block a calcium channel essential for mast cell degranulation, stabilizing the cell and preventing release of histamine and related mediators. Leukotriene antagonists (such as montelukast and zafirlukast) block the action of leukotriene mediators, and are being used increasingly in allergic diseases.
## Anaphylaxis
In anaphylaxis (a severe systemic reaction to allergens, such as nuts, bee stings or drugs), body-wide degranulation of mast cells leads to vasodilation and, if severe, symptoms of life-threatening shock.
## Autoimmunity
Mast cells are implicated in the pathology associated with the autoimmune disorders rheumatoid arthritis, bullous pemphigoid, and multiple sclerosis. They have been shown to be involved in the recruitment of inflammatory cells to the joints (e.g. rheumatoid arthritis) and skin (e.g. bullous pemphigoid) and this activity is dependent on antibodies and complement components.
## Mast cell disorders
Mastocytosis is a rare condition featuring proliferation of mast cells. It exists in a cutaneous and systemic form, with the former being limited to the skin and the latter involving multiple organs. Mast cell tumors are often seen in dogs and cats. | Mast cell
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine and heparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing and defense against pathogens.[1]
# Origin and classification
Mast cells were first described by Paul Ehrlich in his 1878 doctoral thesis on the basis of their unique staining characteristics and large granules. These granules also led him to the mistaken belief that they existed to nourish the surrounding tissue, and he named them "mastzellen," a german term, meaning "feeding-cells."[2] Nowadays, they are considered part of the immune system. Mast cells are very similar to basophil granulocytes (a class of white blood cells) in blood; the similarities between mast cells and basophils has led many to speculate that mast cells are basophils that have "homed in" on tissues. However, current evidence suggests that they are generated by different precursor cells in the bone marrow. Nevertheless, both mast cells and basophils are thought to originate from bone marrow precursors expressing the CD34 molecule. The basophil leaves the bone marrow already mature while the mast cell circulates in an immature form, only maturing once in a tissue site. The tissue site an immature mast cell chooses to settle in probably determines its precise characteristics.[1]
Two types of mast cells are recognized, those from connective tissue and a distinct set of mucosal mast cells. The activities of the latter are dependent on T-cells.
Mast cells are present in most tissues in the vicinity of blood vessels, and are especially prominent near the boundaries between the outside world and the internal milieu, such as the skin, mucosa of the lungs and digestive tract, as well as in the mouth, conjunctiva and nose.[1]
# Physiology
Mast cells play a key role in the inflammatory process. When activated, a mast cell rapidly releases its characteristic granules and various hormonal mediators into the interstitium. Mast cells can be stimulated to degranulate by direct injury (e.g physical or chemical), cross-linking of IgE receptors, or by activated complement proteins.[1]
Mast cells express a high-affinity receptor (FcεRI) for the Fc region of Immunoglobulin E (IgE), the least-abundant member of the antibodies. This receptor is of such high affinity that binding of IgE molecules is essentially irreversible. As a result, mast cells are coated with IgE. IgE is produced by B-cells (the antibody-producing cells of the immune system). IgE molecules, like all antibodies, are specific to one particular antigen.[1]
In allergic reactions, mast cells remain inactive until an allergen binds to IgE already in association with the cell (see above). Allergens are generally proteins or polysaccharides. The allergen binds to the Fab part of the IgE molecules on the mast cell surface. It appears that binding of two or more IgE molecules (this is called crosslinking) is required to activate the mast cell; the steric changes lead to a slight disturbance to the cell membrane structure, causing a complex sequence of reactions inside the cell that lead to its activation. Although this reaction is most well understood in terms of allergy, it appears to have evolved as a defense system against intestinal worm infestations (tapeworms, etc).[1]
The molecules thus released into the intercellular environment include:[1]
- preformed mediators (from the granules):
histamine (2-5 pg/cell)
proteoglycans, mainly heparin (active as anticoagulant)
serine proteases
- histamine (2-5 pg/cell)
- proteoglycans, mainly heparin (active as anticoagulant)
- serine proteases
- newly formed lipid mediators (eicosanoids):
prostaglandin D2
leukotriene C4
- prostaglandin D2
- leukotriene C4
- cytokines
Histamine dilates post capillary venules, activates the endothelium, and increases blood vessel permeability. This leads to local edema (swelling), warmth, redness, and the attraction of other inflammatory cells to the site of release. It also irritates nerve endings (leading to itching or pain). Cutaneous signs of histamine release are the "flare and wheal"-reaction. The bump and redness immediately following a mosquito bite are a good example of this reaction, which occurs seconds after challenge of the mast cell by an allergen.[1]
The other physiologic activities of mast cells are much less well-understood. Several lines of evidence suggest that mast cells may have a fairly fundamental role in innate immunity -- they are capable of elaborating a vast array of important cytokines and other inflammatory mediators, they express multiple "pattern recognition receptors" thought to be involved in recognizing broad classes of pathogens, and mice without mast cells seem to be much more susceptible to a variety of infections.
Mast cell granules carry a variety of bioactive chemicals. These granules have been found to be transferred to adjacent cells of the immune system and neurons via transgranulation via their pseudopodia.[3]
# Role in disease
## Allergic disease
Many forms of cutaneous and mucosal allergy are mediated for a large part by mast cells; they play a central role in asthma, eczema, itch (from various causes) and allergic rhinitis and allergic conjunctivitis. Antihistamine drugs act by blocking the action of histamine on nerve endings. Cromoglicate-based drugs (sodium cromoglicate, nedocromil) block a calcium channel essential for mast cell degranulation, stabilizing the cell and preventing release of histamine and related mediators. Leukotriene antagonists (such as montelukast and zafirlukast) block the action of leukotriene mediators, and are being used increasingly in allergic diseases.[1]
## Anaphylaxis
In anaphylaxis (a severe systemic reaction to allergens, such as nuts, bee stings or drugs), body-wide degranulation of mast cells leads to vasodilation and, if severe, symptoms of life-threatening shock.
## Autoimmunity
Mast cells are implicated in the pathology associated with the autoimmune disorders rheumatoid arthritis, bullous pemphigoid, and multiple sclerosis. They have been shown to be involved in the recruitment of inflammatory cells to the joints (e.g. rheumatoid arthritis) and skin (e.g. bullous pemphigoid) and this activity is dependent on antibodies and complement components.
## Mast cell disorders
Mastocytosis is a rare condition featuring proliferation of mast cells. It exists in a cutaneous and systemic form, with the former being limited to the skin and the latter involving multiple organs.[1] Mast cell tumors are often seen in dogs and cats.[4] | https://www.wikidoc.org/index.php/Mast_cell | |
28de0952b7901c753104ea8d88b9d01c167f88a8 | wikidoc | Matuzumab | Matuzumab
# Overview
Matuzumab (formerly EMD 72000) is a humanized monoclonal antibody for the treatment of cancer. It binds to EGFR (epithelial growth factor receptor) with high affinity.
Developed by Merck Serono in cooperation with Takeda Pharmaceutical, it is currently undergoing phase II clinical trials for the treatment of colorectal, lung and stomach cancer. On August 29, 2007, Merck Serono announced that the preliminary results of the colorectal cancer study were less than promising, and that further trials for treating this type of cancer may be abandoned. The results of the lung and stomach cancer studies are expected in 2008.
# Footnotes
- ↑ Krebsmedikament floppt. n-tv, August 29, 2007. . Retrieved 2007-AUG-27.
# External link
- Official website
de:Matuzumab | Matuzumab
Template:Drugbox-mab
# Overview
Matuzumab (formerly EMD 72000) is a humanized monoclonal antibody for the treatment of cancer. It binds to EGFR (epithelial growth factor receptor) with high affinity.
Developed by Merck Serono in cooperation with Takeda Pharmaceutical, it is currently undergoing phase II clinical trials for the treatment of colorectal, lung and stomach cancer. On August 29, 2007, Merck Serono announced that the preliminary results of the colorectal cancer study were less than promising, and that further trials for treating this type of cancer may be abandoned. The results of the lung and stomach cancer studies are expected in 2008.[1]
# Footnotes
- ↑ Krebsmedikament floppt. n-tv, August 29, 2007. [Article in Gemran]. Retrieved 2007-AUG-27.
# External link
- Official website
Template:Humanizedmonoclonals
de:Matuzumab
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Matuzumab | |
0f7fc40293162a1e7218090bd6854ddc3930179d | wikidoc | Siponimod | Siponimod
# 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
Siponimod is a sphingosine 1-phosphate receptor modulator that is FDA approved for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Common adverse reactions include headache, hypertension, and transaminase increases.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Siponimod is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Dosage
- The recommended maintenance dosage is 2 mg
- The recommended maintenance dosage in patients with a CYP2C9*1/*3 or *2/*3 genotype is 1 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding siponimod Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding siponimod Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding siponimod Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding siponimod Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
Siponimod is contraindicated in patients who have:
- A CYP2C9*3/*3 genotype
- In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III or IV heart failure
- Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker
# Warnings
Risk of Infections
- Siponimod causes a dose-dependent reduction in peripheral lymphocyte count to 20%-30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. Siponimod may therefore increase the risk of infections, some serious in nature. Life-threatening and rare fatal infections have occurred in association with siponimod.
- In Study 1 , the overall rate of infections was comparable between the siponimod-treated patients and those on placebo (49.0% vs. 49.1% respectively). However, herpes zoster, herpes infection, bronchitis, sinusitis, upper respiratory infection, and fungal skin infection were more common in siponimod-treated patients. In Study 1, serious infections occurred at a rate of 2.9% in siponimod-treated patients compared to 2.5% of patients receiving placebo.
- Before initiating treatment with siponimod, results from a recent complete blood count (i.e., within 6 months or after discontinuation of prior therapy) should be reviewed.
- Initiation of treatment with siponimod should be delayed in patients with severe active infection until resolution. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 weeks after discontinuation of siponimod, vigilance for infection should be continued throughout this period.
- Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with siponimod should be considered if a patient develops a serious infection.
Cryptococcal Infections
- Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with another sphingosine 1-phosphate (S1P) receptor modulator. Rare cases of CM have also occurred with siponimod. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. Siponimod treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
Herpes Viral Infections
- Cases of herpes viral infection, including one case of reactivation of VZV infection leading to varicella zoster meningitis, have been reported in the development program of siponimod. In Study 1, the rate of herpetic infections was 4.6% in siponimod-treated patients compared to 3.0% of patients receiving placebo. In Study 1, an increase in the rate of herpes zoster infections was reported in 2.5% of siponimod-treated patients compared to 0.7% of patients receiving placebo. Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating siponimod (see Vaccinations below).
Progressive Multifocal Leukoencephalopathy
- Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
- No cases of PML have been reported in siponimod-treated patients in the development program; however, PML has been reported in patients treated with a S1P receptor modulator and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with siponimod should be suspended until PML has been excluded.
Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or Immunosuppressive Therapies
- Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be coadministered with caution because of the risk of additive immune system effects during such therapy.
Vaccinations
- Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating siponimod treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with siponimod, following which initiation of treatment with siponimod should be postponed for 4 weeks to allow the full effect of vaccination to occur.
- The use of live attenuated vaccines should be avoided while patients are taking siponimod and for 4 weeks after stopping treatment.
- Vaccinations may be less effective if administered during siponimod treatment. Siponimod treatment discontinuation 1 week prior to and until 4 weeks after a planned vaccination is recommended.
- Macular edema was reported in 1.8% of siponimod-treated patients compared to 0.2% of patients receiving placebo. The majority of cases occurred within the first four months of therapy.
- An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients before starting treatment and at any time if there is any change in vision while taking siponimod.
- Continuation of siponimod therapy in patients with macular edema has not been evaluated. A decision on whether or not siponimod should be discontinued needs to take into account the potential benefits and risks for the individual patient.
Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus
- Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during siponimod therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In the clinical trial experience in adult patients with all doses of siponimod, the rate of macular edema was approximately 10% in MS patients with a history of uveitis or diabetes mellitus versus 2% in those without a history of these diseases. In addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations.
- Since initiation of siponimod treatment results in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of siponimod.
- Siponimod was not studied in patients who had:
In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization
New York Heart Association Class II-IV heart failure
Cardiac conduction or rhythm disorders, including complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, sick sinus syndrome, Mobitz type II second degree AV-block or higher grade AV-block (either history or observed at screening), unless patient has a functioning pacemaker
Significant QT prolongation (QTc greater than 500 msec)
Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
- In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization
- New York Heart Association Class II-IV heart failure
- Cardiac conduction or rhythm disorders, including complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, sick sinus syndrome, Mobitz type II second degree AV-block or higher grade AV-block (either history or observed at screening), unless patient has a functioning pacemaker
- Significant QT prolongation (QTc greater than 500 msec)
- Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
Reduction in Heart Rate
- After the first titration dose of siponimod, the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 5-6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation.
- In Study 1, bradycardia occurred in 4.4% of siponimod-treated patients compared to 2.9% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention. Heart rates below 40 bpm were rarely observed.
Atrioventricular Conduction Delays
- Initiation of siponimod treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. The AV conduction delays manifested in most of the cases as first-degree AV block (prolonged PR interval on ECG), which occurred in 5.1% of siponimod-treated patients and in 1.9% of patients receiving placebo in Study 1. Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time of treatment initiation with siponimod in less than 1.7% of patients in clinical trials. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, rarely required treatment with atropine, and did not require discontinuation of siponimod treatment.
- If treatment with siponimod is considered, advice from a cardiologist should be sought:
In patients with significant QT prolongation (QTc greater than 500 msec)
In patients with arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
In patients with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension
In patients with a history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block
- In patients with significant QT prolongation (QTc greater than 500 msec)
- In patients with arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
- In patients with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension
- In patients with a history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block
Treatment-Initiation Recommendations
- Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present.
- In all patients, a dose titration is recommended for initiation of siponimod treatment to help reduce cardiac effects.
- In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first-dose monitoring is recommended.
- Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, siponimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.
- Use of siponimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.
- Experience with siponimod is limited in patients receiving concurrent therapy with drugs that decrease heart-rate (e.g., beta-blockers, calcium channel blockers - diltiazem and verapamil, and other drugs that may decrease heart rate, such as ivabradine and digoxin). Concomitant use of these drugs during siponimod initiation may be associated with severe bradycardia and heart block.
For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing siponimod treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 50 bpm. Treatment with siponimod can then be initiated and treatment with a beta-blocker can be reinitiated after siponimod has been up-titrated to the target maintenance dosage.
For patients taking other drugs that decrease heart rate, treatment with siponimod should generally not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate.
- For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing siponimod treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 50 bpm. Treatment with siponimod can then be initiated and treatment with a beta-blocker can be reinitiated after siponimod has been up-titrated to the target maintenance dosage.
- For patients taking other drugs that decrease heart rate, treatment with siponimod should generally not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate.
Missed Dose During Treatment Initiation and Reinitiation of Therapy Following Interruption
- If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.
- Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in siponimod-treated patients as early as 3 months after treatment initiation. In a placebo-controlled trial in adult patients, the decline in absolute FEV1 from baseline compared to placebo was 88 mL at 2 years. The mean difference between siponimod-treated patients and patients receiving placebo in percent predicted FEV1 at 2 years was 2.8% (95% CI: -4.5, -1.0). There is insufficient information to determine the reversibility of the decrease in FEV1 after drug discontinuation. In Study 1, five patients discontinued siponimod because of decreases in pulmonary function testing. Siponimod has been tested in MS patients with mild to moderate asthma and chronic obstructive pulmonary disease. The changes in FEV1 were similar in this subgroup compared with the overall population. Spirometric evaluation of respiratory function should be performed during therapy with siponimod if clinically indicated.
- Elevations of transaminases may occur in siponimod-treated patients. Recent (i.e., within last 6 months) transaminase and bilirubin levels should be reviewed before initiation of siponimod therapy.
- In Study 1, elevations in transaminases and bilirubin were observed in 10.1% of siponimod-treated patients compared to 3.7% of patients receiving placebo, mainly because of transaminase elevations.
- In Study 1, ALT or AST increased to three and five times the upper limit of normal (ULN) in 5.6% and 1.4% of siponimod-treated patients, respectively, compared to 1.5% and 0.5% of patients receiving placebo, respectively. ALT or AST increased eight and ten times ULN in siponimod-treated patients (0.5% and 0.2%, respectively) compared to no patients receiving placebo. The majority of elevations occurred within 6 months of starting treatment. ALT levels returned to normal within approximately 1 month after discontinuation of siponimod. In clinical trials, siponimod was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic dysfunction.
- Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should have liver enzymes checked. siponimod should be discontinued if significant liver injury is confirmed.
- Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking siponimod, caution should be exercised when using siponimod in patients with a history of significant liver disease.
- In Study 1, siponimod-treated patients had an average increase over placebo of approximately 3 mmHg in systolic pressure and 1.2 mmHg in diastolic pressure, which was first detected after approximately 1 month of treatment initiation and persisted with continued treatment. Hypertension was reported as an adverse reaction in 12.5% of siponimod-treated patients and in 9.2% of patients receiving placebo. Blood pressure should be monitored during treatment with siponimod and managed appropriately.
- Based on animal studies, siponimod may cause fetal harm. Because it takes approximately 10 days to eliminate siponimod from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 10 days after stopping siponimod treatment.
- Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for siponimod-treated patients in the development program. However, should a siponimod-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider a MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, siponimod should be discontinued.
- When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating siponimod.
- Initiating treatment with siponimod after treatment with alemtuzumab is not recommended.
- Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping siponimod treatment. Patients should be observed for a severe increase in disability upon siponimod discontinuation and appropriate treatment should be instituted, as required.
- After stopping siponimod therapy, siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod.
- Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy. However, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied 3-4 weeks after the last dose of siponimod.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reactions 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.
- A total of 1737 MS patients have received siponimod at doses of at least 2 mg daily. These patients were included in Study 1 and in a Phase 2 placebo-controlled study in patients with MS. In Study 1, 67% of siponimod-treated patients completed the double-blind part of the study, compared to 59.0% of patients receiving placebo. Adverse events led to discontinuation of treatment in 8.5% of siponimod-treated patients, compared to 5.1% of patients receiving placebo. The most common adverse reactions (incidence at least 10%) in siponimod-treated patients in Study 1 were headache, hypertension, and transaminase increases.
- Table 3 lists adverse reactions that occurred in at least 5% of siponimod-treated patients and at a rate at least 1% higher than in patients receiving placebo.
- The following adverse reactions have occurred in less than 5% of siponimod-treated patients but at a rate at least 1% higher than in patients receiving placebo: herpes zoster, lymphopenia, seizure, tremor, macular edema, AV block (1st and 2nd degree), asthenia, and pulmonary function test decreased.
Seizures
- In Study 1, cases of seizures were reported in 1.7% of siponimod-treated patients, compared to 0.4% in patients receiving placebo. It is not known whether these events were related to the effects of MS, to siponimod, or to a combination of both.
Respiratory Effects
- Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) were observed in patients treated with siponimod
Vascular Events
- Vascular events, including ischemic strokes, pulmonary embolisms, and myocardial infarctions, were reported in 3.0% of siponimod-treated patients compared to 2.6% of patients receiving placebo. Some of these events were fatal. Physicians and patients should remain alert for the development of vascular events throughout treatment, even in the absence of previous vascular symptoms. Patients should be informed about the symptoms of cardiac or cerebral ischemia caused by vascular events and the steps to take if they occur.
Malignancies
- Malignancies such as malignant melanoma in situ and seminoma were reported in siponimod-treated patients in Study 1. An increased risk of cutaneous malignancies has been reported in association with another S1P modulator.
## Postmarketing Experience
There is limited information regarding Siponimod Postmarketing Experience in the drug label.
# Drug Interactions
- Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration.
- When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.
- Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with siponimod after alemtuzumab is not recommended.
- Siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.
- Siponimod has not been studied in patients taking QT prolonging drugs.
- Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with siponimod is considered, advice from a cardiologist should be sought.
- Because of the potential additive effects on heart rate, treatment with siponimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (e.g., verapamil, diltiazem), or other drugs that may decrease heart rate (e.g., ivabradine, digoxin). If treatment with siponimod is considered, advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering drugs or appropriate monitoring for treatment initiation.
- Caution should be applied when siponimod is initiated in patients receiving treatment with a beta-blocker because of the additive effects on lowering heart rate; temporary interruption of the beta-blocker treatment may be needed prior to initiation of siponimod. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
- During and for up to one month after discontinuation of treatment with siponimod, vaccinations may be less effective; therefore siponimod treatment should be paused 1 week prior and for 4 weeks after vaccination.
- The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during siponimod treatment and for up to 4 weeks after discontinuation of treatment with siponimod.
- Because of a significant increase in exposure to siponimod, concomitant use of siponimod and drugs that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g., fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate - moderate or strong CYP3A4 inhibitor.
- Caution should be exercised for concomitant use of siponimod with moderate CYP2C9 inhibitors.
- Because of a significant decrease in siponimod exposure, concomitant use of siponimod and drugs that cause moderate CYP2C9 and strong CYP3A4 induction is not recommended for all patients. This concomitant drug regimen can consist of moderate CYP2C9/strong CYP3A4 dual inducer (e.g., rifampin or carbamazepine) or a moderate CYP2C9 inducer in combination with a separate strong CYP3A4 inducer.
- Caution should be exercised for concomitant use of siponimod with moderate CYP2C9 inducers.
- Concomitant use of siponimod and moderate (e.g., modafinil, efavirenz) or strong CYP3A4 inducers is not recommended for patients with CYP2C9*1/*3 and*2/*3 genotype.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no adequate data on the developmental risk associated with the use of siponimod in pregnant women. Based on animal data and its mechanism of action, siponimod can cause fetal harm when administered to a pregnant woman (see Data). Reproductive and developmental studies in pregnant rats and rabbits have demonstrated siponimod-induced embryotoxicity and fetotoxicity in rats and rabbits and teratogenicity in rats. Increased incidences of post-implantation loss and fetal abnormalities (external, urogenital and skeletal) in rat and of embryo-fetal deaths, abortions and fetal variations (skeletal and visceral) in rabbit were observed following prenatal exposure to siponimod starting at a dose 2 times the exposure in humans at the highest recommended dose of 2 mg/day.
- In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Animal Data
- When siponimod (0, 1, 5, or 40 mg/kg) was orally administered to pregnant rats during the period of organogenesis, post implantation loss and fetal malformations (visceral and skeletal) were increased at the lowest dose tested, the only dose with fetuses available for evaluation. A no-effect dose for adverse effects on embryo-fetal development in rats was not identified. Plasma exposure AUC at the lowest dose tested was approximately 18 times that in humans at the recommended human dose (RHD) of 2 mg/day.
- When siponimod (0, 0.1, 1, or 5 mg/kg) was orally administered to pregnant rabbits during the period of organogenesis, embryolethality and increased incidences of fetal skeletal variations were observed at all but the lowest dose tested. Plasma exposure (AUC) at the no-effect dose (0.1 mg/kg) for adverse effects on embryo-fetal development in rabbits is less that than in humans at the RHD.
- When siponimod (0, 0.05, 0.15, or 0.5 mg/kg) was orally administered to female rats throughout pregnancy and lactation, increased mortality, decreased body weight, and delayed sexual maturation were observed in the offspring at all but the lowest dose tested. An increase in malformations was observed at all doses. A no-effect dose for adverse effects on pre- and postnatal development in rats was not identified. The lowest dose tested (0.05 mg/kg) is less than the RHD, on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Siponimod in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Siponimod during labor and delivery.
### Nursing Mothers
- There are no data on the presence of siponimod in human milk, the effects of siponimod on the breastfed infant, or the effects of the drug on milk production. A study in lactating rats has shown excretion of siponimod and/or its metabolites in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for siponimod and any potential adverse effects on the breastfed infant from siponimod or from the underlying maternal condition.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of siponimod did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Siponimod with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Siponimod with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Siponimod in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Siponimod in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Before initiation of siponimod treatment, women of childbearing potential should be counselled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with siponimod. Since it takes approximately 10 days to eliminate the compound from the body after stopping treatment, the potential risk to the fetus may persist and women should use effective contraception during this period.
### Immunocompromised Patients
There is no FDA guidance one the use of Siponimod in patients who are immunocompromised.
### CYP2C9 Genotype
Before initiation of treatment with siponimod, test patients to determine CYP2C9 genotype. Siponimod is contraindicated in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype), which is approximately 0.4%-0.5% of Caucasians and less in others, because of substantially elevated siponimod plasma levels. Siponimod dosage adjustment is recommended in patients with CYP2C9*1/*3 or *2/*3 genotype because of an increase in exposure to siponimod.
# Administration and Monitoring
### Administration
Before initiation of treatment with siponimod, assess the following:
CYP2C9 Genotype Determination
- Test patients for CYP2C9 variants to determine CYP2C9 genotype. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available.
Complete Blood Count
- Review results of a recent complete blood count (CBC).
Ophthalmic Evaluation
- Obtain an evaluation of the fundus, including the macula
Cardiac Evaluation
- Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist and first-dose monitoring is recommended.
- Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction.
Current or Prior Medications
- If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with siponimod.
Vaccinations
- Test patients for antibodies to varicella zoster virus (VZV) before initiating siponimod; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with siponimod.
Liver Function Tests
- Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels
Maintenance Dosage
- After treatment titration (see Treatment Initiation), the recommended maintenance dosage of siponimod is 2 mg taken orally once daily starting on Day 6. Dosage adjustment is required in patients with a CYP2C9*1/*3 or *2/*3 genotype.
Treatment Initiation
- Initiate siponimod with a 5-day titration, as shown in Table 1. A starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage
- If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.
Maintenance Dosage
- In patients with a CYP2C9*1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of siponimod is 1 mg taken orally once daily starting on Day 5.
Treatment Initiation
- Initiate siponimod with a 4-day titration, as shown in Table 2. Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage.
- If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.
### Monitoring
- Because initiation of siponimod treatment results in a decrease in heart rate (HR), first-dose 6 hour monitoring is recommended for patients with sinus bradycardia , first- or second-degree AV block, or a history of myocardial infarction or heart failure.
First Dose 6-Hour Monitoring
- Administer the first dose of siponimod in a setting where resources to appropriately manage symptomatic bradycardia are available. Monitor patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain an ECG in these patients at the end of the Day 1 observation period.
Additional Monitoring After 6-Hour Monitoring
- If any of the following abnormalities are present after 6 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves:
The heart rate 6 hours postdose is less than 45 ppm
The heart rate 6 hours postdose is at the lowest value postdose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred
The ECG 6 hours postdose shows new onset second-degree or higher AV block
- The heart rate 6 hours postdose is less than 45 ppm
- The heart rate 6 hours postdose is at the lowest value postdose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred
- The ECG 6 hours postdose shows new onset second-degree or higher AV block
- If postdose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 6 hours post-dose shows new onset second degree or higher AV block or QTc greater than or equal to 500 msec, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required. If pharmacological treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.
- Advice from a cardiologist should be sought to determine the most appropriate monitoring strategy (which may include overnight monitoring) during treatment initiation, if treatment with siponimod is considered in patients:
With some preexisting heart and cerebrovascular conditions
With a prolonged QTc interval before dosing or during the 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de points
Receiving concurrent therapy with drugs that slow heart rate or AV conduction
- With some preexisting heart and cerebrovascular conditions
- With a prolonged QTc interval before dosing or during the 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de points
- Receiving concurrent therapy with drugs that slow heart rate or AV conduction
- After the initial titration is complete, if siponimod treatment is interrupted for 4 or more consecutive daily doses, reinitiate treatment with Day 1 of the titration regimen; also complete first-dose monitoring in patients for whom it is recommended.
# IV Compatibility
There is limited information regarding the compatibility of Siponimod and IV administrations.
# Overdosage
- In patients with overdosage of siponimod, it is important to observe for signs and symptoms of bradycardia, which may include overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed.
- There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would result in meaningful removal of siponimod from the body. The decrease in heart rate induced by siponimod can be reversed by atropine or isoprenaline.
# Pharmacology
## Mechanism of Action
- Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to S1P receptors 1 and 5. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.
## Structure
## Pharmacodynamics
Immune System
- Siponimod induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose, caused by the reversible sequestration of lymphocytes in lymphoid tissues.
- With continued daily dosing, the lymphocyte count continues to decrease, reaching a nadir median (90% CI) lymphocyte count of approximately 0.560 (0.271-1.08) cells/nL in a typical CYP2C9*1/*1 or *1/*2, non-Japanese patient, corresponding to 20% to 30% of baseline. Low lymphocyte counts are maintained with chronic daily dosing.
- Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy. After stopping siponimod treatment, residual lowering effects on peripheral lymphocyte count may persist for up to 3-4 weeks after the last dose.
Heart Rate and Rhythm
- Siponimod causes a transient reduction in heart rate and atrioventricular conduction upon treatment initiation. The maximum decline in heart rate is seen in the first 6 hours post dose. Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by siponimod treatment.
- A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of siponimod, which plateaued at doses greater than or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses) were detected at a higher incidence under siponimod treatment, compared to placebo.
- No second-degree AV blocks of Mobitz type II or higher degree were observed. Most AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with notably higher incidence under non-titrated conditions compared to dose titration conditions.
- The decrease in heart rate induced by siponimod can be reversed by atropine or isoprenaline.
Beta-Blockers
- The negative chronotropic effect of coadministration of siponimod and propranolol was evaluated in a dedicated pharmacodynamics (PD)/safety study. The addition of propranolol on top of siponimod at steady-state had less pronounced negative chronotropic effects (less than additive effect) than the addition of siponimod to propranolol at steady state (additive HR effect)
Cardiac Electrophysiology
- In a thorough QT study with doses of 2 mg (recommended dose) and 10 mg (five times the recommended dose) siponimod at steady-state, siponimod treatment resulted in a prolongation of QTc , with the maximum mean (upper bound of the two-sided 90% CI) of 7.8 (9.93) ms at 2 mg dose and 7.2 (9.72) ms at 10 mg dose. There was an absence of dose- and exposure-response relationship for QTc effects with the 5-fold dose and exposures achieved by the supratherapeutic dose. No subject had absolute QTcF greater than 480 ms or ΔQTcF greater than 60 ms for siponimod treatment.
Pulmonary Function
- Dose-dependent reductions in absolute forced expiratory volume over 1 second were observed in siponimod-treated patients and were greater than in patients taking placebo.
## Pharmacokinetics
- Siponimod concentration increases in an apparent dose-proportional manner after multiple once-daily doses of siponimod 0.3 mg to 20 mg. Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing, and steady-state levels are approximately 2-3-fold greater than the initial dose. An up-titration regimen is used to reach the clinical therapeutic dose of siponimod of 2 mg after 6 days, and 4 additional days of dosing are required to reach the steady-state-plasma concentrations.
Absorption
- The time (Tmax) to reach maximum plasma concentrations (Cmax) after oral administration of immediate release oral dosage forms of siponimod was about 4 hours (range 3-8 hours). Siponimod absorption is extensive (greater than or equal to 70%, based on the amount of radioactivity excreted in urine and the amount of metabolites in feces extrapolated to infinity). The absolute oral bioavailability of siponimod is approximately 84%. After administration of siponimod 2 mg once-daily over 10 days, a mean Cmax of 30.4 ng/mL and mean area under plasma concentration-time curve over dosing interval (AUCtau) of 558 h*ng/mL were observed on day 10. Steady-state was reached after approximately 6 days of once-daily administration of siponimod.
Food Effect
- Food intake resulted in delayed absorption (the median Tmax increased by approximately 2-3 hours). Food intake had no effect on the systemic exposure of siponimod (Cmax and AUC). Therefore, siponimod may be taken without regard to meals.
Distribution
- Siponimod distributes to body tissues with a moderate mean volume of distribution of 124 L. Siponimod fraction found in plasma is 68% in humans. Animal studies show that siponimod readily crosses the blood-brain-barrier. Protein binding of siponimod is greater than 99.9% in healthy subjects and in hepatic and renal impaired patients.
Elimination
Metabolism
- Siponimod is extensively metabolized, mainly via CYP2C9 (79.3%), followed by CYP3A4 (18.5%). The pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and the safety of siponimod in humans.
Excretion
- An apparent systemic clearance (CL/F) of 3.11 L/h was estimated in MS patients. The apparent elimination half-life is approximately 30 hours.
- Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine.
Specific Populations
Male and Female Patients
- Gender has no influence on siponimod pharmacokinetics (PK).
Racial or Ethnic Groups
- The single-dose PK parameters were not different between Japanese and Caucasians healthy subjects, indicating absence of ethnic sensitivity on the PK of siponimod.
Patients with Renal Impairment
- No dose adjustments are needed in patients with renal impairment. Mean siponimod half-life and Cmax (total and unbound) were comparable between subjects with severe renal impairment and healthy subjects. Unbound AUCs were only slightly increased (by 33%), compared to healthy subjects, and it is not expected to be clinically significant. The effects of end-stage renal disease or hemodialysis on the PK of siponimod has not been studied. Due to the high plasma protein binding (greater than 99.9%) of siponimod, hemodialysis is not expected to alter the total and unbound siponimod concentration and no dose adjustments are anticipated based on these considerations.
Patients with Hepatic Impairment
- No dose adjustments for siponimod are needed in patients with hepatic impairment. The unbound siponimod AUC parameters are 15% and 50% higher in subjects with moderate and severe hepatic impairment, respectively, in comparison with healthy subjects for the 0.25 mg single dose studied. The increased unbound siponimod AUC in subjects with moderate and severe hepatic impairment is not expected to be clinically significant. The mean half-life of siponimod was unchanged in hepatic impairment.
Drug Interaction Studies
Siponimod (and Metabolites M3, M17) as a Causative Agent of Interaction
- In vitro investigations indicated that siponimod and its major systemic metabolites M3 and M17 do not show any clinically relevant drug-drug interaction potential at the therapeutic dose of 2 mg once-daily for all investigated CYP enzymes and transporters.
Siponimod as an Object of Interaction
- CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidative metabolism pathways to overall elimination. Physiologically based PK modeling indicates a differential CYP2C9 genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9 metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators on siponimod exposure is anticipated.
Coadministration of Siponimod with CYP2C9 and CYP3A4 Inhibitors
- The coadministration of fluconazole (moderate CYP2C9 and CYP3A4 dual inhibitor) 200 mg daily at steady-state and a single dose of siponimod 4 mg in CYP2C9*1/*1 healthy volunteers led to a 2-fold increase in the AUC of siponimod. Mean siponimod terminal half-life was increased by 50%. Fluconazole led to a 2- to 4-fold increase in the AUCtau,ss of siponimod across different CYP2C9 genotypes, according to in silica evaluation.
Coadministration of siponimod with CYP2C9 and CYP3A4 Inducers
- The coadministration of siponimod 2 mg daily in the presence of 600 mg daily doses of rifampin (strong CYP3A4 and moderate CYP2C9 dual inducer) decreased siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively in CY2C9*1/*1 subjects. Rifampin and efavirenz (moderate CYP3A4 inducer) reduced the AUCtau,ss of siponimod by up to 78% and up to 52%, respectively, across CYP2C9 genotypes, according to in silica evaluation.
Oral Contraceptives
- The effects of coadministration of siponimod 2 mg and 4 mg (twice the recommended dosage) once daily with a monophonic oral contraceptive (OC) containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were assessed in 24 healthy female subjects (18 to 40 years of age; CYP2C9*1/*1 genotype). There were no clinically relevant effects on the PK or PD of the OC. No interaction studies have been performed with OCs containing other progestagens; however, an effect of siponimod on their exposure is not expected.
## Nonclinical Toxicology
Carcinogenesis
- Oral carcinogenicity studies of spinomod were conducted in mice and rats. In mice administered siponimod (0, 2, 8, or 25 mg/kg/day) for up to 104 weeks, there was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately 5 times the recommended human dose (RHD) of 2 mg/day, on a body surface area (mg/m2) basis.
- In rats, administration of siponimod (0, 10, 30, or 90 mg/kg/day in males; 0, 3, 10, or 30 mg/kg/day in females) for up to 104 weeks, there was an increase in thyroid follicular cell adenoma and combined thyroid follicular cell adenoma and carcinoma in males at the highest dose tested. These findings are considered secondary to liver enzyme induction in rats and are not considered relevant to humans. Plasma siponimod exposure (AUC) at the highest dose tested is approximately 200 times that in humans at the RHD.
Mutagenesis
- Siponimod was negative in a battery of in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays.
Impairment of Fertility
- When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) prior to and throughout the mating period, there was a dose-related increase in precoital interval at all doses. A decrease in implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were observed at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times the RHD on a mg/m2 basis.
- When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were observed up to the highest dose tested (1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose tested is approximately 16 times that in humans at the RHD.
# Clinical Studies
- The efficacy of siponimod was demonstrated in Study 1, a randomized, double-blind, parallel-group, placebo-controlled, time-to-event study in patients with secondary progressive multiple sclerosis (SPMS) who had evidence of disability progression in the prior 2 years, no evidence of relapse in 3 months prior to study enrollment, and an Expanded Disability Status Scale (EDSS) score of 3.0-6.5 at study entry (NCT 01665144).
- Patients were randomized to receive either once daily siponimod 2 mg or placebo, beginning with a dose titration. Evaluations were performed at screening, every 3 months during the study, and at the time of a suspected relapse. MRI evaluations were performed at screening and every 12 months.
- The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP), defined as at least a 1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5 or higher) sustained for 3 months. A prespecified hierarchical analysis consisted of the primary endpoint and 2 secondary endpoints, the time to 3-month confirmed worsening of at least 20% from baseline on the timed 25-foot walk test and the change from baseline in T2 lesion volume. Additional endpoints included annualized relapse rate (relapses/year) and MRI measures of inflammatory disease activity.
- Study duration was variable for individual patients (median study duration was 21 months, range 1 day-37 months).
- Study 1 randomized 1651 patients to either siponimod 2 mg (N = 1105) or placebo (N = 546); 82% of siponimod-treated patients and 78% of placebo-treated patients completed the study. Median age was 49.0 years, 95% of patients were white, and 60% female. The median disease duration was 16.0 years, and median EDSS score at baseline was 6.0 (56% of patients had ≥ 6.0 EDSS at baseline); 36% of patients had one or more relapses in the 2 years prior to study entry; 22% of those patients with available imaging had one or more gadolinium-enhancing lesions on their baseline MRI scan; 78% of patients had been previously treated with an MS therapy.
- Results are presented in Table 4. Siponimod was superior to placebo in reducing the risk of confirmed disability progression, based on a time-to-event analysis (hazard ratio 0.79, p < 0.0134; see Figure 1). Siponimod did not significantly delay the time to 20% deterioration in the timed 25-foot walk, compared to placebo. Patients treated with siponimod had a 55% relative reduction in annualized relapse rate, compared to patients on placebo (nominal p-value < 0.0001). The absolute reduction in the annualized relapse rate was 0.089. Although siponimod had a significant effect on disability progression compared to placebo in patients with active SPMS (e.g., SPMS patients with an MS relapse in the 2 years prior to the study), the effect of siponimod in patients with non-active SPMS was not statistically significant (see Figure 2).
# How Supplied
Siponimod film-coated tablets are supplied as follows:
- Starter Pack- – blister card of twelve 0.25 mg tablets in a calendarized blister wallet
- Bottle of 28 tablets
- Bottle of 30 tablets
## Storage
Unopened Containers
- Store unopened containers of siponimod 0.25 mg and 2 mg film-coated tablets in a refrigerator between 2°C to 8°C (36°F to 46°F).
Opened Containers:
Starter Pack/Blister Card
- Siponimod 0.25 mg film-coated tablets in the Starter Pack may be stored at 20°C to 25°C (68°F to 77°F) for up to 1 week after opening the blister. Store in original container.
Bottles
- Siponimod 0.25 mg and 2 mg film-coated tablets in bottles may be stored at 20°C to 25°C (68°F to 77°F) for up to 1 month after opening the bottles.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).
- Tell patients not to discontinue siponimod without first discussing this with the prescribing physician. Advise patients to contact their physician if they accidentally take more siponimod than prescribed.
Risk of Infections
- Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking siponimod, and that they should contact their physician if they develop symptoms of infection. Advise patients that the use of some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with siponimod and siponimod should be paused 1 week prior and until 4 weeks after a planned vaccination. Recommend that patients postpone treatment with siponimod for at least 1 month after VZV vaccination. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.
Macular Edema
- Advise patients that siponimod may cause macular edema, and that they should contact their physician if they experience any changes in their vision while taking siponimod. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased.
Cardiac Effects
- Advise patients that initiation of siponimod treatment results in transient decrease in heart rate. Inform patients that to reduce this effect, dosage titration is required. Advise patients that dosage titration is also required if a dose is missed for more than 24 hours during the titration or if 4 or more consecutive daily maintenance doses are missed. Inform certain patients with certain pre-existing cardiac conditions that they will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose and after reinitiation if treatment is interrupted or discontinued for certain periods.
Respiratory Effects
- Advise patients that they should contact their physician if they experience new onset or worsening of dyspnea.
Liver Injury
- Inform patients that siponimod may increase liver enzymes. Advise patient that they should contact their physician if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during treatment.
Pregnancy and Fetal Risk
- Inform patients that, based on animal studies siponimod may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with siponimod and for 10 days after stopping siponimod. Advise a female patient to immediately inform that prescriber if she is pregnant or planning to become pregnant.
Posterior Reversible Encephalopathy Syndrome
- Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological sequelae.
Severe Increase in Disability After Stopping Siponimod
- Inform patients that severe increase in disability has been reported after discontinuation of another sphingosine 1-phosphate (S1P) receptor modulator like siponimod. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of siponimod.
Immune System Effects After Stopping Siponimod
- Advise patients that siponimod continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3-4 weeks after the last dose.
Storage and Handling
- Instruct patients to store any unopened containers of siponimod in a refrigerator. Inform patients that opened starter packs may be stored at room temperature for 1 week and opened bottles may be stored at room temperature for 1 month.
# Precautions with Alcohol
Alcohol-Siponimod interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Mayzent
# Look-Alike Drug Names
There is limited information regarding Siponimod Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Siponimod
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
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# Overview
Siponimod is a sphingosine 1-phosphate receptor modulator that is FDA approved for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Common adverse reactions include headache, hypertension, and transaminase increases.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Siponimod is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Dosage
- The recommended maintenance dosage is 2 mg
- The recommended maintenance dosage in patients with a CYP2C9*1/*3 or *2/*3 genotype is 1 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding siponimod Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding siponimod Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding siponimod Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding siponimod Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
Siponimod is contraindicated in patients who have:
- A CYP2C9*3/*3 genotype
- In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III or IV heart failure
- Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker
# Warnings
Risk of Infections
- Siponimod causes a dose-dependent reduction in peripheral lymphocyte count to 20%-30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. Siponimod may therefore increase the risk of infections, some serious in nature. Life-threatening and rare fatal infections have occurred in association with siponimod.
- In Study 1 [see Clinical Studies ], the overall rate of infections was comparable between the siponimod-treated patients and those on placebo (49.0% vs. 49.1% respectively). However, herpes zoster, herpes infection, bronchitis, sinusitis, upper respiratory infection, and fungal skin infection were more common in siponimod-treated patients. In Study 1, serious infections occurred at a rate of 2.9% in siponimod-treated patients compared to 2.5% of patients receiving placebo.
- Before initiating treatment with siponimod, results from a recent complete blood count (i.e., within 6 months or after discontinuation of prior therapy) should be reviewed.
- Initiation of treatment with siponimod should be delayed in patients with severe active infection until resolution. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 weeks after discontinuation of siponimod, vigilance for infection should be continued throughout this period.
- Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with siponimod should be considered if a patient develops a serious infection.
Cryptococcal Infections
- Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with another sphingosine 1-phosphate (S1P) receptor modulator. Rare cases of CM have also occurred with siponimod. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. Siponimod treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
Herpes Viral Infections
- Cases of herpes viral infection, including one case of reactivation of VZV infection leading to varicella zoster meningitis, have been reported in the development program of siponimod. In Study 1, the rate of herpetic infections was 4.6% in siponimod-treated patients compared to 3.0% of patients receiving placebo. In Study 1, an increase in the rate of herpes zoster infections was reported in 2.5% of siponimod-treated patients compared to 0.7% of patients receiving placebo. Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating siponimod (see Vaccinations below).
Progressive Multifocal Leukoencephalopathy
- Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
- No cases of PML have been reported in siponimod-treated patients in the development program; however, PML has been reported in patients treated with a S1P receptor modulator and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with siponimod should be suspended until PML has been excluded.
Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or Immunosuppressive Therapies
- Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be coadministered with caution because of the risk of additive immune system effects during such therapy.
Vaccinations
- Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating siponimod treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with siponimod, following which initiation of treatment with siponimod should be postponed for 4 weeks to allow the full effect of vaccination to occur.
- The use of live attenuated vaccines should be avoided while patients are taking siponimod and for 4 weeks after stopping treatment.
- Vaccinations may be less effective if administered during siponimod treatment. Siponimod treatment discontinuation 1 week prior to and until 4 weeks after a planned vaccination is recommended.
- Macular edema was reported in 1.8% of siponimod-treated patients compared to 0.2% of patients receiving placebo. The majority of cases occurred within the first four months of therapy.
- An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients before starting treatment and at any time if there is any change in vision while taking siponimod.
- Continuation of siponimod therapy in patients with macular edema has not been evaluated. A decision on whether or not siponimod should be discontinued needs to take into account the potential benefits and risks for the individual patient.
Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus
- Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during siponimod therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In the clinical trial experience in adult patients with all doses of siponimod, the rate of macular edema was approximately 10% in MS patients with a history of uveitis or diabetes mellitus versus 2% in those without a history of these diseases. In addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations.
- Since initiation of siponimod treatment results in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of siponimod.
- Siponimod was not studied in patients who had:
In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization
New York Heart Association Class II-IV heart failure
Cardiac conduction or rhythm disorders, including complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, sick sinus syndrome, Mobitz type II second degree AV-block or higher grade AV-block (either history or observed at screening), unless patient has a functioning pacemaker
Significant QT prolongation (QTc greater than 500 msec)
Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
- In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization
- New York Heart Association Class II-IV heart failure
- Cardiac conduction or rhythm disorders, including complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, sick sinus syndrome, Mobitz type II second degree AV-block or higher grade AV-block (either history or observed at screening), unless patient has a functioning pacemaker
- Significant QT prolongation (QTc greater than 500 msec)
- Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
Reduction in Heart Rate
- After the first titration dose of siponimod, the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 5-6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation.
- In Study 1, bradycardia occurred in 4.4% of siponimod-treated patients compared to 2.9% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention. Heart rates below 40 bpm were rarely observed.
Atrioventricular Conduction Delays
- Initiation of siponimod treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. The AV conduction delays manifested in most of the cases as first-degree AV block (prolonged PR interval on ECG), which occurred in 5.1% of siponimod-treated patients and in 1.9% of patients receiving placebo in Study 1. Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time of treatment initiation with siponimod in less than 1.7% of patients in clinical trials. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, rarely required treatment with atropine, and did not require discontinuation of siponimod treatment.
- If treatment with siponimod is considered, advice from a cardiologist should be sought:
In patients with significant QT prolongation (QTc greater than 500 msec)
In patients with arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
In patients with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension
In patients with a history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block
- In patients with significant QT prolongation (QTc greater than 500 msec)
- In patients with arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
- In patients with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension
- In patients with a history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block
Treatment-Initiation Recommendations
- Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present.
- In all patients, a dose titration is recommended for initiation of siponimod treatment to help reduce cardiac effects.
- In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first-dose monitoring is recommended.
- Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, siponimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.
- Use of siponimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.
- Experience with siponimod is limited in patients receiving concurrent therapy with drugs that decrease heart-rate (e.g., beta-blockers, calcium channel blockers - diltiazem and verapamil, and other drugs that may decrease heart rate, such as ivabradine and digoxin). Concomitant use of these drugs during siponimod initiation may be associated with severe bradycardia and heart block.
For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing siponimod treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 50 bpm. Treatment with siponimod can then be initiated and treatment with a beta-blocker can be reinitiated after siponimod has been up-titrated to the target maintenance dosage.
For patients taking other drugs that decrease heart rate, treatment with siponimod should generally not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate.
- For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing siponimod treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 50 bpm. Treatment with siponimod can then be initiated and treatment with a beta-blocker can be reinitiated after siponimod has been up-titrated to the target maintenance dosage.
- For patients taking other drugs that decrease heart rate, treatment with siponimod should generally not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate.
Missed Dose During Treatment Initiation and Reinitiation of Therapy Following Interruption
- If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.
- Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in siponimod-treated patients as early as 3 months after treatment initiation. In a placebo-controlled trial in adult patients, the decline in absolute FEV1 from baseline compared to placebo was 88 mL [95% confidence interval (CI): 139, 37] at 2 years. The mean difference between siponimod-treated patients and patients receiving placebo in percent predicted FEV1 at 2 years was 2.8% (95% CI: -4.5, -1.0). There is insufficient information to determine the reversibility of the decrease in FEV1 after drug discontinuation. In Study 1, five patients discontinued siponimod because of decreases in pulmonary function testing. Siponimod has been tested in MS patients with mild to moderate asthma and chronic obstructive pulmonary disease. The changes in FEV1 were similar in this subgroup compared with the overall population. Spirometric evaluation of respiratory function should be performed during therapy with siponimod if clinically indicated.
- Elevations of transaminases may occur in siponimod-treated patients. Recent (i.e., within last 6 months) transaminase and bilirubin levels should be reviewed before initiation of siponimod therapy.
- In Study 1, elevations in transaminases and bilirubin were observed in 10.1% of siponimod-treated patients compared to 3.7% of patients receiving placebo, mainly because of transaminase [alanine aminotransferase/aspartate aminotransferase/gamma-glutamyltransferase (ALT/AST/GGT)] elevations.
- In Study 1, ALT or AST increased to three and five times the upper limit of normal (ULN) in 5.6% and 1.4% of siponimod-treated patients, respectively, compared to 1.5% and 0.5% of patients receiving placebo, respectively. ALT or AST increased eight and ten times ULN in siponimod-treated patients (0.5% and 0.2%, respectively) compared to no patients receiving placebo. The majority of elevations occurred within 6 months of starting treatment. ALT levels returned to normal within approximately 1 month after discontinuation of siponimod. In clinical trials, siponimod was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic dysfunction.
- Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should have liver enzymes checked. siponimod should be discontinued if significant liver injury is confirmed.
- Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking siponimod, caution should be exercised when using siponimod in patients with a history of significant liver disease.
- In Study 1, siponimod-treated patients had an average increase over placebo of approximately 3 mmHg in systolic pressure and 1.2 mmHg in diastolic pressure, which was first detected after approximately 1 month of treatment initiation and persisted with continued treatment. Hypertension was reported as an adverse reaction in 12.5% of siponimod-treated patients and in 9.2% of patients receiving placebo. Blood pressure should be monitored during treatment with siponimod and managed appropriately.
- Based on animal studies, siponimod may cause fetal harm. Because it takes approximately 10 days to eliminate siponimod from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 10 days after stopping siponimod treatment.
- Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for siponimod-treated patients in the development program. However, should a siponimod-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider a MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, siponimod should be discontinued.
- When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating siponimod.
- Initiating treatment with siponimod after treatment with alemtuzumab is not recommended.
- Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping siponimod treatment. Patients should be observed for a severe increase in disability upon siponimod discontinuation and appropriate treatment should be instituted, as required.
- After stopping siponimod therapy, siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod.
- Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy. However, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied 3-4 weeks after the last dose of siponimod.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reactions 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.
- A total of 1737 MS patients have received siponimod at doses of at least 2 mg daily. These patients were included in Study 1 and in a Phase 2 placebo-controlled study in patients with MS. In Study 1, 67% of siponimod-treated patients completed the double-blind part of the study, compared to 59.0% of patients receiving placebo. Adverse events led to discontinuation of treatment in 8.5% of siponimod-treated patients, compared to 5.1% of patients receiving placebo. The most common adverse reactions (incidence at least 10%) in siponimod-treated patients in Study 1 were headache, hypertension, and transaminase increases.
- Table 3 lists adverse reactions that occurred in at least 5% of siponimod-treated patients and at a rate at least 1% higher than in patients receiving placebo.
- The following adverse reactions have occurred in less than 5% of siponimod-treated patients but at a rate at least 1% higher than in patients receiving placebo: herpes zoster, lymphopenia, seizure, tremor, macular edema, AV block (1st and 2nd degree), asthenia, and pulmonary function test decreased.
Seizures
- In Study 1, cases of seizures were reported in 1.7% of siponimod-treated patients, compared to 0.4% in patients receiving placebo. It is not known whether these events were related to the effects of MS, to siponimod, or to a combination of both.
Respiratory Effects
- Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) were observed in patients treated with siponimod
Vascular Events
- Vascular events, including ischemic strokes, pulmonary embolisms, and myocardial infarctions, were reported in 3.0% of siponimod-treated patients compared to 2.6% of patients receiving placebo. Some of these events were fatal. Physicians and patients should remain alert for the development of vascular events throughout treatment, even in the absence of previous vascular symptoms. Patients should be informed about the symptoms of cardiac or cerebral ischemia caused by vascular events and the steps to take if they occur.
Malignancies
- Malignancies such as malignant melanoma in situ and seminoma were reported in siponimod-treated patients in Study 1. An increased risk of cutaneous malignancies has been reported in association with another S1P modulator.
## Postmarketing Experience
There is limited information regarding Siponimod Postmarketing Experience in the drug label.
# Drug Interactions
- Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration.
- When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.
- Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with siponimod after alemtuzumab is not recommended.
- Siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.
- Siponimod has not been studied in patients taking QT prolonging drugs.
- Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with siponimod is considered, advice from a cardiologist should be sought.
- Because of the potential additive effects on heart rate, treatment with siponimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (e.g., verapamil, diltiazem), or other drugs that may decrease heart rate (e.g., ivabradine, digoxin). If treatment with siponimod is considered, advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering drugs or appropriate monitoring for treatment initiation.
- Caution should be applied when siponimod is initiated in patients receiving treatment with a beta-blocker because of the additive effects on lowering heart rate; temporary interruption of the beta-blocker treatment may be needed prior to initiation of siponimod. Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod.
- During and for up to one month after discontinuation of treatment with siponimod, vaccinations may be less effective; therefore siponimod treatment should be paused 1 week prior and for 4 weeks after vaccination.
- The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during siponimod treatment and for up to 4 weeks after discontinuation of treatment with siponimod.
- Because of a significant increase in exposure to siponimod, concomitant use of siponimod and drugs that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g., fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate - moderate or strong CYP3A4 inhibitor.
- Caution should be exercised for concomitant use of siponimod with moderate CYP2C9 inhibitors.
- Because of a significant decrease in siponimod exposure, concomitant use of siponimod and drugs that cause moderate CYP2C9 and strong CYP3A4 induction is not recommended for all patients. This concomitant drug regimen can consist of moderate CYP2C9/strong CYP3A4 dual inducer (e.g., rifampin or carbamazepine) or a moderate CYP2C9 inducer in combination with a separate strong CYP3A4 inducer.
- Caution should be exercised for concomitant use of siponimod with moderate CYP2C9 inducers.
- Concomitant use of siponimod and moderate (e.g., modafinil, efavirenz) or strong CYP3A4 inducers is not recommended for patients with CYP2C9*1/*3 and*2/*3 genotype.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no adequate data on the developmental risk associated with the use of siponimod in pregnant women. Based on animal data and its mechanism of action, siponimod can cause fetal harm when administered to a pregnant woman (see Data). Reproductive and developmental studies in pregnant rats and rabbits have demonstrated siponimod-induced embryotoxicity and fetotoxicity in rats and rabbits and teratogenicity in rats. Increased incidences of post-implantation loss and fetal abnormalities (external, urogenital and skeletal) in rat and of embryo-fetal deaths, abortions and fetal variations (skeletal and visceral) in rabbit were observed following prenatal exposure to siponimod starting at a dose 2 times the exposure in humans at the highest recommended dose of 2 mg/day.
- In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Animal Data
- When siponimod (0, 1, 5, or 40 mg/kg) was orally administered to pregnant rats during the period of organogenesis, post implantation loss and fetal malformations (visceral and skeletal) were increased at the lowest dose tested, the only dose with fetuses available for evaluation. A no-effect dose for adverse effects on embryo-fetal development in rats was not identified. Plasma exposure AUC at the lowest dose tested was approximately 18 times that in humans at the recommended human dose (RHD) of 2 mg/day.
- When siponimod (0, 0.1, 1, or 5 mg/kg) was orally administered to pregnant rabbits during the period of organogenesis, embryolethality and increased incidences of fetal skeletal variations were observed at all but the lowest dose tested. Plasma exposure (AUC) at the no-effect dose (0.1 mg/kg) for adverse effects on embryo-fetal development in rabbits is less that than in humans at the RHD.
- When siponimod (0, 0.05, 0.15, or 0.5 mg/kg) was orally administered to female rats throughout pregnancy and lactation, increased mortality, decreased body weight, and delayed sexual maturation were observed in the offspring at all but the lowest dose tested. An increase in malformations was observed at all doses. A no-effect dose for adverse effects on pre- and postnatal development in rats was not identified. The lowest dose tested (0.05 mg/kg) is less than the RHD, on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Siponimod in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Siponimod during labor and delivery.
### Nursing Mothers
- There are no data on the presence of siponimod in human milk, the effects of siponimod on the breastfed infant, or the effects of the drug on milk production. A study in lactating rats has shown excretion of siponimod and/or its metabolites in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for siponimod and any potential adverse effects on the breastfed infant from siponimod or from the underlying maternal condition.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of siponimod did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Siponimod with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Siponimod with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Siponimod in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Siponimod in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Before initiation of siponimod treatment, women of childbearing potential should be counselled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with siponimod. Since it takes approximately 10 days to eliminate the compound from the body after stopping treatment, the potential risk to the fetus may persist and women should use effective contraception during this period.
### Immunocompromised Patients
There is no FDA guidance one the use of Siponimod in patients who are immunocompromised.
### CYP2C9 Genotype
Before initiation of treatment with siponimod, test patients to determine CYP2C9 genotype. Siponimod is contraindicated in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype), which is approximately 0.4%-0.5% of Caucasians and less in others, because of substantially elevated siponimod plasma levels. Siponimod dosage adjustment is recommended in patients with CYP2C9*1/*3 or *2/*3 genotype because of an increase in exposure to siponimod.
# Administration and Monitoring
### Administration
Before initiation of treatment with siponimod, assess the following:
CYP2C9 Genotype Determination
- Test patients for CYP2C9 variants to determine CYP2C9 genotype. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available.
Complete Blood Count
- Review results of a recent complete blood count (CBC).
Ophthalmic Evaluation
- Obtain an evaluation of the fundus, including the macula
Cardiac Evaluation
- Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist and first-dose monitoring is recommended.
- Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction.
Current or Prior Medications
- If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with siponimod.
Vaccinations
- Test patients for antibodies to varicella zoster virus (VZV) before initiating siponimod; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with siponimod.
Liver Function Tests
- Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels
Maintenance Dosage
- After treatment titration (see Treatment Initiation), the recommended maintenance dosage of siponimod is 2 mg taken orally once daily starting on Day 6. Dosage adjustment is required in patients with a CYP2C9*1/*3 or *2/*3 genotype.
Treatment Initiation
- Initiate siponimod with a 5-day titration, as shown in Table 1. A starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage
- If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.
Maintenance Dosage
- In patients with a CYP2C9*1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of siponimod is 1 mg taken orally once daily starting on Day 5.
Treatment Initiation
- Initiate siponimod with a 4-day titration, as shown in Table 2. Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage.
- If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.
### Monitoring
- Because initiation of siponimod treatment results in a decrease in heart rate (HR), first-dose 6 hour monitoring is recommended for patients with sinus bradycardia [HR less than 55 beats per minute (bpm)], first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure.
First Dose 6-Hour Monitoring
- Administer the first dose of siponimod in a setting where resources to appropriately manage symptomatic bradycardia are available. Monitor patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain an ECG in these patients at the end of the Day 1 observation period.
Additional Monitoring After 6-Hour Monitoring
- If any of the following abnormalities are present after 6 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves:
The heart rate 6 hours postdose is less than 45 ppm
The heart rate 6 hours postdose is at the lowest value postdose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred
The ECG 6 hours postdose shows new onset second-degree or higher AV block
- The heart rate 6 hours postdose is less than 45 ppm
- The heart rate 6 hours postdose is at the lowest value postdose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred
- The ECG 6 hours postdose shows new onset second-degree or higher AV block
- If postdose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 6 hours post-dose shows new onset second degree or higher AV block or QTc greater than or equal to 500 msec, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required. If pharmacological treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.
- Advice from a cardiologist should be sought to determine the most appropriate monitoring strategy (which may include overnight monitoring) during treatment initiation, if treatment with siponimod is considered in patients:
With some preexisting heart and cerebrovascular conditions
With a prolonged QTc interval before dosing or during the 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de points
Receiving concurrent therapy with drugs that slow heart rate or AV conduction
- With some preexisting heart and cerebrovascular conditions
- With a prolonged QTc interval before dosing or during the 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de points
- Receiving concurrent therapy with drugs that slow heart rate or AV conduction
- After the initial titration is complete, if siponimod treatment is interrupted for 4 or more consecutive daily doses, reinitiate treatment with Day 1 of the titration regimen; also complete first-dose monitoring in patients for whom it is recommended.
# IV Compatibility
There is limited information regarding the compatibility of Siponimod and IV administrations.
# Overdosage
- In patients with overdosage of siponimod, it is important to observe for signs and symptoms of bradycardia, which may include overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed.
- There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would result in meaningful removal of siponimod from the body. The decrease in heart rate induced by siponimod can be reversed by atropine or isoprenaline.
# Pharmacology
## Mechanism of Action
- Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to S1P receptors 1 and 5. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.
## Structure
## Pharmacodynamics
Immune System
- Siponimod induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose, caused by the reversible sequestration of lymphocytes in lymphoid tissues.
- With continued daily dosing, the lymphocyte count continues to decrease, reaching a nadir median (90% CI) lymphocyte count of approximately 0.560 (0.271-1.08) cells/nL in a typical CYP2C9*1/*1 or *1/*2, non-Japanese patient, corresponding to 20% to 30% of baseline. Low lymphocyte counts are maintained with chronic daily dosing.
- Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy. After stopping siponimod treatment, residual lowering effects on peripheral lymphocyte count may persist for up to 3-4 weeks after the last dose.
Heart Rate and Rhythm
- Siponimod causes a transient reduction in heart rate and atrioventricular conduction upon treatment initiation. The maximum decline in heart rate is seen in the first 6 hours post dose. Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by siponimod treatment.
- A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of siponimod, which plateaued at doses greater than or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses) were detected at a higher incidence under siponimod treatment, compared to placebo.
- No second-degree AV blocks of Mobitz type II or higher degree were observed. Most AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with notably higher incidence under non-titrated conditions compared to dose titration conditions.
- The decrease in heart rate induced by siponimod can be reversed by atropine or isoprenaline.
Beta-Blockers
- The negative chronotropic effect of coadministration of siponimod and propranolol was evaluated in a dedicated pharmacodynamics (PD)/safety study. The addition of propranolol on top of siponimod at steady-state had less pronounced negative chronotropic effects (less than additive effect) than the addition of siponimod to propranolol at steady state (additive HR effect)
Cardiac Electrophysiology
- In a thorough QT study with doses of 2 mg (recommended dose) and 10 mg (five times the recommended dose) siponimod at steady-state, siponimod treatment resulted in a prolongation of QTc , with the maximum mean (upper bound of the two-sided 90% CI) of 7.8 (9.93) ms at 2 mg dose and 7.2 (9.72) ms at 10 mg dose. There was an absence of dose- and exposure-response relationship for QTc effects with the 5-fold dose and exposures achieved by the supratherapeutic dose. No subject had absolute QTcF greater than 480 ms or ΔQTcF greater than 60 ms for siponimod treatment.
Pulmonary Function
- Dose-dependent reductions in absolute forced expiratory volume over 1 second were observed in siponimod-treated patients and were greater than in patients taking placebo.
## Pharmacokinetics
- Siponimod concentration increases in an apparent dose-proportional manner after multiple once-daily doses of siponimod 0.3 mg to 20 mg. Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing, and steady-state levels are approximately 2-3-fold greater than the initial dose. An up-titration regimen is used to reach the clinical therapeutic dose of siponimod of 2 mg after 6 days, and 4 additional days of dosing are required to reach the steady-state-plasma concentrations.
Absorption
- The time (Tmax) to reach maximum plasma concentrations (Cmax) after oral administration of immediate release oral dosage forms of siponimod was about 4 hours (range 3-8 hours). Siponimod absorption is extensive (greater than or equal to 70%, based on the amount of radioactivity excreted in urine and the amount of metabolites in feces extrapolated to infinity). The absolute oral bioavailability of siponimod is approximately 84%. After administration of siponimod 2 mg once-daily over 10 days, a mean Cmax of 30.4 ng/mL and mean area under plasma concentration-time curve over dosing interval (AUCtau) of 558 h*ng/mL were observed on day 10. Steady-state was reached after approximately 6 days of once-daily administration of siponimod.
Food Effect
- Food intake resulted in delayed absorption (the median Tmax increased by approximately 2-3 hours). Food intake had no effect on the systemic exposure of siponimod (Cmax and AUC). Therefore, siponimod may be taken without regard to meals.
Distribution
- Siponimod distributes to body tissues with a moderate mean volume of distribution of 124 L. Siponimod fraction found in plasma is 68% in humans. Animal studies show that siponimod readily crosses the blood-brain-barrier. Protein binding of siponimod is greater than 99.9% in healthy subjects and in hepatic and renal impaired patients.
Elimination
Metabolism
- Siponimod is extensively metabolized, mainly via CYP2C9 (79.3%), followed by CYP3A4 (18.5%). The pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and the safety of siponimod in humans.
Excretion
- An apparent systemic clearance (CL/F) of 3.11 L/h was estimated in MS patients. The apparent elimination half-life is approximately 30 hours.
- Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine.
Specific Populations
Male and Female Patients
- Gender has no influence on siponimod pharmacokinetics (PK).
Racial or Ethnic Groups
- The single-dose PK parameters were not different between Japanese and Caucasians healthy subjects, indicating absence of ethnic sensitivity on the PK of siponimod.
Patients with Renal Impairment
- No dose adjustments are needed in patients with renal impairment. Mean siponimod half-life and Cmax (total and unbound) were comparable between subjects with severe renal impairment and healthy subjects. Unbound AUCs were only slightly increased (by 33%), compared to healthy subjects, and it is not expected to be clinically significant. The effects of end-stage renal disease or hemodialysis on the PK of siponimod has not been studied. Due to the high plasma protein binding (greater than 99.9%) of siponimod, hemodialysis is not expected to alter the total and unbound siponimod concentration and no dose adjustments are anticipated based on these considerations.
Patients with Hepatic Impairment
- No dose adjustments for siponimod are needed in patients with hepatic impairment. The unbound siponimod AUC parameters are 15% and 50% higher in subjects with moderate and severe hepatic impairment, respectively, in comparison with healthy subjects for the 0.25 mg single dose studied. The increased unbound siponimod AUC in subjects with moderate and severe hepatic impairment is not expected to be clinically significant. The mean half-life of siponimod was unchanged in hepatic impairment.
Drug Interaction Studies
Siponimod (and Metabolites M3, M17) as a Causative Agent of Interaction
- In vitro investigations indicated that siponimod and its major systemic metabolites M3 and M17 do not show any clinically relevant drug-drug interaction potential at the therapeutic dose of 2 mg once-daily for all investigated CYP enzymes and transporters.
Siponimod as an Object of Interaction
- CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidative metabolism pathways to overall elimination. Physiologically based PK modeling indicates a differential CYP2C9 genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9 metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators on siponimod exposure is anticipated.
Coadministration of Siponimod with CYP2C9 and CYP3A4 Inhibitors
- The coadministration of fluconazole (moderate CYP2C9 and CYP3A4 dual inhibitor) 200 mg daily at steady-state and a single dose of siponimod 4 mg in CYP2C9*1/*1 healthy volunteers led to a 2-fold increase in the AUC of siponimod. Mean siponimod terminal half-life was increased by 50%. Fluconazole led to a 2- to 4-fold increase in the AUCtau,ss of siponimod across different CYP2C9 genotypes, according to in silica evaluation.
Coadministration of siponimod with CYP2C9 and CYP3A4 Inducers
- The coadministration of siponimod 2 mg daily in the presence of 600 mg daily doses of rifampin (strong CYP3A4 and moderate CYP2C9 dual inducer) decreased siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively in CY2C9*1/*1 subjects. Rifampin and efavirenz (moderate CYP3A4 inducer) reduced the AUCtau,ss of siponimod by up to 78% and up to 52%, respectively, across CYP2C9 genotypes, according to in silica evaluation.
Oral Contraceptives
- The effects of coadministration of siponimod 2 mg and 4 mg (twice the recommended dosage) once daily with a monophonic oral contraceptive (OC) containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were assessed in 24 healthy female subjects (18 to 40 years of age; CYP2C9*1/*1 genotype). There were no clinically relevant effects on the PK or PD of the OC. No interaction studies have been performed with OCs containing other progestagens; however, an effect of siponimod on their exposure is not expected.
## Nonclinical Toxicology
Carcinogenesis
- Oral carcinogenicity studies of spinomod were conducted in mice and rats. In mice administered siponimod (0, 2, 8, or 25 mg/kg/day) for up to 104 weeks, there was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately 5 times the recommended human dose (RHD) of 2 mg/day, on a body surface area (mg/m2) basis.
- In rats, administration of siponimod (0, 10, 30, or 90 mg/kg/day in males; 0, 3, 10, or 30 mg/kg/day in females) for up to 104 weeks, there was an increase in thyroid follicular cell adenoma and combined thyroid follicular cell adenoma and carcinoma in males at the highest dose tested. These findings are considered secondary to liver enzyme induction in rats and are not considered relevant to humans. Plasma siponimod exposure (AUC) at the highest dose tested is approximately 200 times that in humans at the RHD.
Mutagenesis
- Siponimod was negative in a battery of in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays.
Impairment of Fertility
- When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) prior to and throughout the mating period, there was a dose-related increase in precoital interval at all doses. A decrease in implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were observed at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times the RHD on a mg/m2 basis.
- When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were observed up to the highest dose tested (1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose tested is approximately 16 times that in humans at the RHD.
# Clinical Studies
- The efficacy of siponimod was demonstrated in Study 1, a randomized, double-blind, parallel-group, placebo-controlled, time-to-event study in patients with secondary progressive multiple sclerosis (SPMS) who had evidence of disability progression in the prior 2 years, no evidence of relapse in 3 months prior to study enrollment, and an Expanded Disability Status Scale (EDSS) score of 3.0-6.5 at study entry (NCT 01665144).
- Patients were randomized to receive either once daily siponimod 2 mg or placebo, beginning with a dose titration. Evaluations were performed at screening, every 3 months during the study, and at the time of a suspected relapse. MRI evaluations were performed at screening and every 12 months.
- The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP), defined as at least a 1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5 or higher) sustained for 3 months. A prespecified hierarchical analysis consisted of the primary endpoint and 2 secondary endpoints, the time to 3-month confirmed worsening of at least 20% from baseline on the timed 25-foot walk test and the change from baseline in T2 lesion volume. Additional endpoints included annualized relapse rate (relapses/year) and MRI measures of inflammatory disease activity.
- Study duration was variable for individual patients (median study duration was 21 months, range 1 day-37 months).
- Study 1 randomized 1651 patients to either siponimod 2 mg (N = 1105) or placebo (N = 546); 82% of siponimod-treated patients and 78% of placebo-treated patients completed the study. Median age was 49.0 years, 95% of patients were white, and 60% female. The median disease duration was 16.0 years, and median EDSS score at baseline was 6.0 (56% of patients had ≥ 6.0 EDSS at baseline); 36% of patients had one or more relapses in the 2 years prior to study entry; 22% of those patients with available imaging had one or more gadolinium-enhancing lesions on their baseline MRI scan; 78% of patients had been previously treated with an MS therapy.
- Results are presented in Table 4. Siponimod was superior to placebo in reducing the risk of confirmed disability progression, based on a time-to-event analysis (hazard ratio 0.79, p < 0.0134; see Figure 1). Siponimod did not significantly delay the time to 20% deterioration in the timed 25-foot walk, compared to placebo. Patients treated with siponimod had a 55% relative reduction in annualized relapse rate, compared to patients on placebo (nominal p-value < 0.0001). The absolute reduction in the annualized relapse rate was 0.089. Although siponimod had a significant effect on disability progression compared to placebo in patients with active SPMS (e.g., SPMS patients with an MS relapse in the 2 years prior to the study), the effect of siponimod in patients with non-active SPMS was not statistically significant (see Figure 2).
# How Supplied
Siponimod film-coated tablets are supplied as follows:
- Starter Pack* – blister card of twelve 0.25 mg tablets in a calendarized blister wallet
- Bottle of 28 tablets
- Bottle of 30 tablets
## Storage
Unopened Containers
- Store unopened containers of siponimod 0.25 mg and 2 mg film-coated tablets in a refrigerator between 2°C to 8°C (36°F to 46°F).
Opened Containers:
Starter Pack/Blister Card
- Siponimod 0.25 mg film-coated tablets in the Starter Pack may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 1 week after opening the blister. Store in original container.
Bottles
- Siponimod 0.25 mg and 2 mg film-coated tablets in bottles may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 1 month after opening the bottles.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).
- Tell patients not to discontinue siponimod without first discussing this with the prescribing physician. Advise patients to contact their physician if they accidentally take more siponimod than prescribed.
Risk of Infections
- Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking siponimod, and that they should contact their physician if they develop symptoms of infection. Advise patients that the use of some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with siponimod and siponimod should be paused 1 week prior and until 4 weeks after a planned vaccination. Recommend that patients postpone treatment with siponimod for at least 1 month after VZV vaccination. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.
Macular Edema
- Advise patients that siponimod may cause macular edema, and that they should contact their physician if they experience any changes in their vision while taking siponimod. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased.
Cardiac Effects
- Advise patients that initiation of siponimod treatment results in transient decrease in heart rate. Inform patients that to reduce this effect, dosage titration is required. Advise patients that dosage titration is also required if a dose is missed for more than 24 hours during the titration or if 4 or more consecutive daily maintenance doses are missed. Inform certain patients with certain pre-existing cardiac conditions that they will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose and after reinitiation if treatment is interrupted or discontinued for certain periods.
Respiratory Effects
- Advise patients that they should contact their physician if they experience new onset or worsening of dyspnea.
Liver Injury
- Inform patients that siponimod may increase liver enzymes. Advise patient that they should contact their physician if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during treatment.
Pregnancy and Fetal Risk
- Inform patients that, based on animal studies siponimod may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with siponimod and for 10 days after stopping siponimod. Advise a female patient to immediately inform that prescriber if she is pregnant or planning to become pregnant.
Posterior Reversible Encephalopathy Syndrome
- Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological sequelae.
Severe Increase in Disability After Stopping Siponimod
- Inform patients that severe increase in disability has been reported after discontinuation of another sphingosine 1-phosphate (S1P) receptor modulator like siponimod. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of siponimod.
Immune System Effects After Stopping Siponimod
- Advise patients that siponimod continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3-4 weeks after the last dose.
Storage and Handling
- Instruct patients to store any unopened containers of siponimod in a refrigerator. Inform patients that opened starter packs may be stored at room temperature for 1 week and opened bottles may be stored at room temperature for 1 month.
# Precautions with Alcohol
Alcohol-Siponimod interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Mayzent
# Look-Alike Drug Names
There is limited information regarding Siponimod Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mayzent | |
6f99c9944a6be481ddd4b7be9bf94a87310bc492 | wikidoc | Medazepam | Medazepam
# Overview
Medazepam is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties. It is known by the following brand names: Azepamid, Nobrium, Tranquirax (mixed with Bevonium), Rudotel, Raporan, Ansilan and Mezapam. Medazepam is a long-acting benzodiazepine drug. The half-life of medazepam is 36 – 200 hours.
# Pharmacology
Benzodiazepine drugs including medazepam increase the inhibitory processes in the cerebral cortex by allosteric modulation of the GABA receptor. Benzodiazepines may also act via micromolar benzodiazepine-binding sites as Ca2+ channel blockers and significantly inhibited depolarization-sensitive calcium uptake in experiments with cell components from rat brains. This has been conjectured as a mechanism for high dose effects against seizures in a study. It has major active benzodiazepine metabolites, which gives it a more prolonged therapeutic effects after administration.
# Chemistry
Medazepam can be synthesized in various ways. One is via the reduction of the carbonyl group in diazepam (lacking methyl in Ex 1) by lithium aluminium hydride. N.B. If diazepam is reduced with LAH as in Ex 9, actually the product produced is 7-chloro-1-methyl-5-phenyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine, not medazepam.
A second way of making medazepam consists of the initial reduction of the carbonyl group by lithium aluminum hydride into 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one—the first intermediate product in the synthesis of diazepam—which is synthesized by the cyclocondensation of 2-amino-5-chlorobenzophenone with glycine ethyl ester into 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine, and the subsequent methylation of the secondary amine nitrogen atom of the resulting product by methyl iodide, using sodium hydride as a base.
A third method of making medazepam consists of a new way of making 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine, which consists in heterocyclization of
1-(2,5-dichlorophenyl)-1-phenylimine with ethylenediamine. The starting 1-(2,5-dichlorophenyl)-1-phenylimine is synthesized by the reaction of 2,5-dichlorobenzonitrile
with phenylmagnesium bromide.
A fourth method of making medazepam from 4-chloro-N-methylaniline is suggested. The last is reacted with aziridine (or ethylene imine) in the presence of aluminum chloride, giving N-(4-chlorophenyl)-N-methylethylenediamine. Acylation of the resulting product with BzCl gives the respective amide, which cyclizes into the desired medazepam using phosphorus oxychloride.
A fifth method also exists: | Medazepam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Medazepam is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties. It is known by the following brand names: Azepamid, Nobrium, Tranquirax (mixed with Bevonium), Rudotel, Raporan, Ansilan and Mezapam.[1] Medazepam is a long-acting benzodiazepine drug. The half-life of medazepam is 36 – 200 hours.[2]
# Pharmacology
Benzodiazepine drugs including medazepam increase the inhibitory processes in the cerebral cortex by allosteric modulation of the GABA receptor.[3] Benzodiazepines may also act via micromolar benzodiazepine-binding sites as Ca2+ channel blockers and significantly inhibited depolarization-sensitive calcium uptake in experiments with cell components from rat brains. This has been conjectured as a mechanism for high dose effects against seizures in a study.[4] It has major active benzodiazepine metabolites, which gives it a more prolonged therapeutic effects after administration.[5]
# Chemistry
Medazepam can be synthesized in various ways. One is via the reduction of the carbonyl group in diazepam (lacking methyl in Ex 1) by lithium aluminium hydride. N.B. If diazepam is reduced with LAH as in Ex 9, actually the product produced is 7-chloro-1-methyl-5-phenyl-1,2,4,5-tetrahydro-3H-1,4-benzodiazepine, not medazepam.
A second way of making medazepam consists of the initial reduction of the carbonyl group by lithium aluminum hydride into 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one—the first intermediate product in the synthesis of diazepam—which is synthesized by the cyclocondensation of 2-amino-5-chlorobenzophenone with glycine ethyl ester into 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine, and the subsequent methylation of the secondary amine nitrogen atom of the resulting product by methyl iodide, using sodium hydride as a base.
A third method of making medazepam consists of a new way of making 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine, which consists in heterocyclization of
1-(2,5-dichlorophenyl)-1-phenylimine with ethylenediamine. The starting 1-(2,5-dichlorophenyl)-1-phenylimine is synthesized by the reaction of 2,5-dichlorobenzonitrile
with phenylmagnesium bromide.
A fourth method of making medazepam from 4-chloro-N-methylaniline is suggested. The last is reacted with aziridine (or ethylene imine) in the presence of aluminum chloride, giving N-(4-chlorophenyl)-N-methylethylenediamine.[7] Acylation of the resulting product with BzCl gives the respective amide, which cyclizes into the desired medazepam using phosphorus oxychloride.
A fifth method also exists: | https://www.wikidoc.org/index.php/Medazepam | |
a6a240609a19b95daf67ef82c8199ac2a682bae1 | wikidoc | Physician | Physician
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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The word physician applies to a person who practices some type of medicine. Such practitioners are concerned with maintaining or restoring human health through the study, diagnosis and treatment of disease and injury, through both an area of knowledge — a science — of body systems, their diseases and treatment, and the applied practice — an art or craft — of that knowledge.
# Different meanings of the word "physician"
## "Physician" = any medical practitioner
Physician in the broad sense, usually in North America, now applies to any legally qualified practitioner of medicine. In the United States, the term physician is now commonly used to describe any medical doctor holding the Doctor of Medicine (M.D.) or Doctor of Osteopathic Medicine (D.O.) degree (see below). The American Medical Association, established 1847, uses physician in this broad sense to describe all its members. See the article on Medicine for more information on what physicians (in this broad sense) do in practice.
## "Physician" = specialist (or subspecialist) in internal medicine
However, Physician is still widely used in an older, narrow sense, especially outside North America. In this usage, a physician is a specialist in internal medicine or one of its many sub-specialties (especially as opposed to a specialist in surgery). This traditional meaning of physician still conveys a sense of expertise in treatment by drugs or medications, rather than by the procedures of surgeons.
This older usage is at least six hundred years old in English; physicians and surgeons were once members of separate professions, and traditionally were rivals. The Shorter OED, third edition, gives a Middle English quotation making this contrast, from as early as 1400: "O Lord, whi is it so greet difference betwixe a cirugian and a physician." Henry VIII granted a charter to the Royal College of Physicians (London) in 1518, and granted the Company of Barber/Surgeons (ancestor of the Royal College of Surgeons) its separate charter in 1540. In the same year, the same English monarch established the Regius Professorship of Physic at Cambridge University . Newer universities would probably describe such an academic as a professor of internal medicine. Hence, in the 16th century, physic meant roughly what internal medicine does now.
These days, a specialist physician in this older, narrow sense would probably be described in the United States as a internist (a specialist in internal medicine). The older, narrow usage of physician (= internist) is common in Britain, Ireland, Canada, Australia, Brazil, New Zealand, Japan, South Africa, India, Indonesia, Republic of China, Pakistan, Bangladesh, Sri Lanka, Zimbabwe and Hong Kong. In such places, the terms doctor or medical practitioner are prevalent, to describe any practitioner of medicine (whom an American would likely call a physician, in the newer, broad sense). For information on the work of specialist physicians in the older, narrow sense, see internal medicine, or else visit the web page are Physicians? at The Royal Australasian College of Physicians — the description given here applies fairly well throughout the Commonwealth of Nations. Note that in Commonwealth countries, specialist paediatricians and geriatricians are also described as specialist physicians (who have subspecialized by age of patient rather than by organ system).
## "Physician and Surgeon"
On both sides of the Atlantic, the combined term Physician and Surgeon is a venerable way to describe either a General Practitioner, or else any medical practitioner irrespective of specialty. This usage still shows the older, narrow meaning of physician and preserves the old difference between a physician, as a practitioner of physic, and a surgeon. The term Physician and Surgeon may be used by state medical boards in the USA, and by equivalent bodies in provinces of Canada, to describe any medical practitioner.
## Osteopaths, Chiropractors and Podiatrists
Within the United States, the term physician may also describe Doctors of Osteopathy (D.O.), who are licensed physicians within the USA. However, outside the USA, osteopaths are recognized as complete physicians in only 48 countries. For further information on osteopathy, see the entry on Differences between allopathic and osteopathic medicine.
Those who hold the degrees of Doctor of Chiropractic Medicine (D.C.), Doctor of Naturopathic Medicine (N.D.), or Doctors of Podiatric Medicine (D.P.M.). are physicians according to both the US Federal Government, the Joint Commission (which in 2009 changed its rules to include DC's) and the laws of the vast majority of States. The use of the term "physician" is a legally regulated word, like "university" or "bank", and professional associations do not get to decide who is or is not entitled to use it. Legislatures do.
Like M.D.s or D.O.s, these health care professionals are licensed to diagnose and treat human illnesses. They perform complete physical, orthopedic and neurological examinations, take and interpret their own xrays, and order and interpret laboratory tests, and only then determine if their patient's condition can be resolved within their scope. If not they are trained to refer to another kind of doctor. Despite that they do not prescribe legend drugs, or practice surgery, they have been deemed primary care doctors. Exactly because United States medical boards do not generally give the title Physician and Surgeon, nearly every State now licenses Chiropractic Physicians under their OWN Board. They have served as ringside physicians at boxing meets, and even as Olympic team physicians for both the US and numerous other National Olympic Teams.
Podiatrists perform surgery as well as prescribe legend drugs to their patients.
# Social rôle of physicians
Physicians are traditionally considered to be members of a learned profession, because of the extensive training requirements, and also because of the occupation's special ethical and legal duties.
The practice of medicine has ancient associations with religion and magic; see article on History of medicine.
Physicians commonly enjoy high social status, often combined with expectations of a high and stable income. However, medical practitioners often work long and inflexible hours, with shifts at unsociable times, and may earn less than other professionals whose education is of comparable length.
# Education and training
Medical training and career pathways vary considerably across the world.
## Education of all medical practitioners (physician in the broad sense)
In all developed countries, entry-level medical education programs are tertiary-level courses, undertaken at a medical school attached to a university. Depending on jurisdiction and university, these may be either undergraduate-entry or graduate-entry courses. The former commonly take five or six years. Entrants to graduate-entry courses, usually four or five years, have previously completed a three- or four-year university degree, commonly but by no means always in sciences. Hence, gaining a basic medical degree may take from five to eight or even nine years, depending on jurisdiction and university.
Following completion of entry-level training, newly graduated medical practitioners are often required to undertake a period of supervised practice before full registration is granted, typically one or two years. This may be referred to as "internship" or "conditional registration".
Medical practitioners hold a medical degree specific to the country and sometimes university in which they graduated. This qualifies that doctor to become licensed physicians and surgeons in that country, and sometimes several countries.
## Training of specialists in internal medicine (physician in the narrow sense)
After graduation, any medical practitioner may undertake further training in any particular field, to become a medical specialist. This may take from three to six or more years, depending on speciality and jurisdiction. As explained above, a medical practitioner who completes such training in internal medicine (or in one of its subspecialties) is an internist, or a physician in the older, narrow sense.
In some jurisdictions, speciality training is begun immediately following completion of entry-level training, or even before. In other jurisdictions, junior medical doctors must undertake generalist (unstreamed) training for a number of years before commencing specialization. Hence, depending on jurisdiction, a specialist physician (internist) often does not achieve recognition as a specialist until twelve or even more years after commencing basic medical training.
# Regulation
## Regulation of all medical practitioners (physician in the broad sense)
Among the English-speaking countries, this process is known either as licensure as in the United States, or as registration, eg in the United Kingdom, the Commonwealth and Ireland. Synonyms in use elsewhere include colegiación in Spain, ishi menkyo in Japan, autorisasjon in Norway, Approbation in Germany, and "άδεια εργασίας" in Greece. In France, Italy and Portugal, civilian physicians must be a member of the Order of physicians to practice medicine.
In some countries, including the United Kingdom and Ireland, the profession largely regulates itself, with the government affirming the regulating body's authority. The best known example of this is probably the General Medical Council of Britain. In all countries, the regulating authorities will revoke permission to practice in cases of malpractice or serious misconduct.
In the large English-speaking federations (USA, Canada, Australia), the licensing or registration of medical practitioners is done at a state or provincial level. Australian states usually have a "Medical Board," while Canadian provinces usually have a "College of Physicians and Surgeons." All American states have an agency which is usually called the "Medical Board", although there are alternate names such as "Board of Medicine," "Board of Medical Examiners", "Board of Medical Licensure", "Board of Healing Arts", etc. After graduating from medical school, physicians who wish to practice in the USA usually take standardized exams, such as the USMLE for allopathic physicians or COMLEX-USA for osteopathic physicians, which enable them to obtain a certificate to practice from the appropriate state agency.
## Regulation of specialists in internal medicine (physician in the narrow sense)
Most countries have some method of officially recognizing specialist qualifications in all branches of medicine, including internal medicine. Sometimes, this aims to promote public safety by restricting the use of hazardous treatments. For example, in Australia, only specialist physicians (internists in USA) or specialist dermatologists may lawfully prescribe istretinoin (this is a powerful drug useful in treating severe acne, but may cause severe and varied types of adverse drug reaction). Other reasons for regulating specialists may include: standardization of recognition for hospital employment, restriction on which practitioners are entitled to receive higher insurance payments for specialist services, and, as occasionally alleged, restriction of specialist numbers to reduce competition. | Physician
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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The word physician applies to a person who practices some type of medicine. Such practitioners are concerned with maintaining or restoring human health through the study, diagnosis and treatment of disease and injury, through both an area of knowledge — a science — of body systems, their diseases and treatment, and the applied practice — an art or craft — of that knowledge.
# Different meanings of the word "physician"
## "Physician" = any medical practitioner
Physician in the broad sense, usually in North America, now applies to any legally qualified practitioner of medicine. In the United States, the term physician is now commonly used to describe any medical doctor holding the Doctor of Medicine (M.D.) or Doctor of Osteopathic Medicine (D.O.) degree (see below). The American Medical Association, established 1847, uses physician in this broad sense to describe all its members. See the article on Medicine for more information on what physicians (in this broad sense) do in practice.
## "Physician" = specialist (or subspecialist) in internal medicine
However, Physician is still widely used in an older, narrow sense, especially outside North America. In this usage, a physician is a specialist in internal medicine or one of its many sub-specialties (especially as opposed to a specialist in surgery). This traditional meaning of physician still conveys a sense of expertise in treatment by drugs or medications, rather than by the procedures of surgeons.[1]
This older usage is at least six hundred years old in English; physicians and surgeons were once members of separate professions, and traditionally were rivals. The Shorter OED, third edition, gives a Middle English quotation making this contrast, from as early as 1400: "O Lord, whi is it so greet difference betwixe a cirugian and a physician." [2] Henry VIII granted a charter to the Royal College of Physicians (London) in 1518, and granted the Company of Barber/Surgeons (ancestor of the Royal College of Surgeons) its separate charter in 1540. In the same year, the same English monarch established the Regius Professorship of Physic at Cambridge University [3]. Newer universities would probably describe such an academic as a professor of internal medicine. Hence, in the 16th century, physic meant roughly what internal medicine does now.
These days, a specialist physician in this older, narrow sense would probably be described in the United States as a internist (a specialist in internal medicine). The older, narrow usage of physician (= internist) is common in Britain, Ireland, Canada, Australia, Brazil, New Zealand, Japan, South Africa, India, Indonesia, Republic of China, Pakistan, Bangladesh, Sri Lanka, Zimbabwe and Hong Kong. In such places, the terms doctor or medical practitioner are prevalent, to describe any practitioner of medicine (whom an American would likely call a physician, in the newer, broad sense). For information on the work of specialist physicians in the older, narrow sense, see internal medicine, or else visit the web page are Physicians? at The Royal Australasian College of Physicians — the description given here applies fairly well throughout the Commonwealth of Nations. Note that in Commonwealth countries, specialist paediatricians and geriatricians are also described as specialist physicians (who have subspecialized by age of patient rather than by organ system).
## "Physician and Surgeon"
On both sides of the Atlantic, the combined term Physician and Surgeon is a venerable way to describe either a General Practitioner, or else any medical practitioner irrespective of specialty.[1] This usage still shows the older, narrow meaning of physician and preserves the old difference between a physician, as a practitioner of physic, and a surgeon. The term Physician and Surgeon may be used by state medical boards in the USA, and by equivalent bodies in provinces of Canada, to describe any medical practitioner.
## Osteopaths, Chiropractors and Podiatrists
Within the United States, the term physician may also describe Doctors of Osteopathy (D.O.), who are licensed physicians within the USA. However, outside the USA, osteopaths are recognized as complete physicians in only 48 countries. For further information on osteopathy, see the entry on Differences between allopathic and osteopathic medicine.
Those who hold the degrees of Doctor of Chiropractic Medicine (D.C.), Doctor of Naturopathic Medicine (N.D.), or Doctors of Podiatric Medicine (D.P.M.). are physicians according to both the US Federal Government, the Joint Commission (which in 2009 changed its rules to include DC's) and the laws of the vast majority of States. The use of the term "physician" is a legally regulated word, like "university" or "bank", and professional associations do not get to decide who is or is not entitled to use it. Legislatures do.
Like M.D.s or D.O.s, these health care professionals are licensed to diagnose and treat human illnesses. They perform complete physical, orthopedic and neurological examinations, take and interpret their own xrays, and order and interpret laboratory tests, and only then determine if their patient's condition can be resolved within their scope. If not they are trained to refer to another kind of doctor. Despite that they do not prescribe legend drugs, or practice surgery, they have been deemed primary care doctors. Exactly because United States medical boards do not generally give the title Physician and Surgeon, nearly every State now licenses Chiropractic Physicians under their OWN Board. They have served as ringside physicians at boxing meets, and even as Olympic team physicians for both the US and numerous other National Olympic Teams.
Podiatrists perform surgery as well as prescribe legend drugs to their patients.
# Social rôle of physicians
Physicians are traditionally considered to be members of a learned profession, because of the extensive training requirements, and also because of the occupation's special ethical and legal duties.
The practice of medicine has ancient associations with religion and magic; see article on History of medicine.
Physicians commonly enjoy high social status, often combined with expectations of a high and stable income. However, medical practitioners often work long and inflexible hours, with shifts at unsociable times, and may earn less than other professionals whose education is of comparable length.
# Education and training
Medical training and career pathways vary considerably across the world.
## Education of all medical practitioners (physician in the broad sense)
In all developed countries, entry-level medical education programs are tertiary-level courses, undertaken at a medical school attached to a university. Depending on jurisdiction and university, these may be either undergraduate-entry or graduate-entry courses. The former commonly take five or six years. Entrants to graduate-entry courses, usually four or five years, have previously completed a three- or four-year university degree, commonly but by no means always in sciences. Hence, gaining a basic medical degree may take from five to eight or even nine years, depending on jurisdiction and university.
Following completion of entry-level training, newly graduated medical practitioners are often required to undertake a period of supervised practice before full registration is granted, typically one or two years. This may be referred to as "internship" or "conditional registration".
Medical practitioners hold a medical degree specific to the country and sometimes university in which they graduated. This qualifies that doctor to become licensed physicians and surgeons in that country, and sometimes several countries.
## Training of specialists in internal medicine (physician in the narrow sense)
After graduation, any medical practitioner may undertake further training in any particular field, to become a medical specialist. This may take from three to six or more years, depending on speciality and jurisdiction. As explained above, a medical practitioner who completes such training in internal medicine (or in one of its subspecialties) is an internist, or a physician in the older, narrow sense.
In some jurisdictions, speciality training is begun immediately following completion of entry-level training, or even before. In other jurisdictions, junior medical doctors must undertake generalist (unstreamed) training for a number of years before commencing specialization. Hence, depending on jurisdiction, a specialist physician (internist) often does not achieve recognition as a specialist until twelve or even more years after commencing basic medical training.
# Regulation
## Regulation of all medical practitioners (physician in the broad sense)
Among the English-speaking countries, this process is known either as licensure as in the United States, or as registration, eg in the United Kingdom, the Commonwealth and Ireland. Synonyms in use elsewhere include colegiación in Spain, ishi menkyo in Japan, autorisasjon in Norway, Approbation in Germany, and "άδεια εργασίας" in Greece. In France, Italy and Portugal, civilian physicians must be a member of the Order of physicians to practice medicine.
In some countries, including the United Kingdom and Ireland, the profession largely regulates itself, with the government affirming the regulating body's authority. The best known example of this is probably the General Medical Council of Britain. In all countries, the regulating authorities will revoke permission to practice in cases of malpractice or serious misconduct.
In the large English-speaking federations (USA, Canada, Australia), the licensing or registration of medical practitioners is done at a state or provincial level. Australian states usually have a "Medical Board," while Canadian provinces usually have a "College of Physicians and Surgeons." All American states have an agency which is usually called the "Medical Board", although there are alternate names such as "Board of Medicine," "Board of Medical Examiners", "Board of Medical Licensure", "Board of Healing Arts", etc. After graduating from medical school, physicians who wish to practice in the USA usually take standardized exams, such as the USMLE for allopathic physicians or COMLEX-USA for osteopathic physicians, which enable them to obtain a certificate to practice from the appropriate state agency.
## Regulation of specialists in internal medicine (physician in the narrow sense)
Most countries have some method of officially recognizing specialist qualifications in all branches of medicine, including internal medicine. Sometimes, this aims to promote public safety by restricting the use of hazardous treatments. For example, in Australia, only specialist physicians (internists in USA) or specialist dermatologists may lawfully prescribe istretinoin (this is a powerful drug useful in treating severe acne, but may cause severe and varied types of adverse drug reaction). Other reasons for regulating specialists may include: standardization of recognition for hospital employment, restriction on which practitioners are entitled to receive higher insurance payments for specialist services, and, as occasionally alleged, restriction of specialist numbers to reduce competition. | https://www.wikidoc.org/index.php/Medical_doctor | |
7939d0e319e974752d3e282af45d799b324bc624 | wikidoc | Medrysone | Medrysone
# 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
Medrysone is an ophthalmologic agent that is FDA approved for the treatment of allergic conjunctivitis, vernal conjunctivitis, episcleritis, and epinephrine sensitivity. Common adverse reactions include increased introaocular pressure,anterior uveitis, keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, and ptosis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- HMS® (medrysone ophthalmic suspension) is indicated for the treatment of allergic conjunctivitis, vernal conjunctivitis, episcleritis, and epinephrine sensitivity.
# Dosage
- Shake well before using. Instill one drop into the conjunctival sac up to every four hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Medrysone in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Medrysone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Medrysone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Medrysone in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Medrysone in pediatric patients.
# Contraindications
- HMS® suspension is contraindicated in most viral diseases of the cornea and conjunctiva, including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. HMS® suspension is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids.
# Warnings
- HMS® (medrysone ophthalmic suspension) is not recommended for use in iritis and uveitis as its therapeutic effectiveness has not been demonstrated in these conditions.
- Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in posterior subcapsular cataract formation. Prolonged use may also suppress the host immune response and thus increase the hazard of secondary ocular infections.
- Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation.
- Acute purulent infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication.
- If this product is used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients.
- Steroids should be used with caution in the presence of glaucoma. Intraocular pressure should be checked frequently.
- The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.
- Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is recommended.
- Corticosteroids are not effective in mustard gas keratitis and Sjögren's keratoconjunctivitis.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions include, in decreasing order of frequency, elevation of intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage, posterior subcapsular cataract formation, and delayed wound healing.
- Although systemic effects are extremely uncommon, there have been rare occurrences of systemic hypercorticoidism after use of topical steroids.
- Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis and perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids.
- The development of secondary ocular infection (bacterial, fungal and viral) has occurred. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used.
- Transient burning and stinging upon instillation and other minor symptoms of ocular irritation have been reported with the use of HMS® suspension. Other adverse events reported with the use of HMS® suspension include: allergic reactions, foreign body sensation, and visual disturbance (blurry vision).
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Medrysone in the drug label.
# Drug Interactions
There is limited information regarding Medrysone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Teratogenic effects. Pregnancy Category C. Medrysone has been shown to be embryocidal in rabbits when given in doses 10 and 30 times the human ocular dose. Two drops of medrysone were applied to both eyes of pregnant rabbits 4 times per day on day 6 through 18 of gestation. A significant increase in early resorptions was observed in the treated rabbits. There are no adequate and well-controlled studies of medrysone in pregnant women. Medrysone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Medrysone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Medrysone during labor and delivery.
### Nursing Mothers
- It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from medrysone, 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 3 years have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Medrysone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Medrysone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Medrysone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Medrysone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Medrysone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Medrysone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Medrysone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Medrysone in the drug label.
# Overdosage
- Overdosage will not ordinarily cause acute problems. If accidentally ingested, drink fluids to dilute.
# Pharmacology
## Mechanism of Action
There is limited information regarding Structure of Medrysone in the drug label.
## Structure
- HMS® (medrysone ophthalmic suspension) 1% is a topical anti-inflammatory agent for ophthalmic use.
- Chemical Name:
- 11β-hydroxy-6α-methylpregn-4-ene-3,20-dione
- Structural Formula:
- Contains: Active: Medrysone 1%. Preservative: benzalkonium chloride 0.004%.
- Inactives: edetate disodium; hypromellose; polyvinyl alcohol 1.4%; potassium chloride; purified water; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and sodium hydroxide to adjust the pH (6.2 - 7.5).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Medrysone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Medrysone in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility:
- No studies have been conducted in animals or in humans to evaluate the potential of these effects.
# Clinical Studies
There is limited information regarding Clinical Studies of Medrysone in the drug label.
# How Supplied
- HMS® (medrysone ophthalmic suspension) 1% is supplied sterile in opaque white LDPE plastic bottles with droppers with white high impact polystyrene (HIPS) caps as follows:
## Storage
- Store at temperatures up to 25°C (77°F). Protect from freezing.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients:
- If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician.
- This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children.
# Precautions with Alcohol
- Alcohol-Medrysone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- HMS®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Medrysone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Medrysone is an ophthalmologic agent that is FDA approved for the treatment of allergic conjunctivitis, vernal conjunctivitis, episcleritis, and epinephrine sensitivity. Common adverse reactions include increased introaocular pressure,anterior uveitis, keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, and ptosis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- HMS® (medrysone ophthalmic suspension) is indicated for the treatment of allergic conjunctivitis, vernal conjunctivitis, episcleritis, and epinephrine sensitivity.
# Dosage
- Shake well before using. Instill one drop into the conjunctival sac up to every four hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Medrysone in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Medrysone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Medrysone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Medrysone in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Medrysone in pediatric patients.
# Contraindications
- HMS® suspension is contraindicated in most viral diseases of the cornea and conjunctiva, including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. HMS® suspension is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids.
# Warnings
- HMS® (medrysone ophthalmic suspension) is not recommended for use in iritis and uveitis as its therapeutic effectiveness has not been demonstrated in these conditions.
- Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in posterior subcapsular cataract formation. Prolonged use may also suppress the host immune response and thus increase the hazard of secondary ocular infections.
- Various ocular diseases and long-term use of topical corticosteroids have been known to cause corneal and scleral thinning. Use of topical corticosteroids in the presence of thin corneal or scleral tissue may lead to perforation.
- Acute purulent infections of the eye may be masked or activity enhanced by the presence of corticosteroid medication.
- If this product is used for 10 days or longer, intraocular pressure should be routinely monitored even though it may be difficult in children and uncooperative patients.
- Steroids should be used with caution in the presence of glaucoma. Intraocular pressure should be checked frequently.
- The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.
- Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution; frequent slit lamp microscopy is recommended.
- Corticosteroids are not effective in mustard gas keratitis and Sjögren's keratoconjunctivitis.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions include, in decreasing order of frequency, elevation of intraocular pressure (IOP) with possible development of glaucoma and infrequent optic nerve damage, posterior subcapsular cataract formation, and delayed wound healing.
- Although systemic effects are extremely uncommon, there have been rare occurrences of systemic hypercorticoidism after use of topical steroids.
- Corticosteroid-containing preparations have also been reported to cause acute anterior uveitis and perforation of the globe. Keratitis, conjunctivitis, corneal ulcers, mydriasis, conjunctival hyperemia, loss of accommodation and ptosis have occasionally been reported following local use of corticosteroids.
- The development of secondary ocular infection (bacterial, fungal and viral) has occurred. Fungal and viral infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. The possibility of fungal invasion should be considered in any persistent corneal ulceration where steroid treatment has been used.
- Transient burning and stinging upon instillation and other minor symptoms of ocular irritation have been reported with the use of HMS® suspension. Other adverse events reported with the use of HMS® suspension include: allergic reactions, foreign body sensation, and visual disturbance (blurry vision).
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Medrysone in the drug label.
# Drug Interactions
There is limited information regarding Medrysone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Teratogenic effects. Pregnancy Category C. Medrysone has been shown to be embryocidal in rabbits when given in doses 10 and 30 times the human ocular dose. Two drops of medrysone were applied to both eyes of pregnant rabbits 4 times per day on day 6 through 18 of gestation. A significant increase in early resorptions was observed in the treated rabbits. There are no adequate and well-controlled studies of medrysone in pregnant women. Medrysone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Medrysone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Medrysone during labor and delivery.
### Nursing Mothers
- It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from medrysone, 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 3 years have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Medrysone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Medrysone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Medrysone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Medrysone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Medrysone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Medrysone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Medrysone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Medrysone in the drug label.
# Overdosage
- Overdosage will not ordinarily cause acute problems. If accidentally ingested, drink fluids to dilute.
# Pharmacology
## Mechanism of Action
There is limited information regarding Structure of Medrysone in the drug label.
## Structure
- HMS® (medrysone ophthalmic suspension) 1% is a topical anti-inflammatory agent for ophthalmic use.
- Chemical Name:
- 11β-hydroxy-6α-methylpregn-4-ene-3,20-dione
- Structural Formula:
- Contains: Active: Medrysone 1%. Preservative: benzalkonium chloride 0.004%.
- Inactives: edetate disodium; hypromellose; polyvinyl alcohol 1.4%; potassium chloride; purified water; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and sodium hydroxide to adjust the pH (6.2 - 7.5).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Medrysone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Medrysone in the drug label.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility:
- No studies have been conducted in animals or in humans to evaluate the potential of these effects.
# Clinical Studies
There is limited information regarding Clinical Studies of Medrysone in the drug label.
# How Supplied
- HMS® (medrysone ophthalmic suspension) 1% is supplied sterile in opaque white LDPE plastic bottles with droppers with white high impact polystyrene (HIPS) caps as follows:
## Storage
- Store at temperatures up to 25°C (77°F). Protect from freezing.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients:
- If inflammation or pain persists longer than 48 hours or becomes aggravated, the patient should be advised to discontinue use of the medication and consult a physician.
- This product is sterile when packaged. To prevent contamination, care should be taken to avoid touching the bottle tip to eyelids or to any other surface. The use of this bottle by more than one person may spread infection. Keep bottle tightly closed when not in use. Keep out of the reach of children.
# Precautions with Alcohol
- Alcohol-Medrysone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- HMS®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Medrysone | |
32eb1c83a37fbe36109fbbb8cf494afdb649c1a2 | wikidoc | Medtronic | Medtronic
Medtronic, Inc. (Template:Nyse), based in Fridley, Minnesota, is the world's largest medical technology company. Listed among Fortune 500 companies, Medtronic is a publicly traded company and is listed on the New York Stock Exchange under the symbol MDT. The company was founded in 1949 by Earl Bakken and Palmer Hermundslie and is credited with manufacturing the first wearable artificial pacemakers. However, they started off with much more modest intentions, acting as a repair company, servicing medical equipment in local hospitals. Medtronic's main competitors for cardiac devices are Guidant (now a division of Boston Scientific) and St. Jude Medical.
Medtronic followed a path familiar to technology historians, starting in a garage in northern Minneapolis. The company expanded through the 1950s, mostly selling equipment built by other companies, but some custom hardware was also developed. The employees eventually came to know Dr. C. Walton Lillehei, a noted heart surgeon who was then at the University of Minnesota. Dr. Lillehei was frustrated with the pacemakers of the day, which relied on wall current to operate. This was extremely troublesome because power outages would cause patients to die.
Bakken built a small transistorized pacemaker that could be strapped to the body and powered by batteries. Work into this new field continued, producing an implantable pacemaker in 1960.
The company has continued to innovate in the medical business and is considered an economically-important company for Minnesota. A key attribute in understanding the company is that it remains very focused on the mission originally written by co-founder Earl Bakken in the early-1960s. The first paragraph of the 6 paragraph mission statement reads:
"To contribute to human welfare by application of biomedical engineering in the research, design, manufacture, and sale of instruments or appliances that alleviate pain, restore health, and extend life."
Medtronic makes a wide array of implantable electronic devices, from the relatively common ICD or implantable cardioverter-defibrillator, to devices for managing urinary incontinence and obesity to name just a few.
# Medtronic Diabetes
Medtronic Diabetes is the diabetes management manufacturing and sales division of Medtronic based in Northridge, California. The original company Minimed Technologies was founded in the early 1980s and spun-off from Pacesetter Systems, in order to design a practical insulin pump for lifelong wear. Most devices at the time were either too large or impossible to program and extremely unreliable. The release of the lightweight, menu-driven MiniMed 500 series changed the landscape, and was a major factor in bringing pump usage to the mainstream. By the early 2000s Medtronic had bought out Minimed to form Medtronic Minimed.
Current models consist of the MiniMed Paradigm 522/722. It is the first Insulin Pump which integrates continuous glucose monitoring, allowing patients to see in real time their glucose level. As well as insulin pumps Medtronic Diabetes also makes Continuous Blood Glucose Monitoring Systems (CGMS) for use as a stand alone system or integrated into their Minimed Paradigm 522/722 series pumps. Medtronic Diabetes also makes a large range of accessories and components for their insulin pump and CGMS products.
As of March 2007 the MiniMed name has begun to be absorbed into the parent company, Medtronic. Medtronic has kept the MiniMed name to brand their insulin pumps, for example: The MiniMed Paradigm 722. Medtronic frequently uses Medtronic Diabetes as the name for the division, it is unclear to the extent the division will be integrated into Medtronic, as it still maintains its own website. Many products and marketing material still say Medtronic MiniMed, as the brand is being phased out. | Medtronic
Template:Infobox Company
Medtronic, Inc. (Template:Nyse), based in Fridley, Minnesota, is the world's largest medical technology company. Listed among Fortune 500 companies, Medtronic is a publicly traded company and is listed on the New York Stock Exchange under the symbol MDT. The company was founded in 1949 by Earl Bakken and Palmer Hermundslie and is credited with manufacturing the first wearable artificial pacemakers. However, they started off with much more modest intentions, acting as a repair company, servicing medical equipment in local hospitals. Medtronic's main competitors for cardiac devices are Guidant (now a division of Boston Scientific) and St. Jude Medical.
Medtronic followed a path familiar to technology historians, starting in a garage in northern Minneapolis. The company expanded through the 1950s, mostly selling equipment built by other companies, but some custom hardware was also developed. The employees eventually came to know Dr. C. Walton Lillehei, a noted heart surgeon who was then at the University of Minnesota. Dr. Lillehei was frustrated with the pacemakers of the day, which relied on wall current to operate. This was extremely troublesome because power outages would cause patients to die.
Bakken built a small transistorized pacemaker that could be strapped to the body and powered by batteries. Work into this new field continued, producing an implantable pacemaker in 1960.
The company has continued to innovate in the medical business and is considered an economically-important company for Minnesota. A key attribute in understanding the company is that it remains very focused on the mission originally written by co-founder Earl Bakken in the early-1960s. The first paragraph of the 6 paragraph mission statement reads:
"To contribute to human welfare by application of biomedical engineering in the research, design, manufacture, and sale of instruments or appliances that alleviate pain, restore health, and extend life."
Medtronic makes a wide array of implantable electronic devices, from the relatively common ICD or implantable cardioverter-defibrillator, to devices for managing urinary incontinence and obesity to name just a few.
# Medtronic Diabetes
Medtronic Diabetes is the diabetes management manufacturing and sales division of Medtronic based in Northridge, California. The original company Minimed Technologies was founded in the early 1980s and spun-off from Pacesetter Systems, in order to design a practical insulin pump for lifelong wear. Most devices at the time were either too large or impossible to program and extremely unreliable. The release of the lightweight, menu-driven MiniMed 500 series changed the landscape, and was a major factor in bringing pump usage to the mainstream. By the early 2000s Medtronic had bought out Minimed to form Medtronic Minimed.
Current models consist of the MiniMed Paradigm 522/722. It is the first Insulin Pump which integrates continuous glucose monitoring, allowing patients to see in real time their glucose level. As well as insulin pumps Medtronic Diabetes also makes Continuous Blood Glucose Monitoring Systems (CGMS) for use as a stand alone system or integrated into their Minimed Paradigm 522/722 series pumps. Medtronic Diabetes also makes a large range of accessories and components for their insulin pump and CGMS products.
As of March 2007 the MiniMed name has begun to be absorbed into the parent company, Medtronic. Medtronic has kept the MiniMed name to brand their insulin pumps, for example: The MiniMed Paradigm 722. Medtronic frequently uses Medtronic Diabetes as the name for the division, it is unclear to the extent the division will be integrated into Medtronic, as it still maintains its own website. Many products and marketing material still say Medtronic MiniMed, as the brand is being phased out. | https://www.wikidoc.org/index.php/Medtronic | |
1cec4c69fc8df2a077230fad4d531bc7a1d2cdbd | wikidoc | Megestrol | Megestrol
# 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
Megestrol is a Progestin that is FDA approved for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). Common adverse reactions include Hypertension, Rash, Hot sweats, Weight gain, Diarrhea, flatulence, insomnia, Mood swings, Erectile dysfunction.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- MEGACE Oral Suspension is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS).
### Dosage
- The recommended adult initial dosage of MEGACE Oral Suspension is 800 mg/day (20 mL/day). Shake container well before using.
- In clinical trials evaluating different dose schedules, daily doses of 400 and 800 mg/day were found to be clinically effective.
- A plastic dosage cup with 10 mL and 20 mL markings is provided for convenience.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Megestrol in adult patients.
### Non–Guideline-Supported Use
- Cachexia - Cancer
- Cachexia - Cystic fibrosis
- Carcinoma of prostate, Advanced hormone-refractory
- Endometrial hyperplasia
- Endometriosis
- Hot sweats, In women with a history of breast cancer
- Malignant melanoma
- Malignant neoplasm of liver
- Mullerian mixed tumor, Adenosarcoma
- Ovarian carcinoma
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Megestrol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Megestrol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Megestrol in pediatric patients.
# Contraindications
- History of hypersensitivity to megestrol acetate or any component of the formulation. Known or suspected pregnancy.
# Warnings
- Megestrol acetate may cause fetal harm when administered to a pregnant woman. For animal data on fetal effects. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
- Megestrol acetate is not intended for prophylactic use to avoid weight loss.
- The glucocorticoid activity of MEGACE (megestrol acetate, USP) Oral Suspension has not been fully evaluated. Clinical cases of new onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and overt Cushing’s syndrome have been reported in association with the chronic use of MEGACE. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic MEGACE therapy in the stressed and non-stressed state. Furthermore, adrenocorticotropin (ACTH) stimulation testing has revealed the frequent occurrence of asymptomatic pituitary-adrenal suppression in patients treated with chronic MEGACE therapy. Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic MEGACE therapy who presents with symptoms and/or signs suggestive of hypoadrenalism (eg, hypotension, nausea, vomiting, dizziness, or weakness) in either the stressed or non-stressed state. Laboratory evaluation for adrenal insufficiency and consideration of replacement or stress doses of a rapidly acting glucocorticoid are strongly recommended in such patients. Failure to recognize inhibition of the hypothalamic-pituitary-adrenal axis may result in death. Finally, in patients who are receiving or being withdrawn from chronic MEGACE therapy, consideration should be given to the use of empiric therapy with stress doses of a rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (eg, surgery, infection).
### Precautions
- Therapy with MEGACE Oral Suspension for weight loss should only be instituted after treatable causes of weight loss are sought and addressed. These treatable causes include possible malignancies, systemic infections, gastrointestinal disorders affecting absorption, endocrine disease, and renal or psychiatric diseases.
- Effects on HIV viral replication have not been determined.
- Use with caution in patients with a history of thromboembolic disease.
- Exacerbation of preexisting diabetes with increased insulin requirements has been reported in association with the use of MEGACE.
- Long-term treatment with MEGACE may increase the risk of respiratory infections. A trend toward increased frequency of respiratory infections, decreased lymphocyte counts, and increased neutrophil counts was observed in a 2-year chronic toxicity/carcinogenicity study of megestrol acetate conducted in rats.
# Adverse Reactions
## Clinical Trials Experience
- Adverse events which occurred in at least 5% of patients in any arm of the two clinical efficacy trials and the open trial are listed below by treatment group. All patients listed had at least one post baseline visit during the 12 study weeks. These adverse events should be considered by the physician when prescribing MEGACE Oral Suspension.
- Adverse events which occurred in 1% to 3% of all patients enrolled in the two clinical efficacy trials with at least one follow-up visit during the first 12 weeks of the study are listed below by body system. Adverse events occurring less than 1% are not included. There were no significant differences between incidence of these events in patients treated with megestrol acetate and patients treated with placebo.
- abdominal pain, chest pain, infection, moniliasis and sarcoma
- cardiomyopathy and palpitation
- constipation, dry mouth, hepatomegaly, increased salivation and oral moniliasis
- leukopenia
- LDH increased, edema and peripheral edema
- paresthesia, confusion, convulsion, depression, neuropathy, hypesthesia and abnormal thinking
- dyspnea, cough, pharyngitis and lung disorder
- alopecia, herpes, pruritus, vesiculobullous rash, sweating and skin disorder
- amblyopia
- albuminuria, urinary incontinence, urinary tract infection and gynecomastia
## Postmarketing Experience
- Postmarketing reports associated with MEGACE Oral Suspension include thromboembolic phenomena including thrombophlebitis and pulmonary embolism, and glucose intolerance
# Drug Interactions
- Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. The effects of zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- No adequate animal teratology information is available at clinically relevant doses.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Megestrol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Megestrol during labor and delivery.
### Nursing Mothers
- Because of the potential for adverse effects on the newborn, nursing should be discontinued if MEGACE Oral Suspension is required.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of MEGACE Oral Suspension in the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with AIDS did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- Megestrol acetate is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
- Breakthrough bleeding was observed in all 10 female patients participating in the clinical trials. Megace is a progesterone derivative, which may induce vaginal bleeding in women.
### Race
There is no FDA guidance on the use of Megestrol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Megestrol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Megestrol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Megestrol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Megestrol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
# IV Compatibility
There is limited information regarding IV Compatibility of Megestrol in the drug label.
# Overdosage
- No serious unexpected side effects have resulted from studies involving MEGACE Oral Suspension administered in dosages as high as 1200 mg/day. In post-marketing experience, limited reports of overdose have been received. Signs and symptoms reported in the context of overdose included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose with MEGACE Oral Suspension. In case of overdose, appropriate supportive measures should be taken. Megestrol acetate has not been tested for dialyzability; however, due to its low solubility, it is postulated that dialysis would not be an effective means of treating overdose.
# Pharmacology
## Mechanism of Action
- Several investigators have reported on the appetite enhancing property of megestrol acetate and its possible use in cachexia. The precise mechanism by which megestrol acetate produces effects in anorexia and cachexia is unknown at the present time.
## Structure
- MEGACE® (megestrol acetate, USP) Oral Suspension contains megestrol acetate, a synthetic derivative of the naturally occurring steroid hormone, progesterone. Megestrol acetate is a white, crystalline solid chemically designated as 17α-(acetyloxy)-6-methylpregna-4,6-diene-3,20-dione. Solubility at 37°C in water is 2 µg per mL, solubility in plasma is 24 µg per mL. Its molecular weight is 384.51.
- The empirical formula is C24H32O4 and the structural formula is represented as follows:
- MEGACE Oral Suspension is supplied as an oral suspension containing 40 mg of micronized megestrol acetate per mL.
- MEGACE Oral Suspension contains the following inactive ingredients: alcohol (max. 0.06% v/v from flavor), citric acid, lemon-lime flavor, polyethylene glycol, polysorbate 80, purified water, sodium benzoate, sodium citrate, sucrose, and xanthan gum.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Megestrol in the drug label.
## Pharmacokinetics
- There are several analytical methods used to estimate megestrol acetate plasma concentrations, including gas chromatography-mass fragmentography (GC-MF), high pressure liquid chromatography (HPLC), and radioimmunoassay (RIA). The GC-MF and HPLC methods are specific for megestrol acetate and yield equivalent concentrations. The RIA method reacts to megestrol acetate metabolites and is, therefore, non-specific and indicates higher concentrations than the GC-MF and HPLC methods. Plasma concentrations are dependent, not only on the method used, but also on intestinal and hepatic inactivation of the drug, which may be affected by factors such as intestinal tract motility, intestinal bacteria, antibiotics administered, body weight, diet, and liver function.
- The major route of drug elimination in humans is urine. When radiolabeled megestrol acetate was administered to humans in doses of 4 to 90 mg, the urinary excretion within 10 days ranged from 56.5% to 78.4% (mean 66.4%) and fecal excretion ranged from 7.7% to 30.3% (mean 19.8%). The total recovered radioactivity varied between 83.1% and 94.7% (mean 86.2%). Megestrol acetate metabolites which were identified in urine constituted 5% to 8% of the dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces.
- Plasma steady-state pharmacokinetics of megestrol acetate were evaluated in 10 adult, cachectic male patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline. Patients received single oral doses of 800 mg/day of MEGACE Oral Suspension for 21 days. Plasma concentration data obtained on day 21 were evaluated for up to 48 hours past the last dose.
- Mean (±1SD) peak plasma concentration (Cmax) of megestrol acetate was 753 (±539) ng/mL. Mean area under the concentration-time-curve (AUC) was 10476 (±7788) ng × hr/mL. Median Tmax value was five hours. Seven of 10 patients gained weight in three weeks.
- Additionally, 24 adult, asymptomatic HIV seropositive male subjects were dosed once daily with 750 mg of MEGACE Oral Suspension. The treatment was administered for 14 days. Mean Cmax and AUC values were 490 (±238) ng/mL and 6779 (±3048) ng × hr/mL respectively. The median Tmax value was three hours. The mean Cmin value was 202 (±101) ng/mL. The mean percent of fluctuation value was 107 (±40).
- The effect of food on the bioavailability of MEGACE Oral Suspension has not been evaluated.
## Nonclinical Toxicology
- Data on carcinogenesis were obtained from studies conducted in dogs, monkeys, and rats treated with megestrol acetate at doses 53.2, 26.6, and 1.3 times lower than the proposed dose (13.3 mg/kg/day) for humans. No males were used in the dog and monkey studies. In female beagles, megestrol acetate (0.01, 0.1, or 0.25 mg/kg/day) administered for up to 7 years induced both benign and malignant tumors of the breast. In female monkeys, no tumors were found following 10 years of treatment with 0.01, 0.1, or 0.5 mg/kg/day megestrol acetate. Pituitary tumors were observed in female rats treated with 3.9 or 10 mg/kg/day of megestrol acetate for 2 years. The relationship of these tumors in rats and dogs to humans is unknown but should be considered in assessing the risk-to-benefit ratio when prescribing MEGACE Oral Suspension and in surveillance of patients on therapy.
- No mutagenesis data are currently available.
- Perinatal/postnatal (segment III) toxicity studies were performed in rats at doses (0.05–12.5 mg/kg) less than that indicated for humans (13.3 mg/kg); in these low dose studies, the reproductive capability of male offspring of megestrol acetate-treated females was impaired. Similar results were obtained in dogs. Pregnant rats treated with megestrol acetate showed a reduction in fetal weight and number of live births, and feminization of male fetuses. No toxicity data are currently available on male reproduction (spermatogenesis).
# Clinical Studies
- The clinical efficacy of MEGACE Oral Suspension was assessed in two clinical trials. One was a multicenter, randomized, double-blind, placebo-controlled study comparing megestrol acetate (MA) at doses of 100 mg, 400 mg, and 800 mg per day versus placebo in AIDS patients with anorexia/cachexia and significant weight loss. Of the 270 patients entered on study, 195 met all inclusion/exclusion criteria, had at least two additional post baseline weight measurements over a 12-week period, or had one post baseline weight measurement but dropped out for therapeutic failure. The percent of patients gaining five or more pounds at maximum weight gain in 12 study weeks was statistically significantly greater for the 800 mg (64%) and 400 mg (57%) MA-treated groups than for the placebo group (24%). Mean weight increased from baseline to last evaluation in 12 study weeks in the 800 mg MA-treated group by 7.8 pounds, the 400 mg MA group by 4.2 pounds, the 100 mg MA group by 1.9 pounds, and decreased in the placebo group by 1.6 pounds. Mean weight changes at 4, 8, and 12 weeks for patients evaluable for efficacy in the two clinical trials are shown graphically. Changes in body composition during the 12 study weeks as measured by bioelectrical impedance analysis showed increases in non-water body weight in the MA-treated groups. In addition, edema developed or worsened in only 3 patients.
- Greater percentages of MA-treated patients in the 800 mg group (89%), the 400 mg group (68%), and the 100 mg group (72%), than in the placebo group (50%), showed an improvement in appetite at last evaluation during the 12 study weeks. A statistically significant difference was observed between the 800 mg MA-treated group and the placebo group in the change in caloric intake from baseline to time of maximum weight change. Patients were asked to assess weight change, appetite, appearance, and overall perception of well-being in a 9-question survey. At maximum weight change, only the 800 mg MA-treated group gave responses that were statistically significantly more favorable to all questions when compared to the placebo-treated group. A dose response was noted in the survey with positive responses correlating with higher dose for all questions.
- The second trial was a multicenter, randomized, double-blind, placebo-controlled study comparing megestrol acetate 800 mg/day versus placebo in AIDS patients with anorexia/cachexia and significant weight loss. Of the 100 patients entered on study, 65 met all inclusion/exclusion criteria, had at least two additional post baseline weight measurements over a 12-week period or had one post baseline weight measurement but dropped out for therapeutic failure. Patients in the 800 mg MA-treated group had a statistically significantly larger increase in mean maximum weight change than patients in the placebo group. From baseline to study week 12, mean weight increased by 11.2 pounds in the MA-treated group and decreased 2.1 pounds in the placebo group. Changes in body composition as measured by bioelectrical impedance analysis showed increases in non-water weight in the MA-treated group. No edema was reported in the MA-treated group. A greater percentage of MA-treated patients (67%) than placebo-treated patients (38%) showed an improvement in appetite at last evaluation during the 12 study weeks; this difference was statistically significant. There were no statistically significant differences between treatment groups in mean caloric change or in daily caloric intake at time to maximum weight change. In the same 9-question survey referenced in the first trial, patients’ assessments of weight change, appetite, appearance, and overall perception of well-being showed increases in mean scores in MA-treated patients as compared to the placebo group.
- In both trials, patients tolerated the drug well and no statistically significant differences were seen between the treatment groups with regard to laboratory abnormalities, new opportunistic infections, lymphocyte counts, T4 counts, T8 counts, or skin reactivity tests.
# How Supplied
- MEGACE® (megestrol acetate, USP) Oral Suspension is available as a lemon-lime flavored oral suspension containing 40 mg of micronized megestrol acetate per mL.
- NDC 0015-0508-42 Bottles of 240 mL (8 fl. oz.)
## Storage
- Store MEGACE Oral Suspension between 15°C-25°C (59°F-77°F) and dispense in a tight container. Protect from heat.
### SPECIAL HANDLING
- There is no threshold limit value established by OSHA, NIOSH, or ACGIH.
- Exposure or “overdose” at levels approaching recommended dosing levels could result in side effects described above (see WARNINGS and ADVERSE REACTIONS). Women at risk of pregnancy should avoid such exposure.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
REPRESENTATIVE PACKAGING
See How Supplied section for a complete list of available packages of MEGACE OS.
NDC 0015-0508-42
240 mL (8 fl. oz.)
Megace®
(megestrol acetate, USP)
Oral Suspension
Each mL contains 40 mg of micronized megestrol acetate in a lemon-lime flavored oral suspension. Alcohol: max. 0.06% v/v.
Rx only
40 mg/mL
Bristol-Myers Squibb Company
### Ingredients and Appearance
# Patient Counseling Information
- Patients using megestrol acetate should receive the following instructions:
- This medication is to be used as directed by the physician.
- Report any adverse reaction experiences while taking this medication.
- Use contraception while taking this medication if you are a woman capable of becoming pregnant.
- Notify your physician if you become pregnant while taking this medication..
# Precautions with Alcohol
- Alcohol-Megestrol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Megace®
# Look-Alike Drug Names
There is limited information regarding Megestrol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Megestrol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Megestrol is a Progestin that is FDA approved for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). Common adverse reactions include Hypertension, Rash, Hot sweats, Weight gain, Diarrhea, flatulence, insomnia, Mood swings, Erectile dysfunction.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- MEGACE Oral Suspension is indicated for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS).
### Dosage
- The recommended adult initial dosage of MEGACE Oral Suspension is 800 mg/day (20 mL/day). Shake container well before using.
- In clinical trials evaluating different dose schedules, daily doses of 400 and 800 mg/day were found to be clinically effective.
- A plastic dosage cup with 10 mL and 20 mL markings is provided for convenience.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Megestrol in adult patients.
### Non–Guideline-Supported Use
- Cachexia - Cancer[1]
- Cachexia - Cystic fibrosis[2]
- Carcinoma of prostate, Advanced hormone-refractory[3]
- Endometrial hyperplasia[4]
- Endometriosis[5]
- Hot sweats, In women with a history of breast cancer[6]
- Malignant melanoma[7]
- Malignant neoplasm of liver[8]
- Mullerian mixed tumor, Adenosarcoma[9]
- Ovarian carcinoma[10]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Megestrol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Megestrol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Megestrol in pediatric patients.
# Contraindications
- History of hypersensitivity to megestrol acetate or any component of the formulation. Known or suspected pregnancy.
# Warnings
- Megestrol acetate may cause fetal harm when administered to a pregnant woman. For animal data on fetal effects. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
- Megestrol acetate is not intended for prophylactic use to avoid weight loss.
- The glucocorticoid activity of MEGACE (megestrol acetate, USP) Oral Suspension has not been fully evaluated. Clinical cases of new onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and overt Cushing’s syndrome have been reported in association with the chronic use of MEGACE. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic MEGACE therapy in the stressed and non-stressed state. Furthermore, adrenocorticotropin (ACTH) stimulation testing has revealed the frequent occurrence of asymptomatic pituitary-adrenal suppression in patients treated with chronic MEGACE therapy. Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic MEGACE therapy who presents with symptoms and/or signs suggestive of hypoadrenalism (eg, hypotension, nausea, vomiting, dizziness, or weakness) in either the stressed or non-stressed state. Laboratory evaluation for adrenal insufficiency and consideration of replacement or stress doses of a rapidly acting glucocorticoid are strongly recommended in such patients. Failure to recognize inhibition of the hypothalamic-pituitary-adrenal axis may result in death. Finally, in patients who are receiving or being withdrawn from chronic MEGACE therapy, consideration should be given to the use of empiric therapy with stress doses of a rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (eg, surgery, infection).
### Precautions
- Therapy with MEGACE Oral Suspension for weight loss should only be instituted after treatable causes of weight loss are sought and addressed. These treatable causes include possible malignancies, systemic infections, gastrointestinal disorders affecting absorption, endocrine disease, and renal or psychiatric diseases.
- Effects on HIV viral replication have not been determined.
- Use with caution in patients with a history of thromboembolic disease.
- Exacerbation of preexisting diabetes with increased insulin requirements has been reported in association with the use of MEGACE.
- Long-term treatment with MEGACE may increase the risk of respiratory infections. A trend toward increased frequency of respiratory infections, decreased lymphocyte counts, and increased neutrophil counts was observed in a 2-year chronic toxicity/carcinogenicity study of megestrol acetate conducted in rats.
# Adverse Reactions
## Clinical Trials Experience
- Adverse events which occurred in at least 5% of patients in any arm of the two clinical efficacy trials and the open trial are listed below by treatment group. All patients listed had at least one post baseline visit during the 12 study weeks. These adverse events should be considered by the physician when prescribing MEGACE Oral Suspension.
- Adverse events which occurred in 1% to 3% of all patients enrolled in the two clinical efficacy trials with at least one follow-up visit during the first 12 weeks of the study are listed below by body system. Adverse events occurring less than 1% are not included. There were no significant differences between incidence of these events in patients treated with megestrol acetate and patients treated with placebo.
- abdominal pain, chest pain, infection, moniliasis and sarcoma
- cardiomyopathy and palpitation
- constipation, dry mouth, hepatomegaly, increased salivation and oral moniliasis
- leukopenia
- LDH increased, edema and peripheral edema
- paresthesia, confusion, convulsion, depression, neuropathy, hypesthesia and abnormal thinking
- dyspnea, cough, pharyngitis and lung disorder
- alopecia, herpes, pruritus, vesiculobullous rash, sweating and skin disorder
- amblyopia
- albuminuria, urinary incontinence, urinary tract infection and gynecomastia
## Postmarketing Experience
- Postmarketing reports associated with MEGACE Oral Suspension include thromboembolic phenomena including thrombophlebitis and pulmonary embolism, and glucose intolerance
# Drug Interactions
- Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. The effects of zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- No adequate animal teratology information is available at clinically relevant doses.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Megestrol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Megestrol during labor and delivery.
### Nursing Mothers
- Because of the potential for adverse effects on the newborn, nursing should be discontinued if MEGACE Oral Suspension is required.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of MEGACE Oral Suspension in the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with AIDS did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- Megestrol acetate is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
- Breakthrough bleeding was observed in all 10 female patients participating in the clinical trials. Megace is a progesterone derivative, which may induce vaginal bleeding in women.
### Race
There is no FDA guidance on the use of Megestrol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Megestrol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Megestrol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Megestrol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Megestrol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
# IV Compatibility
There is limited information regarding IV Compatibility of Megestrol in the drug label.
# Overdosage
- No serious unexpected side effects have resulted from studies involving MEGACE Oral Suspension administered in dosages as high as 1200 mg/day. In post-marketing experience, limited reports of overdose have been received. Signs and symptoms reported in the context of overdose included diarrhea, nausea, abdominal pain, shortness of breath, cough, unsteady gait, listlessness, and chest pain. There is no specific antidote for overdose with MEGACE Oral Suspension. In case of overdose, appropriate supportive measures should be taken. Megestrol acetate has not been tested for dialyzability; however, due to its low solubility, it is postulated that dialysis would not be an effective means of treating overdose.
# Pharmacology
## Mechanism of Action
- Several investigators have reported on the appetite enhancing property of megestrol acetate and its possible use in cachexia. The precise mechanism by which megestrol acetate produces effects in anorexia and cachexia is unknown at the present time.
## Structure
- MEGACE® (megestrol acetate, USP) Oral Suspension contains megestrol acetate, a synthetic derivative of the naturally occurring steroid hormone, progesterone. Megestrol acetate is a white, crystalline solid chemically designated as 17α-(acetyloxy)-6-methylpregna-4,6-diene-3,20-dione. Solubility at 37°C in water is 2 µg per mL, solubility in plasma is 24 µg per mL. Its molecular weight is 384.51.
- The empirical formula is C24H32O4 and the structural formula is represented as follows:
- MEGACE Oral Suspension is supplied as an oral suspension containing 40 mg of micronized megestrol acetate per mL.
- MEGACE Oral Suspension contains the following inactive ingredients: alcohol (max. 0.06% v/v from flavor), citric acid, lemon-lime flavor, polyethylene glycol, polysorbate 80, purified water, sodium benzoate, sodium citrate, sucrose, and xanthan gum.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Megestrol in the drug label.
## Pharmacokinetics
- There are several analytical methods used to estimate megestrol acetate plasma concentrations, including gas chromatography-mass fragmentography (GC-MF), high pressure liquid chromatography (HPLC), and radioimmunoassay (RIA). The GC-MF and HPLC methods are specific for megestrol acetate and yield equivalent concentrations. The RIA method reacts to megestrol acetate metabolites and is, therefore, non-specific and indicates higher concentrations than the GC-MF and HPLC methods. Plasma concentrations are dependent, not only on the method used, but also on intestinal and hepatic inactivation of the drug, which may be affected by factors such as intestinal tract motility, intestinal bacteria, antibiotics administered, body weight, diet, and liver function.
- The major route of drug elimination in humans is urine. When radiolabeled megestrol acetate was administered to humans in doses of 4 to 90 mg, the urinary excretion within 10 days ranged from 56.5% to 78.4% (mean 66.4%) and fecal excretion ranged from 7.7% to 30.3% (mean 19.8%). The total recovered radioactivity varied between 83.1% and 94.7% (mean 86.2%). Megestrol acetate metabolites which were identified in urine constituted 5% to 8% of the dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces.
- Plasma steady-state pharmacokinetics of megestrol acetate were evaluated in 10 adult, cachectic male patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline. Patients received single oral doses of 800 mg/day of MEGACE Oral Suspension for 21 days. Plasma concentration data obtained on day 21 were evaluated for up to 48 hours past the last dose.
- Mean (±1SD) peak plasma concentration (Cmax) of megestrol acetate was 753 (±539) ng/mL. Mean area under the concentration-time-curve (AUC) was 10476 (±7788) ng × hr/mL. Median Tmax value was five hours. Seven of 10 patients gained weight in three weeks.
- Additionally, 24 adult, asymptomatic HIV seropositive male subjects were dosed once daily with 750 mg of MEGACE Oral Suspension. The treatment was administered for 14 days. Mean Cmax and AUC values were 490 (±238) ng/mL and 6779 (±3048) ng × hr/mL respectively. The median Tmax value was three hours. The mean Cmin value was 202 (±101) ng/mL. The mean percent of fluctuation value was 107 (±40).
- The effect of food on the bioavailability of MEGACE Oral Suspension has not been evaluated.
## Nonclinical Toxicology
- Data on carcinogenesis were obtained from studies conducted in dogs, monkeys, and rats treated with megestrol acetate at doses 53.2, 26.6, and 1.3 times lower than the proposed dose (13.3 mg/kg/day) for humans. No males were used in the dog and monkey studies. In female beagles, megestrol acetate (0.01, 0.1, or 0.25 mg/kg/day) administered for up to 7 years induced both benign and malignant tumors of the breast. In female monkeys, no tumors were found following 10 years of treatment with 0.01, 0.1, or 0.5 mg/kg/day megestrol acetate. Pituitary tumors were observed in female rats treated with 3.9 or 10 mg/kg/day of megestrol acetate for 2 years. The relationship of these tumors in rats and dogs to humans is unknown but should be considered in assessing the risk-to-benefit ratio when prescribing MEGACE Oral Suspension and in surveillance of patients on therapy.
- No mutagenesis data are currently available.
- Perinatal/postnatal (segment III) toxicity studies were performed in rats at doses (0.05–12.5 mg/kg) less than that indicated for humans (13.3 mg/kg); in these low dose studies, the reproductive capability of male offspring of megestrol acetate-treated females was impaired. Similar results were obtained in dogs. Pregnant rats treated with megestrol acetate showed a reduction in fetal weight and number of live births, and feminization of male fetuses. No toxicity data are currently available on male reproduction (spermatogenesis).
# Clinical Studies
- The clinical efficacy of MEGACE Oral Suspension was assessed in two clinical trials. One was a multicenter, randomized, double-blind, placebo-controlled study comparing megestrol acetate (MA) at doses of 100 mg, 400 mg, and 800 mg per day versus placebo in AIDS patients with anorexia/cachexia and significant weight loss. Of the 270 patients entered on study, 195 met all inclusion/exclusion criteria, had at least two additional post baseline weight measurements over a 12-week period, or had one post baseline weight measurement but dropped out for therapeutic failure. The percent of patients gaining five or more pounds at maximum weight gain in 12 study weeks was statistically significantly greater for the 800 mg (64%) and 400 mg (57%) MA-treated groups than for the placebo group (24%). Mean weight increased from baseline to last evaluation in 12 study weeks in the 800 mg MA-treated group by 7.8 pounds, the 400 mg MA group by 4.2 pounds, the 100 mg MA group by 1.9 pounds, and decreased in the placebo group by 1.6 pounds. Mean weight changes at 4, 8, and 12 weeks for patients evaluable for efficacy in the two clinical trials are shown graphically. Changes in body composition during the 12 study weeks as measured by bioelectrical impedance analysis showed increases in non-water body weight in the MA-treated groups. In addition, edema developed or worsened in only 3 patients.
- Greater percentages of MA-treated patients in the 800 mg group (89%), the 400 mg group (68%), and the 100 mg group (72%), than in the placebo group (50%), showed an improvement in appetite at last evaluation during the 12 study weeks. A statistically significant difference was observed between the 800 mg MA-treated group and the placebo group in the change in caloric intake from baseline to time of maximum weight change. Patients were asked to assess weight change, appetite, appearance, and overall perception of well-being in a 9-question survey. At maximum weight change, only the 800 mg MA-treated group gave responses that were statistically significantly more favorable to all questions when compared to the placebo-treated group. A dose response was noted in the survey with positive responses correlating with higher dose for all questions.
- The second trial was a multicenter, randomized, double-blind, placebo-controlled study comparing megestrol acetate 800 mg/day versus placebo in AIDS patients with anorexia/cachexia and significant weight loss. Of the 100 patients entered on study, 65 met all inclusion/exclusion criteria, had at least two additional post baseline weight measurements over a 12-week period or had one post baseline weight measurement but dropped out for therapeutic failure. Patients in the 800 mg MA-treated group had a statistically significantly larger increase in mean maximum weight change than patients in the placebo group. From baseline to study week 12, mean weight increased by 11.2 pounds in the MA-treated group and decreased 2.1 pounds in the placebo group. Changes in body composition as measured by bioelectrical impedance analysis showed increases in non-water weight in the MA-treated group. No edema was reported in the MA-treated group. A greater percentage of MA-treated patients (67%) than placebo-treated patients (38%) showed an improvement in appetite at last evaluation during the 12 study weeks; this difference was statistically significant. There were no statistically significant differences between treatment groups in mean caloric change or in daily caloric intake at time to maximum weight change. In the same 9-question survey referenced in the first trial, patients’ assessments of weight change, appetite, appearance, and overall perception of well-being showed increases in mean scores in MA-treated patients as compared to the placebo group.
- In both trials, patients tolerated the drug well and no statistically significant differences were seen between the treatment groups with regard to laboratory abnormalities, new opportunistic infections, lymphocyte counts, T4 counts, T8 counts, or skin reactivity tests.
# How Supplied
- MEGACE® (megestrol acetate, USP) Oral Suspension is available as a lemon-lime flavored oral suspension containing 40 mg of micronized megestrol acetate per mL.
- NDC 0015-0508-42 Bottles of 240 mL (8 fl. oz.)
## Storage
- Store MEGACE Oral Suspension between 15°C-25°C (59°F-77°F) and dispense in a tight container. Protect from heat.
### SPECIAL HANDLING
- There is no threshold limit value established by OSHA, NIOSH, or ACGIH.
- Exposure or “overdose” at levels approaching recommended dosing levels could result in side effects described above (see WARNINGS and ADVERSE REACTIONS). Women at risk of pregnancy should avoid such exposure.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
REPRESENTATIVE PACKAGING
See How Supplied section for a complete list of available packages of MEGACE OS.
NDC 0015-0508-42
240 mL (8 fl. oz.)
Megace®
(megestrol acetate, USP)
Oral Suspension
Each mL contains 40 mg of micronized megestrol acetate in a lemon-lime flavored oral suspension. Alcohol: max. 0.06% v/v.
Rx only
40 mg/mL
Bristol-Myers Squibb Company
### Ingredients and Appearance
# Patient Counseling Information
- Patients using megestrol acetate should receive the following instructions:
- This medication is to be used as directed by the physician.
- Report any adverse reaction experiences while taking this medication.
- Use contraception while taking this medication if you are a woman capable of becoming pregnant.
- Notify your physician if you become pregnant while taking this medication..
# Precautions with Alcohol
- Alcohol-Megestrol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Megace®[11]
# Look-Alike Drug Names
There is limited information regarding Megestrol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Megace | |
a5af62362c4336333be35b787707ac7e3b41beba | wikidoc | Melatonin | Melatonin
# 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.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Melatonin is a hormone that is FDA approved for the treatment of sleep cycle support. Common adverse reactions include hypothermia, somnolence, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Sleep cycle support.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Cancer: 20 mg ORALLY once daily has been used in clinical trials
- Cancer: up to 40 years, immediate-release, 1.5 mg ORALLY daily
- Cancer: 40 to 60 years, immediate-release, 1.5 to 3 mg ORALLY daily
- Cancer: older than 60 years, immediate-release, 3 to 6 mg ORALLY daily
- Jet lag: 1.5 to 3 mg ORALLY at 11 PM (local time in the destination country) on day 1, 10:30 PM on day 2, and 10 PM on day 3
- Sleep disorder: immediate-release, 5 mg ORALLY 30 minutes prior to time of sleep ; up to 10 mg ORALLY daily
- Sleep disorder: extended-release, 2 mg ORALLY 1 to 2 hours before bedtime
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Melatonin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Melatonin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Melatonin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Melatonin in pediatric patients.
# Contraindications
- Specific contraindications have not been determined.
# Warnings
Stop use and seek medical attention if symptoms worsen or persist more than 5 days
# Adverse Reactions
## Clinical Trials Experience
- Erythema
- Fixed drug eruption
- Fixed-drug eruptions on the glans was described as burning, itching, and sharply marginated, erythematous, vesicular plaques and well-demarcated erosions on the shaft in 2 adult males, occurring within 6 to 8 hours after taking melatonin for jet lag. Lesions dissipated within 10 days.
- Flushing
- Occasional vasodilation has been reported in patients with Parkinson disease treated with a maximum of melatonin 1000 mg/day.
- Pruritus
- Pruritus was reported in 1 of 12 elderly subjects with insomnia during therapy with sustained-release melatonin in one study.
- Gynaecomastia
- Hypothermia
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Melatonin in the drug label.
# Drug Interactions
Drug interactions have been reported with the following drugs.
Concomitant use can cause central nervous depression.
Concomitant use can cause increased blood pressure.
Increased risk of bleeding has been noted with concomitant use of warfarin.
# 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 Melatonin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Melatonin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Melatonin with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Melatonin with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Melatonin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Melatonin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Melatonin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Melatonin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Melatonin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Melatonin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Melatonin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Improvement of sleep in insomnia (eg, reduced sleep latency, longer sleep duration, improved quality of sleep) may indicate efficacy.
- Alleviation of symptoms in jet lag (eg, correction of disturbed sleep, reduced daytime tiredness) may indicate efficacy.
# IV Compatibility
There is limited information regarding IV Compatibility of Melatonin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Melatonin in the drug label.
# Pharmacology
## Mechanism of Action
- The binding of melatonin to melatonin receptors activates a few signaling pathways.
- MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorylation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell.The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.
- As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.
- When melatonin receptor agonists activate their receptors it causes numerous physiological processes.
- MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. The SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions.
- Melatonin receptors have been identified in the cardiovascular system. Evidence from animal studies points to a dual role of melatonin in the vasculature.
- Activation of MT1 receptors mediates vasoconstriction and the activation of MT2 receptors mediates vasodilation. Melatonin is involved in regulating immune responses in both human and animals through activation of both MT1 and MT2 receptors.
- MT1 and MT2 receptors are widespread in the eye and are involved in regulating aqueous humor secretion, which is important for glaucoma, and in phototransduction. This is not a complete list since many of the possible processes need further confirmation
## Structure
There is limited information regarding Melatonin Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Melatonin in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Melatonin in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Melatonin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Melatonin in the drug label.
# How Supplied
There is limited information regarding Melatonin How Supplied in the drug label.
## Storage
There is limited information regarding Melatonin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Take 15 minutes before meals.
- Adults and children 12 years and older 20 drops twice a day in a little water. Hold in the mouth for about 30 seconds then swallow.
- Children between 12 years and 6 years of age 10 drops twice a day in a little water. Hold in the mouth for about 30 seconds then swallow.
- Children under 6 years
# Precautions with Alcohol
- Alcohol-Melatonin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GUNA-MELATONIN ®
# Look-Alike Drug Names
There is limited information regarding Melatonin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Melatonin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Melatonin is a hormone that is FDA approved for the treatment of sleep cycle support. Common adverse reactions include hypothermia, somnolence, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Sleep cycle support.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Cancer: 20 mg ORALLY once daily has been used in clinical trials[1]
- Cancer: up to 40 years, immediate-release, 1.5 mg ORALLY daily
- Cancer: 40 to 60 years, immediate-release, 1.5 to 3 mg ORALLY daily
- Cancer: older than 60 years, immediate-release, 3 to 6 mg ORALLY daily
- Jet lag: 1.5 to 3 mg ORALLY at 11 PM (local time in the destination country) on day 1, 10:30 PM on day 2, and 10 PM on day 3
- Sleep disorder: immediate-release, 5 mg ORALLY 30 minutes prior to time of sleep[2][3] ; up to 10 mg ORALLY daily
- Sleep disorder: extended-release, 2 mg ORALLY 1 to 2 hours before bedtime [4]
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Melatonin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Melatonin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Melatonin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Melatonin in pediatric patients.
# Contraindications
- Specific contraindications have not been determined.
# Warnings
Stop use and seek medical attention if symptoms worsen or persist more than 5 days
# Adverse Reactions
## Clinical Trials Experience
- Erythema
- Fixed drug eruption
- Fixed-drug eruptions on the glans was described as burning, itching, and sharply marginated, erythematous, vesicular plaques and well-demarcated erosions on the shaft in 2 adult males, occurring within 6 to 8 hours after taking melatonin for jet lag. Lesions dissipated within 10 days.
- Flushing
- Occasional vasodilation has been reported in patients with Parkinson disease treated with a maximum of melatonin 1000 mg/day.
- Pruritus
- Pruritus was reported in 1 of 12 elderly subjects with insomnia during therapy with sustained-release melatonin in one study.
- Gynaecomastia
- Hypothermia
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Melatonin in the drug label.
# Drug Interactions
Drug interactions have been reported with the following drugs.
Concomitant use can cause central nervous depression.
Concomitant use can cause increased blood pressure.
Increased risk of bleeding has been noted with concomitant use of warfarin.
# 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 Melatonin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Melatonin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Melatonin with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Melatonin with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Melatonin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Melatonin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Melatonin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Melatonin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Melatonin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Melatonin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Melatonin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Improvement of sleep in insomnia (eg, reduced sleep latency, longer sleep duration, improved quality of sleep) may indicate efficacy.
- Alleviation of symptoms in jet lag (eg, correction of disturbed sleep, reduced daytime tiredness) may indicate efficacy.
# IV Compatibility
There is limited information regarding IV Compatibility of Melatonin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Melatonin in the drug label.
# Pharmacology
## Mechanism of Action
- The binding of melatonin to melatonin receptors activates a few signaling pathways.[5]
- MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorylation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB.[4] MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell.[5][6][7]The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[7]
- As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.[7]
- When melatonin receptor agonists activate their receptors it causes numerous physiological processes.[7][8]
- MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. The SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions.[9]
- Melatonin receptors have been identified in the cardiovascular system. Evidence from animal studies points to a dual role of melatonin in the vasculature.
- Activation of MT1 receptors mediates vasoconstriction and the activation of MT2 receptors mediates vasodilation. Melatonin is involved in regulating immune responses in both human and animals through activation of both MT1 and MT2 receptors.
- MT1 and MT2 receptors are widespread in the eye and are involved in regulating aqueous humor secretion, which is important for glaucoma, and in phototransduction. This is not a complete list since many of the possible processes need further confirmation
## Structure
There is limited information regarding Melatonin Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Melatonin in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Melatonin in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Melatonin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Melatonin in the drug label.
# How Supplied
There is limited information regarding Melatonin How Supplied in the drug label.
## Storage
There is limited information regarding Melatonin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Take 15 minutes before meals.
- Adults and children 12 years and older 20 drops twice a day in a little water. Hold in the mouth for about 30 seconds then swallow.
- Children between 12 years and 6 years of age 10 drops twice a day in a little water. Hold in the mouth for about 30 seconds then swallow.
- Children under 6 years
# Precautions with Alcohol
- Alcohol-Melatonin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GUNA-MELATONIN ®[10]
# Look-Alike Drug Names
There is limited information regarding Melatonin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Melatonin | |
4210192878a3799c9f2018b8dd2972e5f465b478 | wikidoc | Meldonium | Meldonium
# Overview
Meldonium (also known as Mildronate, THP, MET-88, Mildronāts or Quaterine) is a clinically used anti-ischemic drug that is currently manufactured and marketed by Grindeks, a pharmaceutical company based in Latvia. It is used in Lithuania and the Russian Federation, but is not approved by the Food and Drug Administration for use in the United States.
# Medical use
Meldonium is clinically used to treat angina and myocardial infarction. The first clinical trial testing the efficacy of using a combination of meldonium and lisinopril, an angiotensin-converting enzyme inhibitor, to treat chronic heart failure was reported in 2005. The report demonstrated that the combined treatment of meldonium and lisinopril may improve the quality of life, exercise capacity and mechanisms of peripheral circulation of patients with chronic heart failure. A later report in 2008 further demonstrated the efficacy of combined meldonium-lisinopril treatment by showing improved carotid baroreceptor reflex in patients with chronic heart failure. In February 2010, the clinical trial testing the efficacy and safety of meldonium treatment in combination with standard exercise tolerance therapy on angina patients was successfully completed. The studies revealed that meldonium treatment significantly improves the exercise tolerance of stable angina patients. A phase II clinical trial on the efficacy and safety of meldonium for acute ischemic stroke was completed in August 2013 and the studies showed that meldonium is as effective and safe as cinepazide injection.
Besides clinical trials, a number of scientific research projects have also been conducted to improve the efficacy of meldonium and its applicability to other diseases. For example, a report published by Vilskersts et al. suggested that the effect of mildronate treatment may be enhanced with co-treatment of other compounds such as orotic acid.
Using animal models, the applications of meldonium, sometimes in tandem with other drugs such as metformin, have shown beneficial effects on neurological disorder and diabetes.
Meldonium may also be beneficial for the treatment of seizures and alcohol intoxication.
Recent reports also suggest that meldonium may improve the ability of learning and memory, as the drug changes the expression of hippocampal proteins related to synaptic plasticity using rat model.
Meldonium was reported to elevate the concentrations of γ-butyrobetaine hydroxylase in testes tissues; in addition, long term (90 days) administration of meldonium was reported to improve sexual performance, sperm motility and concentration of testosterone in boars, although further studies are needed to confirm the potential of using meldonium as a sperm motility and sperm quality-enhancing agent.
To date, meldonium is one of Latvia's most exported products, and can be readily obtained in countries including Russia, Ukraine, Moldova, Belarus, Azerbaijan and Armenia.
# Mechanism of action
The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl)propionate, a structural analogue of γ-butyrobetaine, with a NH group replacing the CH2 at the C-4 position of γ-butyrobetaine. γ-Butyrobetaine is a precursor in the biosynthesis of carnitine.
The mechanism of action of meldonium is to act as a fatty acid oxidation inhibitor, presumably by inhibiting enzymes in the carnitine biosynthesis pathway such as γ-butyrobetaine hydroxylase. γ-Butyrobetaine hydroxylase is an enzyme that belongs to the 2-oxoglutarate (2OG) oxygenase superfamily and catalyses the formation of L-carnitine from γ-butyrobetaine. X-ray crystallographic and in vitro biochemical studies suggest meldonium binds to the substrate pocket of γ-butyrobetaine hydroxylase and acts as a competitive substrate/inhibitor to form malonic acid semialdehyde, dimethylamine, formaldehyde, 3-amino-4-(methyamino)butanoic acid and (1-methylimidazolidin-4-yl)acetic acid, likely via a Steven's type rearrangement mechanism. Mildronate is a potent γ-butyrobetaine hydroxylase inhibitor, with a half maximal inhibitory concentration (IC50) value of 62 μM. Meldonium is an example of a non-peptidyl substrate mimic inhibitor for human 2OG oxygenase.
Meldonium has also been shown by NMR to bind to carnitine acetyltransferase. Carnitine acetyltransferase belongs to a family of ubiquitous enzymes that play pivotal roles in cellular energy metabolism. Meldonium therefore may act as a regulator of energy metabolism. Meldonium is a relatively weak inhibitor to carnitine acetyltransferase (when compared to γ-butyrobetaine hydroxylase), with an inhibition constant (KI) of 1.6 mM.
# Forms
- 250 mg capsules N60
- 500 mg capsules N60
- Injection 10% 5 ml N10 | Meldonium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Meldonium (also known as Mildronate, THP, MET-88, Mildronāts or Quaterine[1]) is a clinically used anti-ischemic drug that is currently manufactured and marketed by Grindeks, a pharmaceutical company based in Latvia.[2] It is used in Lithuania and the Russian Federation,[3] but is not approved by the Food and Drug Administration for use in the United States.
# Medical use
Meldonium is clinically used to treat angina and myocardial infarction.[4][5][6] The first clinical trial testing the efficacy of using a combination of meldonium and lisinopril, an angiotensin-converting enzyme inhibitor, to treat chronic heart failure was reported in 2005.[7] The report demonstrated that the combined treatment of meldonium and lisinopril may improve the quality of life, exercise capacity and mechanisms of peripheral circulation of patients with chronic heart failure.[7] A later report in 2008 further demonstrated the efficacy of combined meldonium-lisinopril treatment by showing improved carotid baroreceptor reflex in patients with chronic heart failure.[8] In February 2010, the clinical trial testing the efficacy and safety of meldonium treatment in combination with standard exercise tolerance therapy on angina patients was successfully completed.[9] The studies revealed that meldonium treatment significantly improves the exercise tolerance of stable angina patients.[10][11] A phase II clinical trial on the efficacy and safety of meldonium for acute ischemic stroke was completed in August 2013 and the studies showed that meldonium is as effective and safe as cinepazide injection.[12][13]
Besides clinical trials, a number of scientific research projects have also been conducted to improve the efficacy of meldonium and its applicability to other diseases. For example, a report published by Vilskersts et al. suggested that the effect of mildronate treatment may be enhanced with co-treatment of other compounds such as orotic acid.[14]
Using animal models, the applications of meldonium, sometimes in tandem with other drugs such as metformin, have shown beneficial effects on neurological disorder[15][16] and diabetes.[17]
Meldonium may also be beneficial for the treatment of seizures and alcohol intoxication.[18]
Recent reports also suggest that meldonium may improve the ability of learning and memory, as the drug changes the expression of hippocampal proteins related to synaptic plasticity using rat model.[19]
Meldonium was reported to elevate the concentrations of γ-butyrobetaine hydroxylase in testes tissues;[5] in addition, long term (90 days) administration of meldonium was reported to improve sexual performance, sperm motility and concentration of testosterone in boars, although further studies are needed to confirm the potential of using meldonium as a sperm motility and sperm quality-enhancing agent.[20]
To date, meldonium is one of Latvia's most exported products, and can be readily obtained in countries including Russia, Ukraine, Moldova, Belarus, Azerbaijan and Armenia.[21][22][23]
# Mechanism of action
The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl)propionate,[24][25] a structural analogue of γ-butyrobetaine, with a NH group replacing the CH2 at the C-4 position of γ-butyrobetaine. γ-Butyrobetaine is a precursor in the biosynthesis of carnitine.[26]
The mechanism of action of meldonium is to act as a fatty acid oxidation inhibitor, presumably by inhibiting enzymes in the carnitine biosynthesis pathway such as γ-butyrobetaine hydroxylase.[27] γ-Butyrobetaine hydroxylase is an enzyme that belongs to the 2-oxoglutarate (2OG) oxygenase superfamily and catalyses the formation of L-carnitine from γ-butyrobetaine.[28][29] X-ray crystallographic and in vitro biochemical studies suggest meldonium binds to the substrate pocket of γ-butyrobetaine hydroxylase and acts as a competitive substrate/inhibitor to form malonic acid semialdehyde, dimethylamine, formaldehyde, 3-amino-4-(methyamino)butanoic acid and (1-methylimidazolidin-4-yl)acetic acid,[30][31] likely via a Steven's type rearrangement mechanism.[32] Mildronate is a potent γ-butyrobetaine hydroxylase inhibitor, with a half maximal inhibitory concentration (IC50) value of 62 μM.[33] Meldonium is an example of a non-peptidyl substrate mimic inhibitor for human 2OG oxygenase.[34]
Meldonium has also been shown by NMR to bind to carnitine acetyltransferase.[35] Carnitine acetyltransferase belongs to a family of ubiquitous enzymes that play pivotal roles in cellular energy metabolism.[36] Meldonium therefore may act as a regulator of energy metabolism. Meldonium is a relatively weak inhibitor to carnitine acetyltransferase (when compared to γ-butyrobetaine hydroxylase), with an inhibition constant (KI) of 1.6 mM.
# Forms
- 250 mg capsules N60
- 500 mg capsules N60
- Injection 10% 5 ml N10 | https://www.wikidoc.org/index.php/Meldonium | |
45deb50346072bfe2d0486a5685f24876c470374 | wikidoc | Meloxicam | Meloxicam
# 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
Meloxicam is an analgesic, anti-inflammatory agent that is FDA approved for the treatment of osteoarthritis (OA), rheumatoid arthritis (RA). There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, upper respiratory tract infections, dyspepsia, and influenza-like symptoms.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### osteoarthritis (OA)=
- Meloxicam is indicated for relief of the signs and symptoms of osteoarthritis.
- Dosing Information:
- General Instructions
- Carefully consider the potential benefits and risks of meloxicam and other treatment options before deciding to use meloxicam. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
- After observing the response to initial therapy with meloxicam, adjust the dose to suit an individual patient's needs.
- In adults, the maximum recommended daily oral dose of meloxicam is 15 mg regardless of formulation. In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended.
- Meloxicam may be taken without regard to timing of meals.
- Osteoarthritis
- For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
- Meloxicam is indicated for relief of the signs and symptoms of rheumatoid arthritis.
- Dosing Information
- For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meloxicam in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Meloxicam in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Before initiating treatment with meloxicam, weigh the potential benefits and risks of meloxicam and other treatment options.
- To reduce the risk of serious adverse effects, use the lowest effective dose of meloxicam for the shortest duration consistent with individual patient treatment goals.
- After the initial response to treatment is observed, adjust the meloxicam dose and frequency to suit the individual patient's needs.
- The recommended dose of meloxicam for the treatment of symptoms of pauciarticular and/or polyarticular course juvenile rheumatoid arthritis in children 2 years and older is 0.125 milligram/kilogram (mg/kg) given orally, once daily, up to a maximum of 7.5 mg. For smaller weight children, use of meloxicam oral suspension (strength 7.5 mg/5 milliliters) is recommended to improve dosing accuracy. Dosing for the oral suspension should be individualized based on child's weight as indicated in the table below.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meloxicam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Meloxicam in pediatric patients.
# Contraindications
Allergic Reactions
- Meloxicam is contraindicated in patients with known hypersensitivity (e.g., anaphylactoid reactions and serious skin reactions) to meloxicam.
- Meloxicam should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
Coronary Surgery
- Meloxicam is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
# Warnings
Cardiovascular Thrombotic Events
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years' duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an CV disease event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation
- NSAIDs, including meloxicam, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs, occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- Prescribe NSAIDs, including meloxicam, with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during meloxicam therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of meloxicam until a serious GI adverse event is ruled out. For high-risk patients, consider alternate therapies that do not involve NSAIDs.
Hepatic Effects
- Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including meloxicam. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
- A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with meloxicam. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue meloxicam.
Hypertension
- NSAIDs, including meloxicam, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. NSAIDs, including meloxicam, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Patients taking ACE inhibitors, thiazides, or loop diuretics may have impaired response to these therapies when taking NSAIDs.
Congestive Heart Failure and Edema
- Fluid retention and edema have been observed in some patients taking NSAIDs. Use meloxicam with caution in patients with fluid retention, hypertension, or heart failure.
Renal Effects
- Long-term administration of NSAIDs, including meloxicam, can result in renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors, and angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
- A pharmacokinetic study in patients with mild and moderate renal impairment revealed that no dosage adjustments in these patient populations are required. Patients with severe renal impairment have not been studied. The use of meloxicam in patients with severe renal impairment with CrCl less than 20 mL/min is not recommended. A study performed in patients on hemodialysis revealed that although overall Cmax was diminished in this population, the proportion of free drug not bound to plasma was increased. Therefore it is recommended that meloxicam dosage in this population not exceed 7.5 mg per day. Closely monitor the renal function of patients with impaired renal function who are taking meloxicam.
- Use caution when initiating treatment with meloxicam in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with meloxicam. Caution is also recommended in patients with pre-existing kidney disease.
- The extent to which metabolites may accumulate in patients with renal impairment has not been studied with meloxicam. Because some meloxicam metabolites are excreted by the kidney, monitor patients with significant renal impairment closely.
Anaphylactoid Reactions
- As with other NSAIDs, anaphylactoid reactions have occurred in patients without known prior exposure to meloxicam. Meloxicam should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Seek emergency help in cases where an anaphylactoid reaction occurs.
Adverse Skin Reactions
- NSAIDs, including meloxicam, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations and discontinue use of the drug at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
- Starting at 30 weeks gestation, avoid the use of meloxicam because it may cause premature closure of the ductus arteriosus.
Corticosteroid Treatment
- Meloxicam cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Slowly taper patients on prolonged corticosteroid therapy if a decision is made to discontinue corticosteroids.
Masking of Inflammation and Fever
- The pharmacological activity of meloxicam in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hematological Effects
- Anemia may occur in patients receiving NSAIDs, including meloxicam. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including meloxicam, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Carefully monitor patients treated with meloxicam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.
Use in Patients with Pre-existing Asthma
- Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, meloxicam should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.
Monitoring
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, meloxicam should be discontinued.
# 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 following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular thrombotic events
- Gastrointestinal effects – risk of GI ulceration, bleeding, and perforation
- Hepatic effects
- Hypertension
- Congestive heart failure and edema
- Renal effects
- Anaphylactoid reactions
- Adverse skin reactions
Clinical Trials Experience
Adults
-steoarthritis and rheumatoid arthritis
- The meloxicam Phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with meloxicam 7.5 mg/day, 3505 OA patients and 1351 RA patients treated with meloxicam 15 mg/day. Meloxicam at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo- and/or active-controlled osteoarthritis trials and 2363 of these patients were treated in ten placebo- and/or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across meloxicam trials.
- A 12-week multicenter, double-blind, randomized trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of meloxicam with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients with rheumatoid arthritis to compare the efficacy and safety of meloxicam with placebo.
- Table 1a depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in a 12-week placebo- and active-controlled osteoarthritis trial.
- Table 1b depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in two 12-week placebo- controlled rheumatoid arthritis trials.
- The adverse events that occurred with meloxicam in ≥ 2% of patients treated short-term (4 to 6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 2.
- Higher doses of meloxicam (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore the daily dose of meloxicam should not exceed 15 mg.
- The following is a list of adverse drug reactions occurring in < 2% of patients receiving meloxicam in clinical trials involving approximately 16,200 patients.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of meloxicam. 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. Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug. Adverse reactions reported in worldwide post marketing experience or the literature include: acute urinary retention; agranulocytosis; alterations in mood (such as mood elevation); anaphylactoid reactions including shock; erythema multiforme; exfoliative dermatitis; interstitial nephritis; jaundice; liver failure; Stevens-Johnson syndrome, and toxic epidermal necrolysis.
# Drug Interactions
- See also Pharmacology.
ACE-inhibitors
- NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking meloxicam concomitantly with ACE-inhibitors.
Aspirin
- When meloxicam is administered with aspirin (1000 mg three times daily) to healthy volunteers, an increase the AUC (10%) and Cmax (24%) of meloxicam was noted. The clinical significance of this interaction is not known; however, as with other NSAIDs concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects.
- Concomitant administration of low-dose aspirin with meloxicam may result in an increased rate of GI ulceration or other complications, compared to use of meloxicam alone. Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis.
Diuretics
- Clinical studies, as well as post marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with meloxicam, patients should be observed closely for signs of renal failure, as well as to ensure diuretic efficacy.
Lithium
- In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam 15 mg every day as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by meloxicam. Closely monitor patients on lithium treatment for signs of lithium toxicity when meloxicam is introduced, adjusted, or withdrawn.
Methotrexate
- NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Therefore, NSAIDs may reduce the elimination of methotrexate, thereby enhancing the toxicity of methotrexate. Use caution when meloxicam is administered concomitantly with methotrexate.
Cyclosporine
- Meloxicam, like other NSAIDs, may affect renal prostaglandins, thereby altering the renal toxicity of certain drugs. Therefore, concomitant therapy with meloxicam may increase cyclosporine's nephrotoxicity. Use caution when meloxicam is administered concomitantly with cyclosporine.
Warfarin
- The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
- Monitor anticoagulant activity, particularly in the first few days after initiating or changing meloxicam therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding than with the use of either drug alone. Use caution when administering meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C; Category D starting 30 weeks gestation
- There are no adequate and well-controlled studies in pregnant women. Meloxicam crosses the placental barrier. Prior to 30 weeks gestation, use meloxicam during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, avoid meloxicam and other NSAIDs, in pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, inform the patient of the potential hazard to a fetus.
Teratogenic Effects
- Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the maximum recommended human daily dose based on body surface area comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day. The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion).
Nonteratogenic Effects
- In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65-and 6.5-fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Meloxicam in women who are pregnant.
### Labor and Delivery
- The effects of meloxicam on labor and delivery of pregnant women are unknown. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (at least 12.5 times lower than the maximum recommended human daily dose based on body surface area comparison).
### Nursing Mothers
- It is not known whether this drug is excreted in human milk; however, meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from meloxicam, 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
- Use of meloxicam for a pediatric indication is protected by marketing exclusivity.
### Geriatic Use
- As with any NSAID, caution should be exercised in treating the elderly (65 years and older).
- Of the total number of subjects in clinical studies, 5157 were age 65 and over (4044 in OA studies and 1113 in RA studies). 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 Meloxicam with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Meloxicam with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of meloxicam in subjects with severe renal impairment is not recommended. Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore, it is recommended that meloxicam dosage in this population not exceed 7.5 mg per day Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable.
### Hepatic Impairment
- No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Since meloxicam is significantly metabolized in the liver; the use of meloxicam in these patients should be done with caution.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Meloxicam in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Meloxicam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
General Instructions
- Carefully consider the potential benefits and risks of meloxicam and other treatment options before deciding to use meloxicam. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals .
- After observing the response to initial therapy with meloxicam, adjust the dose to suit an individual patient's needs.
- In adults, the maximum recommended daily oral dose of meloxicam is 15 mg regardless of formulation. In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended.
- Meloxicam may be taken without regard to timing of meals.
-steoarthritis
- For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
rheumatoid arthritis
- For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
DOSAGE FORMS AND STRENGTHS
- Tablets:
- 7.5 mg: pastel yellow, round, biconvex, uncoated tablet containing meloxicam 7.5 mg. The 7.5 mg tablet is impressed with “5” mark on one side.
- 15 mg: pastel yellow, round, biconvex, uncoated tablet containing meloxicam 15 mg. The 15 mg tablet is impressed with “100” mark on one side.
### Monitoring
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, meloxicam should be discontinued.
- New onset or worsening of hypertension can occur. Blood pressure should be monitored closely during treatment.
- Closely monitor the renal function of patients with impaired renal function who are taking meloxicam as some meloxicam metabolites are excreted by the kidney.
- Monitor patients treated with meloxicam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.
- Closely monitor patients on lithium treatment for signs of lithium toxicity when meloxicam is introduced, adjusted, or withdrawn.
- Monitor anticoagulant activity, particularly in the first few days after initiating or changing meloxicam therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding than with the use of either drug alone. Use caution when administering meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.
# IV Compatibility
There is limited information regarding the compatibility of Meloxicam and IV administrations.
# Overdosage
- There is limited experience with meloxicam overdose. Four cases have taken 6 to 11 times the highest recommended dose; all recovered. Cholestyramine is known to accelerate the clearance of meloxicam.
- Symptoms following acute NSAID overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular collapse, and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
- Patients should be managed with symptomatic and supportive care following an NSAID overdose. Administration of activated charcoal is recommended for patients who present 1 to 2 hours after overdose. For substantial overdose or severely symptomatic patients, activated charcoal may be administered repeatedly. Accelerated removal of meloxicam by 4 gm oral doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
- For additional information about overdose treatment, call a poison control center (1-800-222-1222).
# Pharmacology
## Mechanism of Action
- The mechanism of action of meloxicam, like that of other NSAIDs, may be related to prostaglandin synthetase (cyclo-oxygenase) inhibition which is involved in the intial steps of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin. It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy.
## Structure
- Meloxicam, an oxicam derivative, is a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each pastel yellow Meloxicam Tablets, USP contains 7.5 mg or 15 mg meloxicam for oral administration. Meloxicam is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the following structural formula:
- Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app = 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2.
- Meloxicam is available as a tablet for oral administration containing 7.5 mg or 15 mg meloxicam.
- The inactive ingredients in Meloxicam Tablets, USP include Colloidal Silicon Dioxide, Sodium Starch Glycolate, Lactose, Magnesium Stearate, Microcrystalline Cellulose, Povidone K-30, and Sodium Citrate.
## Pharmacodynamics
- Meloxicam exhibits anti-inflammatory, analgesic, and antipyretic activities.
## Pharmacokinetics
Absorption
- The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean Cmax was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady-state concentrations were reached by Day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling.
Food and Antacid Effects
- Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., Cmax) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (Tmax) was achieved between 5 and 6 hours. In comparison, neither the AUC nor the Cmax values for meloxicam suspension were affected following a similar high fat meal, while mean Tmax values were increased to approximately 7 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, meloxicam can be administered without regard to timing of meals or concomitant administration of antacids.
Distribution
- The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam.
- Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.
Metabolism
- Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. All the four metabolites are not known to have any in vivo pharmacological activity.
Excretion
- Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%.
- The mean elimination half-life (t1/2) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min.
Special Populations
Pediatric
- After single (0.25 mg/kg) dose administration and after achieving steady state (0.375 mg/kg/day), there was a general trend of approximately 30% lower exposure in younger patients (2 to 6 years old) as compared to the older patients (7 to 16 years old). The older patients had meloxicam exposures similar (single dose) or slightly reduced (steady state) to those in the adult patients, when using AUC values normalized to a dose of 0.25 mg/kg. The meloxicam mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0) for the 2 to 6 year old patients, and 7 to 16 year old patients, respectively.
- In a covariate analysis, utilizing population pharmacokinetics body-weight, but not age, was the single predictive covariate for differences in the meloxicam apparent oral plasma clearance. The body-weight normalized apparent oral clearance values were adequate predictors of meloxicam exposure in pediatric patients.
- The pharmacokinetics of meloxicam in pediatric patients under 2 years of age have not been investigated.
Geriatric
- Elderly males (≥65 years of age) exhibited meloxicam plasma concentrations and steady-state pharmacokinetics similar to young males. Elderly females (≥65 years of age) had a 47% higher AUCss and 32% higher Cmax,ss as compared to younger females (≤55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients.
Gender
- Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or Tmax across genders.
Hepatic Impairment
- Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied.
Renal Impairment
- Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of meloxicam in subjects with severe renal impairment is not recommended.
Hemodialysis
Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable.
Drug Interactions
- Aspirin: When meloxicam is administered with aspirin (1000 mg three times daily) to healthy volunteers, it tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known.
- Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established.
- Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam.
- Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam.
- Lithium: In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam 15 mg QD every day as compared to subjects receiving lithium alone.
- Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites.
- Warfarin: The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis: There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.5- and 2.6-fold, respectively, the maximum recommended human daily dose based on body surface area comparison).
- Mutagenesis: Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow.
- Impairment of Fertility: Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 5.8- and 3.2-fold greater, respectively, than the maximum recommended human daily dose based on body surface area comparison).
# Clinical Studies
-steoarthritis and rheumatoid arthritis
- The use of meloxicam for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a 12-week, double-blind, controlled trial. Meloxicam (3.75 mg, 7.5 mg, and 15 mg daily) was compared to placebo. The four primary endpoints were investigator's global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function, and stiffness). Patients on meloxicam 7.5 mg daily and meloxicam 15 mg daily showed significant improvement in each of these endpoints compared with placebo.
- The use of meloxicam for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S. ranging from 4 weeks' to 6 months' duration. In these trials, the efficacy of meloxicam, in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S. trial.
- The use of meloxicam for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a 12-week, double-blind, controlled multinational trial. Meloxicam (7.5 mg, 15 mg, and 22.5 mg daily) was compared to placebo. The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory, and functional measures of RA response. Patients receiving meloxicam 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo. No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose.
# How Supplied
- Meloxicam is available as a pastel yellow, round, biconvex, uncoated tablet containing meloxicam 7.5 mg or 15 mg. The 7.5 mg tablet is impressed with “5” mark on one side, and the 15 mg tablet is impressed with “100” mark on one side.
- Meloxicam Tablets, USP 7.5 mg is supplied in blister punch material as follows:
- NDC 50268-525-15- 10 Tablets per card, 5 cards per carton
- Meloxicam Tablets, USP 15 mg is supplied in blister punch material as follows:
- NDC 50268-526-15- 10 Tablets per card, 5 cards per carton
## Storage
- Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
- Keep Meloxicam Tablets, USP in a dry place.
- Dispense tablets in a tight container.
- Keep this and all medications out of the reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- See FDA-approved Medication Guide
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy.
Medication Guide
- Inform patients of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and instruct them to read the Medication Guide prior to using meloxicam.
Cardiovascular Effects
- NSAIDs including meloxicam may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up.
Gastrointestinal Effects
- NSAIDs including meloxicam, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up.
Hepatotoxicity
- Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop therapy and seek immediate medical therapy.
Adverse Skin Reactions
- NSAIDs, including meloxicam, can cause serious skin side effects such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
Weight Gain and Edema
- Advise patients to promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
Anaphylactoid Reactions
- Inform patients of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help.
Effects During Pregnancy
- Starting at 30 weeks gestation, meloxicam should be avoided as premature closure of the ductus arteriosus in the fetus may occur.
- Please address medical inquiries to 1-866-562-4706
# Precautions with Alcohol
Alcohol-Meloxicam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Mobic
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Meloxicam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
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# Black Box Warning
# Overview
Meloxicam is an analgesic, anti-inflammatory agent that is FDA approved for the treatment of osteoarthritis (OA), rheumatoid arthritis (RA). There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, upper respiratory tract infections, dyspepsia, and influenza-like symptoms.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### osteoarthritis (OA)=
- Meloxicam is indicated for relief of the signs and symptoms of osteoarthritis.
- Dosing Information:
- General Instructions
- Carefully consider the potential benefits and risks of meloxicam and other treatment options before deciding to use meloxicam. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
- After observing the response to initial therapy with meloxicam, adjust the dose to suit an individual patient's needs.
- In adults, the maximum recommended daily oral dose of meloxicam is 15 mg regardless of formulation. In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended.
- Meloxicam may be taken without regard to timing of meals.
- Osteoarthritis
- For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
- Meloxicam is indicated for relief of the signs and symptoms of rheumatoid arthritis.
- Dosing Information
- For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meloxicam in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Meloxicam in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Before initiating treatment with meloxicam, weigh the potential benefits and risks of meloxicam and other treatment options.
- To reduce the risk of serious adverse effects, use the lowest effective dose of meloxicam for the shortest duration consistent with individual patient treatment goals.
- After the initial response to treatment is observed, adjust the meloxicam dose and frequency to suit the individual patient's needs.
- The recommended dose of meloxicam for the treatment of symptoms of pauciarticular and/or polyarticular course juvenile rheumatoid arthritis in children 2 years and older is 0.125 milligram/kilogram (mg/kg) given orally, once daily, up to a maximum of 7.5 mg. For smaller weight children, use of meloxicam oral suspension (strength 7.5 mg/5 milliliters) is recommended to improve dosing accuracy. Dosing for the oral suspension should be individualized based on child's weight as indicated in the table below.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meloxicam in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Meloxicam in pediatric patients.
# Contraindications
Allergic Reactions
- Meloxicam is contraindicated in patients with known hypersensitivity (e.g., anaphylactoid reactions and serious skin reactions) to meloxicam.
- Meloxicam should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
Coronary Surgery
- Meloxicam is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
# Warnings
Cardiovascular Thrombotic Events
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years' duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an CV disease event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation
- NSAIDs, including meloxicam, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs, occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- Prescribe NSAIDs, including meloxicam, with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during meloxicam therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of meloxicam until a serious GI adverse event is ruled out. For high-risk patients, consider alternate therapies that do not involve NSAIDs.
Hepatic Effects
- Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including meloxicam. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
- A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with meloxicam. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue meloxicam.
Hypertension
- NSAIDs, including meloxicam, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. NSAIDs, including meloxicam, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Patients taking ACE inhibitors, thiazides, or loop diuretics may have impaired response to these therapies when taking NSAIDs.
Congestive Heart Failure and Edema
- Fluid retention and edema have been observed in some patients taking NSAIDs. Use meloxicam with caution in patients with fluid retention, hypertension, or heart failure.
Renal Effects
- Long-term administration of NSAIDs, including meloxicam, can result in renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors, and angiotensin II receptor antagonists, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
- A pharmacokinetic study in patients with mild and moderate renal impairment revealed that no dosage adjustments in these patient populations are required. Patients with severe renal impairment have not been studied. The use of meloxicam in patients with severe renal impairment with CrCl less than 20 mL/min is not recommended. A study performed in patients on hemodialysis revealed that although overall Cmax was diminished in this population, the proportion of free drug not bound to plasma was increased. Therefore it is recommended that meloxicam dosage in this population not exceed 7.5 mg per day. Closely monitor the renal function of patients with impaired renal function who are taking meloxicam.
- Use caution when initiating treatment with meloxicam in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with meloxicam. Caution is also recommended in patients with pre-existing kidney disease.
- The extent to which metabolites may accumulate in patients with renal impairment has not been studied with meloxicam. Because some meloxicam metabolites are excreted by the kidney, monitor patients with significant renal impairment closely.
Anaphylactoid Reactions
- As with other NSAIDs, anaphylactoid reactions have occurred in patients without known prior exposure to meloxicam. Meloxicam should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Seek emergency help in cases where an anaphylactoid reaction occurs.
Adverse Skin Reactions
- NSAIDs, including meloxicam, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations and discontinue use of the drug at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
- Starting at 30 weeks gestation, avoid the use of meloxicam because it may cause premature closure of the ductus arteriosus.
Corticosteroid Treatment
- Meloxicam cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Slowly taper patients on prolonged corticosteroid therapy if a decision is made to discontinue corticosteroids.
Masking of Inflammation and Fever
- The pharmacological activity of meloxicam in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hematological Effects
- Anemia may occur in patients receiving NSAIDs, including meloxicam. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including meloxicam, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Carefully monitor patients treated with meloxicam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.
Use in Patients with Pre-existing Asthma
- Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, meloxicam should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.
Monitoring
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, meloxicam should be discontinued.
# 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 following serious adverse reactions are discussed elsewhere in the labeling:
- Cardiovascular thrombotic events
- Gastrointestinal effects – risk of GI ulceration, bleeding, and perforation
- Hepatic effects
- Hypertension
- Congestive heart failure and edema
- Renal effects
- Anaphylactoid reactions
- Adverse skin reactions
Clinical Trials Experience
Adults
osteoarthritis and rheumatoid arthritis
- The meloxicam Phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with meloxicam 7.5 mg/day, 3505 OA patients and 1351 RA patients treated with meloxicam 15 mg/day. Meloxicam at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo- and/or active-controlled osteoarthritis trials and 2363 of these patients were treated in ten placebo- and/or active-controlled rheumatoid arthritis trials. Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across meloxicam trials.
- A 12-week multicenter, double-blind, randomized trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of meloxicam with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients with rheumatoid arthritis to compare the efficacy and safety of meloxicam with placebo.
- Table 1a depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in a 12-week placebo- and active-controlled osteoarthritis trial.
- Table 1b depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in two 12-week placebo- controlled rheumatoid arthritis trials.
- The adverse events that occurred with meloxicam in ≥ 2% of patients treated short-term (4 to 6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 2.
- Higher doses of meloxicam (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore the daily dose of meloxicam should not exceed 15 mg.
- The following is a list of adverse drug reactions occurring in < 2% of patients receiving meloxicam in clinical trials involving approximately 16,200 patients.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of meloxicam. 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. Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug. Adverse reactions reported in worldwide post marketing experience or the literature include: acute urinary retention; agranulocytosis; alterations in mood (such as mood elevation); anaphylactoid reactions including shock; erythema multiforme; exfoliative dermatitis; interstitial nephritis; jaundice; liver failure; Stevens-Johnson syndrome, and toxic epidermal necrolysis.
# Drug Interactions
- See also Pharmacology.
ACE-inhibitors
- NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking meloxicam concomitantly with ACE-inhibitors.
Aspirin
- When meloxicam is administered with aspirin (1000 mg three times daily) to healthy volunteers, an increase the AUC (10%) and Cmax (24%) of meloxicam was noted. The clinical significance of this interaction is not known; however, as with other NSAIDs concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects.
- Concomitant administration of low-dose aspirin with meloxicam may result in an increased rate of GI ulceration or other complications, compared to use of meloxicam alone. Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis.
Diuretics
- Clinical studies, as well as post marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with meloxicam, patients should be observed closely for signs of renal failure, as well as to ensure diuretic efficacy.
Lithium
- In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam 15 mg every day as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by meloxicam. Closely monitor patients on lithium treatment for signs of lithium toxicity when meloxicam is introduced, adjusted, or withdrawn.
Methotrexate
- NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Therefore, NSAIDs may reduce the elimination of methotrexate, thereby enhancing the toxicity of methotrexate. Use caution when meloxicam is administered concomitantly with methotrexate.
Cyclosporine
- Meloxicam, like other NSAIDs, may affect renal prostaglandins, thereby altering the renal toxicity of certain drugs. Therefore, concomitant therapy with meloxicam may increase cyclosporine's nephrotoxicity. Use caution when meloxicam is administered concomitantly with cyclosporine.
Warfarin
- The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
- Monitor anticoagulant activity, particularly in the first few days after initiating or changing meloxicam therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding than with the use of either drug alone. Use caution when administering meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C; Category D starting 30 weeks gestation
- There are no adequate and well-controlled studies in pregnant women. Meloxicam crosses the placental barrier. Prior to 30 weeks gestation, use meloxicam during pregnancy only if the potential benefit justifies the potential risk to the fetus. Starting at 30 weeks gestation, avoid meloxicam and other NSAIDs, in pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, inform the patient of the potential hazard to a fetus.
Teratogenic Effects
- Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the maximum recommended human daily dose [MRHD] based on body surface area [BSA] comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day. The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion).
Nonteratogenic Effects
- In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65-and 6.5-fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Meloxicam in women who are pregnant.
### Labor and Delivery
- The effects of meloxicam on labor and delivery of pregnant women are unknown. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (at least 12.5 times lower than the maximum recommended human daily dose based on body surface area comparison).
### Nursing Mothers
- It is not known whether this drug is excreted in human milk; however, meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from meloxicam, 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
- Use of meloxicam for a pediatric indication is protected by marketing exclusivity.
### Geriatic Use
- As with any NSAID, caution should be exercised in treating the elderly (65 years and older).
- Of the total number of subjects in clinical studies, 5157 were age 65 and over (4044 in OA studies and 1113 in RA studies). 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 Meloxicam with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Meloxicam with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of meloxicam in subjects with severe renal impairment is not recommended. Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore, it is recommended that meloxicam dosage in this population not exceed 7.5 mg per day Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable.
### Hepatic Impairment
- No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Since meloxicam is significantly metabolized in the liver; the use of meloxicam in these patients should be done with caution.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Meloxicam in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Meloxicam in patients who are immunocompromised.
# Administration and Monitoring
### Administration
General Instructions
- Carefully consider the potential benefits and risks of meloxicam and other treatment options before deciding to use meloxicam. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.4)].
- After observing the response to initial therapy with meloxicam, adjust the dose to suit an individual patient's needs.
- In adults, the maximum recommended daily oral dose of meloxicam is 15 mg regardless of formulation. In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended.
- Meloxicam may be taken without regard to timing of meals.
osteoarthritis
- For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
rheumatoid arthritis
- For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily.
DOSAGE FORMS AND STRENGTHS
- Tablets:
- 7.5 mg: pastel yellow, round, biconvex, uncoated tablet containing meloxicam 7.5 mg. The 7.5 mg tablet is impressed with “5” mark on one side.
- 15 mg: pastel yellow, round, biconvex, uncoated tablet containing meloxicam 15 mg. The 15 mg tablet is impressed with “100” mark on one side.
### Monitoring
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, meloxicam should be discontinued.
- New onset or worsening of hypertension can occur. Blood pressure should be monitored closely during treatment.
- Closely monitor the renal function of patients with impaired renal function who are taking meloxicam as some meloxicam metabolites are excreted by the kidney.
- Monitor patients treated with meloxicam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.
- Closely monitor patients on lithium treatment for signs of lithium toxicity when meloxicam is introduced, adjusted, or withdrawn.
- Monitor anticoagulant activity, particularly in the first few days after initiating or changing meloxicam therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding than with the use of either drug alone. Use caution when administering meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.
# IV Compatibility
There is limited information regarding the compatibility of Meloxicam and IV administrations.
# Overdosage
- There is limited experience with meloxicam overdose. Four cases have taken 6 to 11 times the highest recommended dose; all recovered. Cholestyramine is known to accelerate the clearance of meloxicam.
- Symptoms following acute NSAID overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular collapse, and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
- Patients should be managed with symptomatic and supportive care following an NSAID overdose. Administration of activated charcoal is recommended for patients who present 1 to 2 hours after overdose. For substantial overdose or severely symptomatic patients, activated charcoal may be administered repeatedly. Accelerated removal of meloxicam by 4 gm oral doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
- For additional information about overdose treatment, call a poison control center (1-800-222-1222).
# Pharmacology
## Mechanism of Action
- The mechanism of action of meloxicam, like that of other NSAIDs, may be related to prostaglandin synthetase (cyclo-oxygenase) inhibition which is involved in the intial steps of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin. It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy.
## Structure
- Meloxicam, an oxicam derivative, is a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each pastel yellow Meloxicam Tablets, USP contains 7.5 mg or 15 mg meloxicam for oral administration. Meloxicam is chemically designated as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C14H13N3O4S2 and it has the following structural formula:
- Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app = 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2.
- Meloxicam is available as a tablet for oral administration containing 7.5 mg or 15 mg meloxicam.
- The inactive ingredients in Meloxicam Tablets, USP include Colloidal Silicon Dioxide, Sodium Starch Glycolate, Lactose, Magnesium Stearate, Microcrystalline Cellulose, Povidone K-30, and Sodium Citrate.
## Pharmacodynamics
- Meloxicam exhibits anti-inflammatory, analgesic, and antipyretic activities.
## Pharmacokinetics
Absorption
- The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean Cmax was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady-state concentrations were reached by Day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling.
Food and Antacid Effects
- Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., Cmax) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (Tmax) was achieved between 5 and 6 hours. In comparison, neither the AUC nor the Cmax values for meloxicam suspension were affected following a similar high fat meal, while mean Tmax values were increased to approximately 7 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, meloxicam can be administered without regard to timing of meals or concomitant administration of antacids.
Distribution
- The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam.
- Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.
Metabolism
- Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. All the four metabolites are not known to have any in vivo pharmacological activity.
Excretion
- Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%.
- The mean elimination half-life (t1/2) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min.
Special Populations
Pediatric
- After single (0.25 mg/kg) dose administration and after achieving steady state (0.375 mg/kg/day), there was a general trend of approximately 30% lower exposure in younger patients (2 to 6 years old) as compared to the older patients (7 to 16 years old). The older patients had meloxicam exposures similar (single dose) or slightly reduced (steady state) to those in the adult patients, when using AUC values normalized to a dose of 0.25 mg/kg. The meloxicam mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0) for the 2 to 6 year old patients, and 7 to 16 year old patients, respectively.
- In a covariate analysis, utilizing population pharmacokinetics body-weight, but not age, was the single predictive covariate for differences in the meloxicam apparent oral plasma clearance. The body-weight normalized apparent oral clearance values were adequate predictors of meloxicam exposure in pediatric patients.
- The pharmacokinetics of meloxicam in pediatric patients under 2 years of age have not been investigated.
Geriatric
- Elderly males (≥65 years of age) exhibited meloxicam plasma concentrations and steady-state pharmacokinetics similar to young males. Elderly females (≥65 years of age) had a 47% higher AUCss and 32% higher Cmax,ss as compared to younger females (≤55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients.
Gender
- Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cmax or Tmax across genders.
Hepatic Impairment
- Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied.
Renal Impairment
- Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of meloxicam in subjects with severe renal impairment is not recommended.
Hemodialysis
Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable.
Drug Interactions
- Aspirin: When meloxicam is administered with aspirin (1000 mg three times daily) to healthy volunteers, it tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known.
- Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established.
- Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam.
- Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam.
- Lithium: In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam 15 mg QD every day as compared to subjects receiving lithium alone.
- Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites.
- Warfarin: The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis: There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.5- and 2.6-fold, respectively, the maximum recommended human daily dose based on body surface area comparison).
- Mutagenesis: Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow.
- Impairment of Fertility: Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 5.8- and 3.2-fold greater, respectively, than the maximum recommended human daily dose based on body surface area comparison).
# Clinical Studies
osteoarthritis and rheumatoid arthritis
- The use of meloxicam for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a 12-week, double-blind, controlled trial. Meloxicam (3.75 mg, 7.5 mg, and 15 mg daily) was compared to placebo. The four primary endpoints were investigator's global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function, and stiffness). Patients on meloxicam 7.5 mg daily and meloxicam 15 mg daily showed significant improvement in each of these endpoints compared with placebo.
- The use of meloxicam for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S. ranging from 4 weeks' to 6 months' duration. In these trials, the efficacy of meloxicam, in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S. trial.
- The use of meloxicam for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a 12-week, double-blind, controlled multinational trial. Meloxicam (7.5 mg, 15 mg, and 22.5 mg daily) was compared to placebo. The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory, and functional measures of RA response. Patients receiving meloxicam 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo. No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose.
# How Supplied
- Meloxicam is available as a pastel yellow, round, biconvex, uncoated tablet containing meloxicam 7.5 mg or 15 mg. The 7.5 mg tablet is impressed with “5” mark on one side, and the 15 mg tablet is impressed with “100” mark on one side.
- Meloxicam Tablets, USP 7.5 mg is supplied in blister punch material as follows:
- NDC 50268-525-15- 10 Tablets per card, 5 cards per carton
- Meloxicam Tablets, USP 15 mg is supplied in blister punch material as follows:
- NDC 50268-526-15- 10 Tablets per card, 5 cards per carton
## Storage
- Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)[see USP Controlled Room Temperature].
- Keep Meloxicam Tablets, USP in a dry place.
- Dispense tablets in a tight container.
- Keep this and all medications out of the reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- See FDA-approved Medication Guide
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy.
Medication Guide
- Inform patients of the availability of a Medication Guide for NSAIDs that accompanies each prescription dispensed, and instruct them to read the Medication Guide prior to using meloxicam.
Cardiovascular Effects
- NSAIDs including meloxicam may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up.
Gastrointestinal Effects
- NSAIDs including meloxicam, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up.
Hepatotoxicity
- Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop therapy and seek immediate medical therapy.
Adverse Skin Reactions
- NSAIDs, including meloxicam, can cause serious skin side effects such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
Weight Gain and Edema
- Advise patients to promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
Anaphylactoid Reactions
- Inform patients of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help.
Effects During Pregnancy
- Starting at 30 weeks gestation, meloxicam should be avoided as premature closure of the ductus arteriosus in the fetus may occur.
- Please address medical inquiries to 1-866-562-4706
# Precautions with Alcohol
Alcohol-Meloxicam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Mobic
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Meloxicam | |
359b83a9f1e55e72a3c5f86b4400a11a698e0d2f | wikidoc | Melperone | Melperone
# Overview
Melperone (Bunil (PT), Buronil (AT, BE, CZ, DK, FL†, NL†, NO†, SE), Eunerpan (DE)) is an atypical antipsychotic of the butyrophenone chemical class, making it structurally related to the typical antipsychotic haloperidol. It first entered clinical use in 1960s.
# Marketing and indications
It has been tried in treatment-resistant cases of schizophrenia with some (albeit limited) success. It has also been reported effective in the treatment of L-DOPA and other forms of psychosis in Parkinson's disease (although a multicentre, double-blind, placebo-controlled study conducted in 2012 failed to support these findings). It is also known to possess anxiolytic properties. It is marketed in the following countries:
- Austria
- Belgium
- Czech Republic
- Denmark
- Estonia
- Finland
- Germany
- Iceland
- Lithuania
- Portugal
- Sweden
# Adverse effects
Melperone is reported to produce significantly less weight gain than clozapine and approximately as much weight gain as typical antipsychotics. It is also purported to produce around as much prolactin secretion as clozapine (which is virtually nill). It is also purported to produce sedative effects and QT interval prolongation. It is also known to produce less extrapyramidal side effects than the first-generation (typical) antipsychotic, thiothixene. It can also produce (usually relatively mild) dry mouth.
- Constipation
- Diarrhoea
- Nausea
- Vomiting
- Appetite loss
- Hypersalivation (drooling)
- Extrapyramidal side effects*
- Insomnia
- Agitation
- Headache
- Dizziness
- Fatigue
- Miosis
- Mydriasis
- Blurred vision
- Elevated liver enzymes (esp. ALT and GGTP)
- tremor, dystonia, hypokinesis, akathisia, dyskinesias
- Tardive dyskinesia
- Neuroleptic malignant syndrome
- Blood dyscrasias (pancytopaenia, agranulocytosis, leukopaenia, thrombocytopaenia, etc.)
- Seizures (probably rare/uncommon)
- Increased intraocular pressure
- Intrahepatic cholestasis (probably rare)
- Orthostatic hypotension (probably common)
- Arrhythmias
- Rash
- Hyperprolactinaemia
- Weight gain
- Increased appetite
which can lead to galactorrhoea, gynecomastia, etc.
## Interactions
Melperone is reported to be a CYP2D6 inhibitor.
# Pharmacology
Melperone binds to the dopamine D2 receptor, just like all other clinically-utilised antipsychotics, but it does so with a very low affinity and hence may be liable to rapidly dissociate from the D2 receptor hence potentially giving it the profile of an atypical antipsychotic. | Melperone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Melperone (Bunil (PT), Buronil (AT, BE, CZ, DK, FL†, NL†, NO†, SE), Eunerpan (DE))[3] is an atypical antipsychotic of the butyrophenone chemical class, making it structurally related to the typical antipsychotic haloperidol. It first entered clinical use in 1960s.[4]
# Marketing and indications
It has been tried in treatment-resistant cases of schizophrenia with some (albeit limited) success.[4][5][6][7] It has also been reported effective in the treatment of L-DOPA and other forms of psychosis in Parkinson's disease[8] (although a multicentre, double-blind, placebo-controlled study conducted in 2012 failed to support these findings[9]). It is also known to possess anxiolytic properties.[10] It is marketed in the following countries:[3]
- Austria
- Belgium
- Czech Republic
- Denmark
- Estonia
- Finland
- Germany
- Iceland
- Lithuania
- Portugal
- Sweden
# Adverse effects
Melperone is reported to produce significantly less weight gain than clozapine and approximately as much weight gain as typical antipsychotics.[11] It is also purported to produce around as much prolactin secretion as clozapine (which is virtually nill).[12] It is also purported to produce sedative effects[13] and QT interval prolongation.[14] It is also known to produce less extrapyramidal side effects than the first-generation (typical) antipsychotic, thiothixene.[15] It can also produce (usually relatively mild) dry mouth.[16]
- Constipation
- Diarrhoea
- Nausea
- Vomiting
- Appetite loss
- Hypersalivation (drooling)
- Extrapyramidal side effects*
- Insomnia
- Agitation
- Headache
- Dizziness
- Fatigue
- Miosis
- Mydriasis
- Blurred vision
- Elevated liver enzymes (esp. ALT and GGTP)
* tremor, dystonia, hypokinesis, akathisia, dyskinesias
- Tardive dyskinesia
- Neuroleptic malignant syndrome
- Blood dyscrasias (pancytopaenia, agranulocytosis, leukopaenia, thrombocytopaenia, etc.)
- Seizures (probably rare/uncommon)
- Increased intraocular pressure
- Intrahepatic cholestasis (probably rare)
- Orthostatic hypotension (probably common)
- Arrhythmias
- Rash
- Hyperprolactinaemia**
- Weight gain
- Increased appetite
** which can lead to galactorrhoea, gynecomastia, etc.
## Interactions
Melperone is reported to be a CYP2D6 inhibitor.[20][21][22]
# Pharmacology
Melperone binds to the dopamine D2 receptor, just like all other clinically-utilised antipsychotics, but it does so with a very low affinity and hence may be liable to rapidly dissociate from the D2 receptor hence potentially giving it the profile of an atypical antipsychotic.[23] | https://www.wikidoc.org/index.php/Melperone | |
7d9101efb1dba363da4179b575e28c18baa56289 | wikidoc | Melphalan | Melphalan
# 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
Melphalan is an alkylating agent that is FDA approved for the treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. There is a Black Box Warning for this drug as shown here. Common adverse reactions include stomatitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
For the palliative treatment of multiple myeloma
- Dosage:
- The usual oral dose is 6 mg (3 tablets) daily. The entire daily dose may be given at one time.
- The dose is adjusted, as required, on the basis of blood counts done at approximately weekly intervals.
- After 2 to 3 weeks of treatment, the drug should be discontinued for up to 4 weeks, during which time the blood count should be followed carefully.
- When the white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be instituted.
For the palliation of non-resectable epithelial carcinoma of the ovary.
- Dosage:
- 0.2 mg/kg daily for 5 days as a single course. Courses are repeated every 4 to 5 weeks depending upon hematologic tolerance.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Melphalan in adult patients.
### Non–Guideline-Supported Use
- Bone marrow transplant
- Breast cancer
- Chronic myeloid leukemia
- Dosage: 0.25 mg/kg/day for 4 to 7 days, repeated at 4 to 6 week interval
- Endometrial carcinoma
- Waldenström macroglobulinemia
# 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 Melphalan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Melphalan in pediatric patients.
# Contraindications
Melphalan should not be used in patients whose disease has demonstrated a prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug.
# Warnings
As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow suppression.Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent course of melphalan: platelet count, hemoglobin, white blood cell count, and differential. Thrombocytopenia and/or leukopenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity. Dose adjustment on the basis of blood counts at the nadir and day of treatment should be considered.
Hypersensitivity reactions, including anaphylaxis, have occurred rarely. These reactions have occurred after multiple courses of treatment and have recurred in patients who experienced a hypersensitivity reaction to IV melphalan. If a hypersensitivity reaction occurs, oral or IV melphalan should not be readministered.
# Adverse Reactions
## Clinical Trials Experience
The most common side effect is bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. Although bone marrow suppression frequently occurs, it is usually reversible if melphalan is withdrawn early enough. However, irreversible bone marrow failure has been reported.
Nausea, vomiting, diarrhea, and oral ulceration occur. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported.
Other reported adverse reactions include: pulmonary fibrosis (including fatal outcomes) and interstitial pneumonitis, skin hypersensitivity, maculopapular rashes, vasculitis, alopecia, and hemolytic anemia. Allergic reactions, including urticaria, edema, skin rashes, and rare anaphylaxis, have occurred after multiple courses of treatment. Cardiac arrest has also been reported rarely in association with such reports.
## Postmarketing Experience
There is limited information regarding Melphalan Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Melphalan Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Melphalan may cause fetal harm when administered to a pregnant woman. Melphalan was embryolethal and teratogenic in rats following oral (6 to 18 mg/m2/day for 10 days) and intraperitoneal (18 mg/m2) administration. Malformations resulting from melphalan included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as hepatocele (exomphaly).
There are no adequate and well-controlled studies in pregnant women. 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. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Melphalan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Melphalan during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk. melphalan should not be given to nursing mothers.
### Pediatric Use
The safety and effectiveness of melphalan in pediatric patients have not been established.
### Geriatic Use
Clinical studies of melphalan Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Melphalan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Melphalan with respect to specific racial populations.
### Renal Impairment
In patients with moderate to severe renal impairment, currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction to those patients, but it may be prudent to use a reduced dose initially.
### Hepatic Impairment
There is no FDA guidance on the use of Melphalan in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported.
### Immunocompromised Patients
There is no FDA guidance one the use of Melphalan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Bood counts done at approximately weekly intervals.
# IV Compatibility
There is limited information regarding the compatibility of Melphalan and IV administrations.
# Overdosage
Overdoses, including doses up to 50 mg/day for 16 days, have been reported. Immediate effects are likely to be vomiting, ulceration of the mouth, diarrhea, and hemorrhage of the gastrointestinal tract. The principal toxic effect is bone marrow suppression. Hematologic parameters should be closely followed for 3 to 6 weeks. An uncontrolled study suggests that administration of autologous bone marrow or hematopoietic growth factors (i.e., sargramostim, filgrastim) may shorten the period of pancytopenia. General supportive measures, together with appropriate blood transfusions and antibiotics, should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by hemodialysis.
# Pharmacology
## Mechanism of Action
Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.
## Structure
The molecular formula is C13H18Cl2N2O2 and the molecular weight is 305.20. The structural formula is:
## Pharmacodynamics
There is limited information regarding Melphalan Pharmacodynamics in the drug label.
## Pharmacokinetics
The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the drug in plasma (range: 0 to 6 hours) and peak plasma concentration (Cmax). The average absolute bioavailability of melphalan is also highly variable (range: 56% to 93%). These results may be due to incomplete intestinal absorption, a variable “first pass” hepatic metabolism, or to rapid hydrolysis. Oral administration of melphalan with a high fat meal may reduce melphalan exposure (AUC) by 36% to 54%.
In 18 patients given a single oral dose of 0.6 mg/kg of melphalan, the terminal elimination plasma half-life (t1/2) of parent drug was 1.5 ± 0.83 hours. The 24-hour urinary excretion of parent drug in these patients was 10% ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug. In a separate study in 18 patients given single oral doses of 0.2 to 0.25 mg/kg of melphalan, Cmax and plasma concentration-time curves (AUC), when dose adjusted to a dose of 14 mg, were (mean ± SD) 212 ± 74 ng/mL and 498 ± 137 nghr/mL, respectively. Elimination phase t½ in these patients was approximately 1 hour and the median tmax was 1 hour.
One study using universally labeled 14C-melphalan, found substantially less radioactivity in the urine of patients given the drug by mouth (30% of administered dose in 9 days) than in the urine of those given it intravenously (35% to 65% in 7 days). Following either oral or IV administration, the pattern of label recovery was similar, with the majority being recovered in the first 24 hours. Following oral administration, peak radioactivity occurred in plasma at 2 hours and then disappeared with a half-life of approximately 160 hours. In 1 patient where parent drug (rather than just radiolabel) was determined, the melphalan half-disappearance time was 67 minutes.
The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The average melphalan binding to plasma proteins is highly variable (range: 53% to 92%). Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while α1-acid glycoprotein accounts for about 20% of the plasma protein binding. Approximately 30% of melphalan is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one pharmacokinetic study showed a significant positive correlation between the elimination rate constant for melphalan and renal function and a significant negative correlation between renal function and the area under the plasma melphalan concentration/time curve.
## Nonclinical Toxicology
Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukemia, myeloproliferative syndrome, or carcinoma is not possible. Published reports of leukemia in patients who have received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis increases with chronicity of treatment and with cumulative dose. In one study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was 19.5% for cumulative doses ranging from 730 mg to 9,652 mg. In this same study, as well as in an additional study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was less than 2% for cumulative doses under 600 mg. This does not mean that there is a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy.
Adequate and well-controlled carcinogenicity studies have not been conducted in animals. However, i.p. administration of melphalan in rats (5.4 to 10.8 mg/m2) and in mice (2.25 to 4.5 mg/m2) 3 times per week for 6 months followed by 12 months post-dose observation produced peritoneal sarcoma and lung tumors, respectively.
melphalan has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of melphalan at 6 and 60 mg/m2 produced structural aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats.
# Clinical Studies
There is limited information regarding Melphalan Clinical Studies in the drug label.
# How Supplied
Melphalan tablets 2 mg
- Bottle of 50 (NDC 52609-0001-5).
## Storage
Store in a refrigerator, 2° to 8°C (36° to 46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that the major toxicities of melphalan are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and pulmonary toxicity. The major long-term toxicities are related to infertility and secondary malignancies. Patients should never be allowed to take the drug without close medical supervision and should be advised to consult their physician if they experience skin rash, vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming pregnant.
# Precautions with Alcohol
Alcohol-Melphalan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alkeran
# Look-Alike Drug Names
There is limited information regarding Melphalan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Melphalan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Melphalan is an alkylating agent that is FDA approved for the treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. There is a Black Box Warning for this drug as shown here. Common adverse reactions include stomatitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
For the palliative treatment of multiple myeloma
- Dosage:
- The usual oral dose is 6 mg (3 tablets) daily. The entire daily dose may be given at one time.
- The dose is adjusted, as required, on the basis of blood counts done at approximately weekly intervals.
- After 2 to 3 weeks of treatment, the drug should be discontinued for up to 4 weeks, during which time the blood count should be followed carefully.
- When the white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily may be instituted.
For the palliation of non-resectable epithelial carcinoma of the ovary.
- Dosage:
- 0.2 mg/kg daily for 5 days as a single course. Courses are repeated every 4 to 5 weeks depending upon hematologic tolerance.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Melphalan in adult patients.
### Non–Guideline-Supported Use
- Bone marrow transplant
- Breast cancer
- Chronic myeloid leukemia
- Dosage: 0.25 mg/kg/day for 4 to 7 days, repeated at 4 to 6 week interval
- Endometrial carcinoma
- Waldenström macroglobulinemia
# 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 Melphalan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Melphalan in pediatric patients.
# Contraindications
Melphalan should not be used in patients whose disease has demonstrated a prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug.
# Warnings
As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow suppression.Bone marrow suppression is the most significant toxicity associated with melphalan in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent course of melphalan: platelet count, hemoglobin, white blood cell count, and differential. Thrombocytopenia and/or leukopenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity. Dose adjustment on the basis of blood counts at the nadir and day of treatment should be considered.
Hypersensitivity reactions, including anaphylaxis, have occurred rarely. These reactions have occurred after multiple courses of treatment and have recurred in patients who experienced a hypersensitivity reaction to IV melphalan. If a hypersensitivity reaction occurs, oral or IV melphalan should not be readministered.
# Adverse Reactions
## Clinical Trials Experience
The most common side effect is bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. Although bone marrow suppression frequently occurs, it is usually reversible if melphalan is withdrawn early enough. However, irreversible bone marrow failure has been reported.
Nausea, vomiting, diarrhea, and oral ulceration occur. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported.
Other reported adverse reactions include: pulmonary fibrosis (including fatal outcomes) and interstitial pneumonitis, skin hypersensitivity, maculopapular rashes, vasculitis, alopecia, and hemolytic anemia. Allergic reactions, including urticaria, edema, skin rashes, and rare anaphylaxis, have occurred after multiple courses of treatment. Cardiac arrest has also been reported rarely in association with such reports.
## Postmarketing Experience
There is limited information regarding Melphalan Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Melphalan Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Melphalan may cause fetal harm when administered to a pregnant woman. Melphalan was embryolethal and teratogenic in rats following oral (6 to 18 mg/m2/day for 10 days) and intraperitoneal (18 mg/m2) administration. Malformations resulting from melphalan included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as hepatocele (exomphaly).
There are no adequate and well-controlled studies in pregnant women. 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. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Melphalan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Melphalan during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk. melphalan should not be given to nursing mothers.
### Pediatric Use
The safety and effectiveness of melphalan in pediatric patients have not been established.
### Geriatic Use
Clinical studies of melphalan Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Melphalan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Melphalan with respect to specific racial populations.
### Renal Impairment
In patients with moderate to severe renal impairment, currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction to those patients, but it may be prudent to use a reduced dose initially.
### Hepatic Impairment
There is no FDA guidance on the use of Melphalan in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported.
### Immunocompromised Patients
There is no FDA guidance one the use of Melphalan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Bood counts done at approximately weekly intervals.
# IV Compatibility
There is limited information regarding the compatibility of Melphalan and IV administrations.
# Overdosage
Overdoses, including doses up to 50 mg/day for 16 days, have been reported. Immediate effects are likely to be vomiting, ulceration of the mouth, diarrhea, and hemorrhage of the gastrointestinal tract. The principal toxic effect is bone marrow suppression. Hematologic parameters should be closely followed for 3 to 6 weeks. An uncontrolled study suggests that administration of autologous bone marrow or hematopoietic growth factors (i.e., sargramostim, filgrastim) may shorten the period of pancytopenia. General supportive measures, together with appropriate blood transfusions and antibiotics, should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by hemodialysis.
# Pharmacology
## Mechanism of Action
Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.
## Structure
The molecular formula is C13H18Cl2N2O2 and the molecular weight is 305.20. The structural formula is:
## Pharmacodynamics
There is limited information regarding Melphalan Pharmacodynamics in the drug label.
## Pharmacokinetics
The absorption of oral melphalan is highly variable with respect to both the time to first appearance of the drug in plasma (range: 0 to 6 hours) and peak plasma concentration (Cmax). The average absolute bioavailability of melphalan is also highly variable (range: 56% to 93%). These results may be due to incomplete intestinal absorption, a variable “first pass” hepatic metabolism, or to rapid hydrolysis. Oral administration of melphalan with a high fat meal may reduce melphalan exposure (AUC) by 36% to 54%.
In 18 patients given a single oral dose of 0.6 mg/kg of melphalan, the terminal elimination plasma half-life (t1/2) of parent drug was 1.5 ± 0.83 hours. The 24-hour urinary excretion of parent drug in these patients was 10% ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug. In a separate study in 18 patients given single oral doses of 0.2 to 0.25 mg/kg of melphalan, Cmax and plasma concentration-time curves (AUC), when dose adjusted to a dose of 14 mg, were (mean ± SD) 212 ± 74 ng/mL and 498 ± 137 ng•hr/mL, respectively. Elimination phase t½ in these patients was approximately 1 hour and the median tmax was 1 hour.
One study using universally labeled 14C-melphalan, found substantially less radioactivity in the urine of patients given the drug by mouth (30% of administered dose in 9 days) than in the urine of those given it intravenously (35% to 65% in 7 days). Following either oral or IV administration, the pattern of label recovery was similar, with the majority being recovered in the first 24 hours. Following oral administration, peak radioactivity occurred in plasma at 2 hours and then disappeared with a half-life of approximately 160 hours. In 1 patient where parent drug (rather than just radiolabel) was determined, the melphalan half-disappearance time was 67 minutes.
The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The average melphalan binding to plasma proteins is highly variable (range: 53% to 92%). Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while α1-acid glycoprotein accounts for about 20% of the plasma protein binding. Approximately 30% of melphalan is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one pharmacokinetic study showed a significant positive correlation between the elimination rate constant for melphalan and renal function and a significant negative correlation between renal function and the area under the plasma melphalan concentration/time curve.
## Nonclinical Toxicology
Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukemia, myeloproliferative syndrome, or carcinoma is not possible. Published reports of leukemia in patients who have received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis increases with chronicity of treatment and with cumulative dose. In one study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was 19.5% for cumulative doses ranging from 730 mg to 9,652 mg. In this same study, as well as in an additional study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after melphalan therapy was less than 2% for cumulative doses under 600 mg. This does not mean that there is a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy.
Adequate and well-controlled carcinogenicity studies have not been conducted in animals. However, i.p. administration of melphalan in rats (5.4 to 10.8 mg/m2) and in mice (2.25 to 4.5 mg/m2) 3 times per week for 6 months followed by 12 months post-dose observation produced peritoneal sarcoma and lung tumors, respectively.
melphalan has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of melphalan at 6 and 60 mg/m2 produced structural aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats.
# Clinical Studies
There is limited information regarding Melphalan Clinical Studies in the drug label.
# How Supplied
Melphalan tablets 2 mg
- Bottle of 50 (NDC 52609-0001-5).
## Storage
Store in a refrigerator, 2° to 8°C (36° to 46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that the major toxicities of melphalan are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and pulmonary toxicity. The major long-term toxicities are related to infertility and secondary malignancies. Patients should never be allowed to take the drug without close medical supervision and should be advised to consult their physician if they experience skin rash, vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming pregnant.
# Precautions with Alcohol
Alcohol-Melphalan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Alkeran [1]
# Look-Alike Drug Names
There is limited information regarding Melphalan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Melphalan | |
5a6b8894677ae6910065e3b86d750e80ea1d136f | wikidoc | Memantine | Memantine
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# Overview
Memantine is an Uncompetitive N-methyl-D-aspartate Receptor Antagonist that is FDA approved for the treatment of moderate to severe dementia of the Alzheimer's type. Common adverse reactions include Hypertension, Hypotension, Syncope, Diarrhea, Vomiting, Backache, Confusion, Dizziness, Headache, Cough, Pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Dementia
- Dosing information
- Recommended dosage: 28 mg PO qd. (In a controlled clinical trial)
- Recommended starting dosage: 7 mg PO qd.
- Recommended target dosage: 28 mg PO qd. The dose should be increased in 7 mg increments to 28 mg once daily. The minimum recommended interval between dose increases is one week, and only if the previous dose has been well tolerated. The maximum recommended dose is 28 mg once daily.
- Memantine can be taken with or without food. Memantine capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed. The entire contents of each Memantine capsule should be consumed; the dose should not be divided.
Except when opened and sprinkled on applesauce, as described above, Memantine should be swallowed whole. Memantine capsules should not be divided, chewed, or crushed.
Switching from Memantine Tablets to Memantine Capsules
- Patients treated with Memantine tablets may be switched to Memantine capsules as follows:
- It is recommended that a patient who is on a regimen of 10 mg twice daily of Memantine tablets be switched to Memantine 28 mg once daily capsules the day following the last dose of a 10 mg Memantine tablet. There is no study addressing the comparative efficacy of these 2 regimens.
- In a patient with severe renal impairment, it is recommended that a patient who is on a regimen of 5 mg twice daily of NAMENDA tablets be switched to Memantine 14 mg once daily capsules the day following the last dose of a 5 mg NAMENDA tablet.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Memantine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Memantine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of memantine in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Memantine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Memantine in pediatric patients.
# Contraindications
Memantine is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.
# Warnings
### Genitourinary Conditions
Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine.
### Seizures
Memantine has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine, seizures occurred in 0.3% of patients treated with memantine and 0.6% of patients treated with placebo.
# Adverse Reactions
## Clinical Trials Experience
### Clinical Trial Data Sources
Memantine was evaluated in a double-blind placebo-controlled trial treating a total of 676 patients with moderate to severe dementia of the Alzheimer's type (341 patients treated with Memantine 28 mg/day dose and 335 patients treated with placebo) for a treatment period up to 24 weeks.
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.
### Adverse Reactions Leading to Discontinuation
In the placebo-controlled clinical trial of Memantine , which treated a total of 676 patients, the proportion of patients in the Memantine 28 mg/day dose and placebo groups who discontinued treatment due to adverse events were 10.0% and 6.3%, respectively. The most common adverse reaction in the Memantine treated group that led to treatment discontinuation in this study was dizziness at a rate of 1.5%.
### Most Common Adverse Reactions
The most commonly observed adverse reactions seen in patients administered Memantine in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the Memantine group and at a higher frequency than placebo were headache, diarrhea and dizziness.
Table 1 lists treatment-emergent adverse reactions that were observed at an incidence of ≥ 2% in the Memantine treated group and occurred at a rate greater than placebo.
### Vital Sign Changes
Memantine and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, diastolic blood pressure, and weight) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. There were no clinically important changes in vital signs in patients treated with Memantine. A comparison of supine and standing vital sign measures for Memantine and placebo in Alzheimer's patients indicated that Memantine treatment is not associated with orthostatic changes.
### Laboratory Changes
Memantine and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Memantine treatment.
### ECG Changes
Memantine and placebo groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in ECG parameters associated with Memantine treatment.
### Other Adverse Reactions Observed During Clinical Trials of Memantine
Following is a list of treatment-emergent adverse reactions reported from 750 patients treated with Memantine for periods up to 52 weeks in double-blind or open-label clinical trials. The listing does not include those events already listed in Table 1, those events for which a drug cause was remote, those events for which descriptive terms were so lacking in specificity as to be uninformative, and those events reported only once which did not have a substantial probability of being immediately life threatening. Events are categorized by body system.
Blood and Lymphatic System Disorders: anemia.
Cardiac Disorders: bradycardia, myocardial infarction.
Gastrointestinal Disorders: fecal incontinence, nausea.
General Disorders: asthenia, fatigue, gait disturbance, irritability, peripheral edema, pyrexia.
Infections and Infestations: bronchitis, nasopharyngitis, pneumonia, upper respiratory tract infection, urinary tract infection.
Injury, Poisoning and Procedural Complications: fall.
Investigations: weight decreased.
Metabolism and Nutrition Disorders: anorexia, dehydration, decreased appetite, hyperglycemia.
Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity.
Nervous System Disorders: convulsion, Alzheimer's disease, syncope, tremor.
Psychiatric Disorders: agitation, confusional state, delirium, delusion, disorientation, hallucination, insomnia, restlessness.
Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnea.
### Memantine Immediate Release Clinical Trial and Post Marketing Spontaneous Reports
The following additional adverse reactions have been identified from previous worldwide experience with memantine (immediate release) use. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to memantine and have not been listed elsewhere in labeling. However, because some of these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship between their occurrence and the administration of memantine. These events include:
Blood and Lymphatic System Disorders: agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia and thrombotic thrombocytopenic purpura.
Cardiac Disorders: atrial fibrillation, atrioventricular block (including 2nd and 3rd degree block), cardiac failure, orthostatic hypotension, and torsades de pointes.
Endocrine Disorders: Syndrome of inappropriate antidiuretic hormone.
Gastrointestinal disorders: colitis, pancreatitis.
General disorders and administration site conditions: malaise, sudden death.
Hepatobiliary Disorders: hepatitis (including abnormal hepatic function test, cytolytic and cholestatic hepatitis ), hepatic failure.
Infections and infestations: sepsis.
Investigations: electrocardiogram QT prolonged, international normalized ratio increased.
Metabolism and Nutrition Disorders: hypoglycaemia, hyponatraemia.
Nervous System Disorders: convulsions (including grand mal), cerebrovascular accident, dyskinesia, extrapyramidal disorder, hypertonia, loss of consciousness, neuroleptic malignant syndrome, Parkinsonism, tardive dyskinesia, transient ischemic attack.
Psychiatric Disorders: hallucinations (both visual and auditory), restlessness, suicidal ideation.
Renal and Urinary Disorders:acute renal failure (including abnormal renal function test), urinary retention.
Skin Disorders: rash, Stevens Johnson syndrome.
Vascular Disorders: pulmonary embolism, thrombophlebitis, deep venous thrombosis.
The following adverse events have been reported to be temporally associated with memantine treatment and are not described elsewhere in the product labeling: aspiration pneumonia, bone fracture, carpal tunnel syndrome, cerebral infarction, chest pain, cholelithiasis, claudication, depressed level of consciousness (including rare reports of coma), dysphagia, encephalopathy, gastritis, gastroesophageal reflux, intracranial hemorrhage, hyperglycemia, hyperlipidemia, ileus, impotence, lethargy, myoclonus, supraventricular tachycardia, and tachycardia. However, there is again no evidence that any of these additional adverse events are caused by memantine.
## Postmarketing Experience
FDA Package Insert for Memantine contains no information regarding postmarketing experience.
# Drug Interactions
No drug-drug interaction studies have been conducted with Memantine, specifically.
## Use with other N-methyl-D-aspartate (NMDA) Antagonists
The combined use of Memantine with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.
## Effect of Memantine on the Metabolism of Other Drugs
In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine. In addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome P450 isozymes CYP1A2, -2C9, -2E1 and -3A4/5. No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.
Pharmacokinetic studies evaluated the potential of memantine for interaction with donepezil and bupropion. Coadministration of memantine with the AChE inhibitor donepezil HCl does not affect the pharmacokinetics of either compound. Memantine did not affect the pharmacokinetics of the CYP2B6 substrate bupropion or its metabolite hydroxybupropion.
## Effect of Other Drugs on Memantine
Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the pharmacokinetics of memantine. A clinical drug-drug interaction study indicated that bupropion did not affect the pharmacokinetics of memantine.
## Drugs Eliminated via Renal Mechanisms
Because memantine is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents. However, coadministration of memantine and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ decreased by 20%. In addition, coadministration of memantine with the antihyperglycemic drug Glucovance® (glyburide and metformin HCl) did not affect the pharmacokinetics of memantine, metformin and glyburide. Furthermore, memantine did not modify the serum glucose lowering effect of Glucovance®, indicating the absence of a pharmacodynamic interaction.
## Drugs That Make the Urine Alkaline
The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate ) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions.
## Drugs Highly Bound to Plasma Proteins
Because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, is unlikely.
## Use with Cholinesterase Inhibitors
Coadministration of memantine with the AChE inhibitor donepezil HCl did not affect the pharmacokinetics of either compound. In a 24-week controlled clinical study in patients with moderate to severe Alzheimer's disease, the adverse event profile observed with a combination of memantine immediate-release and donepezil was similar to that of donepezil alone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled studies of Memantine in pregnant women. Memantine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 6 and 21 times, respectively, the maximum recommended human dose on a mg/m2 basis).
Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Memantine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Memantine during labor and delivery.
### Nursing Mothers
It is not known whether memantine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when memantine is administered to a nursing mother.
### Pediatric Use
The safety and effectiveness of memantine in pediatric patients have not been established.
Memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric patients aged 6-12 years with autism spectrum disorders (ASD), including autism, Asperger's disorder, and Pervasive Development Disorder - Not Otherwise Specified (PDD-NOS). Memantine has not been studied in pediatric patients under 6 years of age or over 12 years of age. Memantine treatment was initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6. Oral doses of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20-39 kg, 40-59 kg and ≥ 60 kg, respectively.
In a randomized, 12-week double-blind, placebo-controlled parallel study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53). In a 12-week responder-enriched randomized withdrawal study (Study B) in 471 patients with ASD, there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo (n=158).
The overall safety profile of memantine in pediatric patients was generally consistent with the known safety profile in adults.
In Study A, the treatment emergent adverse events in the memantine group (n=56) that were reported in at least 5% of patients and twice that in the placebo group (N=58) are listed in Table 2:
The treatment emergent adverse events that were reported in at least 5% of patients in the 12-48 week open-label study to identify responders to enroll in Study B are listed in Table 3:
In the randomized withdrawal study (Study B), the treatment emergent adverse event in patients randomized to placebo (n=160) and reported in at least 5% of patients and twice that of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%).
In a juvenile animal study, male and female juvenile rats were administered memantine (15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 14 through PND 70. Body weights were reduced at 45 mg/kg/day. Delays in sexual maturation were noted in male and female rats at doses ≥ 30 mg/kg/day. Memantine induced neuronal lesions in several areas of the brain on PND 15 and 17 at doses ≥ 30 mg/kg/day. Behavioral toxicity (decrease percent of auditory startle habituation) was noted for animals in the 45 mg/kg/day dose group. The 15 mg/kg/day dose was considered the No-Observed-Adverse-Effect-Level (NOAEL) for this study.
In a second juvenile rat toxicity study, male and female juvenile rats were administered memantine (1, 3, 8, 15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 7 through PND 70. Due to early memantine-related mortality, the 30 and 45 mg/kg/day dose groups were terminated without further evaluation. Memantine induced apoptosis or neuronal degeneration in several areas of the brain on PND 8, 10, and 17 at a dose of 15 mg/kg/day. The NOAEL for apoptosis and neuronal degeneration was 8 mg/kg/day. Behavioral toxicity (effects on motor activity, auditory startle habituation, and learning and memory) was noted at doses ≥ 3 mg/kg/day during treatment, but was not seen after drug discontinuation. Therefore, the 1 mg/kg/day dose was considered the NOAEL for the neurobehavioral effect in this study.
### Geriatic Use
There is no FDA guidance on the use of Memantine in geriatric settings.
### Gender
There is no FDA guidance on the use of Memantine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Memantine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Memantine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Memantine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Memantine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Memantine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Monitor your patient if :
- If the patient have, or ever had seizures.
- If the patient have, or ever had difficulty passing urine.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
Signs and symptoms most often accompanying overdosage with other formulations of memantine in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in an individual who took memantine in conjunction with unspecified antidiabetic medications. This person experienced coma, diplopia, and agitation, but subsequently recovered.
One patient participating in a Memantine clinical trial unintentionally took 112 mg of Memantine daily for 31 days and experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count.
No fatalities have been noted with overdoses of memantine alone. A fatal outcome has very rarely been reported when memantine has been ingested as part of overdosing with multiple drugs; in those instances, the relationship between memantine and a fatal outcome has been unclear.
Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine.
# Pharmacology
## Mechanism of Action
Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.
## Structure
Memantine is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:
The molecular formula is C12H21NHCl and the molecular weight is 215.76. Memantine HCl occurs as a fine white to off-white powder and is soluble in water.
NAMENDA XR capsules are supplied for oral administration as 7, 14, 21 and 28 mg capsules. Each capsule contains extended release beads with the labeled amount of memantine HCl and the following inactive ingredients: sugar spheres, polyvinylpyrrolidone, hypromellose, talc, polyethylene glycol, ethylcellulose, ammonium hydroxide, oleic acid, and medium chain triglycerides in hard gelatin capsules.
## Pharmacodynamics
Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+ or K+ channels. Memantine also showed antagonistic effects at the 5HT3 receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.
In vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine.
## Pharmacokinetics
Memantine is well absorbed after oral administration and has linear pharmacokinetics over the therapeutic dose range. It is excreted predominantly unchanged in urine and has a terminal elimination half-life of about 60-80 hours. In a study comparing 28 mg once daily NAMENDA XR to 10 mg twice daily NAMENDA Cmax and AUC0-24 values were 48% and 33% higher for the XR dosage regimen, respectively.
### Absorption
After multiple dose administration of Memantine, memantine peak concentrations occur around 9-12 hours postdose. There is no difference in the absorption of Memantine when the capsule is taken intact or when the contents are sprinkled on applesauce.
There is no difference in memantine exposure, based on Cmax or AUC, for Memantine whether that drug product is administered with food or on an empty stomach. However, peak plasma concentrations are achieved about 18 hours after administration with food versus approximately 25 hours after administration on an empty stomach.
### Distribution
The mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%).
### Metabolism
Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.
### Elimination
Memantine is excreted predominantly in the urine, unchanged, and has a terminal elimination half-life of about 60-80 hours. About 48% of administered drug is excreted unchanged in urine; the remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.
## Pharmacokinetics in Special Populations
### Hepatic Impairment
Memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B,score 7-9) and 8 subjects who were age-, gender-, and weight-matched to the hepatically-impaired subjects. There was no change in memantine exposure (based on Cmax and AUC) in subjects with moderate hepatic impairment as compared with healthy subjects. However, terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects. No dose adjustment is recommended for patients with mild and moderate hepatic impairment. Memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine have not been evaluated in that population.
### Renal Impairment
Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine HCl in 8 subjects with mild renal impairment (creatinine clearance, CLcr, > 50 – 80 mL/min), 8 subjects with moderate renal impairment (CLcr 30 – 49 mL/min), 7 subjects with severe renal impairment (CLcr 5 – 29 mL/min) and 8 healthy subjects (CLcr > 80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment. Mean AUC0-∞ increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects.
No dosage adjustment is recommended for patients with mild and moderate renal impairment. Dosage should be reduced in patients with severe renal impairment.
### Gender
Following multiple dose administration of memantine HCl 20 mg daily, females had about 45% higher exposure than males, but there was no difference in exposure when body weight was taken into account.
### Elderly
The pharmacokinetics of memantine in young and elderly subjects are similar.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (7 times the maximum recommended human dose on a mg/m2 basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (14 and 7 times the MRHD on a mg/m2 basis, respectively) through 128 weeks.
Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, an in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.
No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (6 times the MRHD on a mg/m2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.
## Animal Toxicology
Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 4 times the maximum recommended human dose (MRHD of 28 mg/day) on a mg/m2 basis.
In a neurotoxicity study, female rats were given oral doses of memantine (3, 10, 30, 60 mg/kg/day) alone or in combination with donepezil (3, 10 mg/kg/day) for 28 days. When administered alone, memantine induced neurodegeneration only at 60 mg/kg/day; however, when administered in combination with 10 mg/kg/day donepezil, memantine induced neurodegeneration at doses of 30 and 60 mg/kg/day. When 60 mg/kg/day memantine and 10 mg/kg/day donepezil were administered in combination, the incidence and severity of neurodegeneration was increased compared to that with 60 mg/kg/day memantine alone or with 30 mg/kg/day memantine in combination with 10 mg/kg/day donepezil. In addition, the combination of 60 mg/kg/day memantine and 10 mg/kg/day donepezil was associated with widespread neurodegeneration in cortical areas (perirhinal, temporal, entorhinal, frontal, insular, piriform) and in olfactory nucleus and subiculum, whereas in the other affected groups, there was limited cortical (entorhinal, retrosplenial) involvement. At the no-effect level of the combination (10 mg/kg/day memantine + 10 mg/kg/day donepezil), plasma exposures of memantine were similar to (AUC) or two times (Cmax) those expected in humans at the MRHD; plasma exposures of donepezil were 3 (AUC) or 6 (Cmax) times those in humans at the MRHD of donepezil (10 mg/day). In a published study, similar donepezil-mediated exacerbation of memantine-induced neurodegeneration was observed in female rats given single doses of memantine in combination with donepezil, both administered by intraperitoneal injection.
The potential for induction of central neurodegenerative lesions by NMDA receptor antagonists in humans is unknown.
# Clinical Studies
The effectiveness of Memantine as a treatment for patients with moderate to severe Alzheimer's disease was based on the results of a double-blind, placebo-controlled trial.
## 24-week Study of Memantine Capsules
This was a randomized double-blind clinical investigation in outpatients with moderate to severe Alzheimer's disease (diagnosed by DSM-IV criteria and NINCDS-ADRDA criteria for AD with a Mini Mental State Examination (MMSE) score ≥ 3 and ≤ 14 at Screening and Baseline) receiving acetylcholinesterase inhibitor (AChEI) therapy at a stable dose for 3 months prior to screening. The mean age of patients participating in this trial was 76.5 years with a range of 49-97 years. Approximately 72% of patients were female and 94% were Caucasian.
## Study Outcome Measures
The effectiveness of Memantine was evaluated in this study using the co-primary efficacy parameters of Severe Impairment Battery (SIB) and the Clinician's Interview-Based Impression of Change (CIBIC-Plus).
The ability of Memantine to improve cognitive performance was assessed with the Severe Impairment Battery (SIB), a multi-item instrument that has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB examines selected aspects of cognitive performance, including elements of attention, orientation, language, memory, visuospatial ability, construction, praxis, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
The ability of Memantine to produce an overall clinical effect was assessed using a Clinician's Interview Based Impression of Change that required the use of caregiver information, the CIBIC-Plus. The CIBIC-Plus is not a single instrument and is not a standardized instrument like the ADCS-ADL or SIB. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC-Plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-Plus evaluations from other clinical trials. The CIBIC-Plus used in this trial was a structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. It represents the assessment of a skilled clinician using validated scales based on his/her observation during an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-Plus is scored as a seven point categorical rating, ranging from a score of 1, indicating “marked improvement” to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening.” The CIBIC-Plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.
## Study Results
In this study, 677 patients were randomized to one of the following 2 treatments: Memantine 28 mg/day or placebo while still receiving an AChEI (either donepezil, galantamine, or rivastigmine).
Effects on Severe Impairment Battery (SIB)
Figure 1 shows the time course for the change from baseline in SIB score for the two treatment groups completing the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the SIB change scores for the Memantine 28 mg/AChEI-treated (combination therapy) patients compared to the patients on placebo/AChEI (monotherapy) was 2.6 units. Using an LOCF analysis, Memantine 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.
Figure 2 shows the cumulative percentages of patients from each treatment group who had attained at least the measure of improvement in SIB score shown on the X axis. The curves show that both patients assigned to Memantine 28 mg/AChEI and placebo/AChEI have a wide range of responses, but that the Memantine 28 mg/AChEI group is more likely to show an improvement or a smaller decline.
Figure 3 shows the time course for the CIBIC-Plus score for patients in the two treatment groups completing the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the CIBIC-Plus scores for the Memantine 28 mg/AChEI-treated patients compared to the patients on placebo/AChEI was 0.3 units. Using an LOCF analysis, Memantine 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.
Figure 4 is a histogram of the percentage distribution of CIBIC-Plus scores attained by patients assigned to each of the treatment groups who completed 24 weeks of treatment.
# How Supplied
‘’‘7 mg Capsule:’‘’
Yellow opaque capsule, with “FLI 7 mg” black imprint.
Bottle of 30: NDC# 0456-3407-33
’‘’14 mg Capsule:‘’‘
Yellow cap and dark green opaque capsule with “FLI 14 mg” black imprint on the yellow cap.
Bottle of 30: NDC# 0456-3414-33
Bottle of 90: NDC# 0456-3414-90
10 x 10 Unit Dose: NDC# 0456-3414-63
‘’‘21 mg Capsule:’‘’
White to off-white cap and dark green opaque capsule, with “FLI 21 mg” black imprint on the white to off-white cap.
Bottle of 30: NDC# 0456-3421-33
‘’‘28 mg Capsule:‘’‘
Dark green opaque capsule, with “FLI 28 mg” white imprint.
Bottle of 30: NDC# 0456-3428-33
Bottle of 90: NDC# 0456-3428-90
10 x 10 Unit Dose: NDC# 0456-3428-63
’‘’Titration Pack:‘’‘
NDC# 0456-3400-29
Contains 28 capsules (7 x 7 mg, 7 x 14 mg, 7 x 21 mg, 7 x 28 mg)
## Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
See FDA-approved patient labeling.
To assure safe and effective use of Memantine, the information and instructions provided in the patient information section should be discussed with patients and caregivers.
Patients and caregivers should be instructed to take Memantine only once per day, as prescribed.
Patients and caregivers should be instructed that Memantine capsules be swallowed whole. Alternatively, Memantine capsules may be opened and sprinkled on applesauce and the entire contents should be consumed. The capsules should not be divided, chewed or crushed.
Patients and caregivers should be advised that the product may cause headache, diarrhea and dizziness.
Manufactured for:Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045
Manufactured by:
Forest Laboratories Ireland Ltd
Licensed from Merz Pharmaceuticals GmbH
PATIENT INFORMATION
NAMENDA XR
(memantine hydrochloride) Extended Release Capsules
What is NAMENDA XR and what is it used for?
NAMENDA XR belongs to a class of substances called NMDA antagonists. It is used for the treatment of patients with Alzheimer's disease.
Do not take NAMENDA XR in the following cases:
If you know that you are allergic (hyper-sensitive) to NAMENDA XR (the active substance in NAMENDA XR) or to any of the other ingredients of NAMENDA XR.
Take special care with NAMENDA XR if:
You have, or ever had seizures.
You have, or ever had difficulty passing urine.
If any of these apply to you, your doctor may need to monitor you more closely while you are on this medicine.
NAMENDA XR with food and drink:
NAMENDA XR may be taken with or without food. NAMENDA XR capsules may be opened and sprinkled on applesauce before swallowing, but the contents of the entire capsule should be taken and the dose should not be divided. Except when opened and sprinkled on applesauce, NAMENDA XR capsules must be swallowed whole and never crushed, divided or chewed.
NAMENDA XR and older people:
NAMENDA XR can be used by patients over the age of 65, as well as by patients with Alzheimer's Disease who are aged 65 years or younger.
NAMENDA XR and children:
The use of NAMENDA XR in children is not recommended.
Pregnant women:
Tell your doctor if you are pregnant or planning to become pregnant. In the event of pregnancy, the benefits of NAMENDA XR must be assessed against the possible effects on your unborn child. Ask your doctor or pharmacist for advice before taking any medicine during pregnancy.
Breast-feeding mothers:
You should not breast-feed during treatment with NAMENDA XR. Ask your doctor or pharmacist for advice before taking any medicine while you are breast-feeding.
Taking other medicines:
Tell your doctor or pharmacist about any other medicines you are taking or have recently taken, including any you have taken without a prescription.
How to use NAMENDA XR:
Follow all instructions given to you by your doctor carefully, even if they differ from the ones given in this leaflet.
How to start treatment:
Treatment begins at a low dose (7 mg, once a day) and is gradually increased until the target dose (28 mg, once a day) is reached. To be effective, NAMENDA XR must be taken correctly, according to the following schedule:
Week 1: Start on Day 1
Take one 7 mg capsule each day.
Week 2: Start on Day 8
Take one 14 mg capsule each day.
Week 3: Start on Day 15
Take one 21 mg capsule each day.
Week 4: Start on Day 22
Take one 28 mg capsule each day.
Once the target dose (28 mg, once a day) has been reached, you can continue with that daily schedule unless told otherwise by your healthcare professional. (For patients with severe renal impairment, 14 mg once a day is the recommended dose.)
During the course of treatment, your healthcare professional may change the dose to suit your individual needs.
If you are currently taking another formulation of NAMENDA XR, talk to your healthcare professional about how to switch to NAMENDA XR.
What to do if you take more NAMENDA XR capsules than you should:
If you accidentally take more NAMENDA XR capsules than you should, inform your healthcare professional that you have accidentally taken more NAMENDA XR than you should have. You may require medical attention. Some people who have accidentally taken too much NAMENDA XR have experienced dizziness, unsteadiness, weakness, tiredness, confusion, as well as other symptoms.
If you forget to take NAMENDA XR:
If you forget to take one dose of NAMENDA XR, do not double-up on your next dose. Take only your next dose as scheduled.
If you have forgotten to take NAMENDA XR for several days, do not take the next dose until you have talked to your healthcare professional.
Possible side effects:
Like all medicines, NAMENDA XR can cause side effects, although not everyone gets them.
Do not be alarmed by this list of possible side effects. You may not experience any of them.
The most common side effects in patients taking NAMENDA XR were headache, diarrhea and dizziness.
How to store NAMENDA XR:
Do not use NAMENDA XR after the expiration date shown on the carton and bottle.
Store at 25°C (77°F).
Do not use any capsules of NAMENDA XR that are damaged or show signs of tampering.
Keep NAMENDA XR out of the reach and sight of children and pets.
Manufactured for:Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045
Manufactured by:
Forest Laboratories Ireland Ltd
Licensed from Merz Pharmaceuticals GmbH
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 7 MG BOTTLE LABEL
Rx Only
NDC 0456-3407-33
30 capsules
Once-Daily
Namenda XR™
(memantine HCl) extended release capsules
7 mg
FOREST PHARMACEUTICALS, INC.
# Precautions with Alcohol
Signs and symptoms most often accompanying overdosage with other formulations of memantine in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol.
# Brand Names
NAMENDA XR
# Look-Alike Drug Names
There is limited information regarding Memantine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Memantine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Turky Alkathery, M.D. [3]
# Disclaimer
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# Overview
Memantine is an Uncompetitive N-methyl-D-aspartate Receptor Antagonist that is FDA approved for the treatment of moderate to severe dementia of the Alzheimer's type. Common adverse reactions include Hypertension, Hypotension, Syncope, Diarrhea, Vomiting, Backache, Confusion, Dizziness, Headache, Cough, Pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Dementia
- Dosing information
- Recommended dosage: 28 mg PO qd. (In a controlled clinical trial)
- Recommended starting dosage: 7 mg PO qd.
- Recommended target dosage: 28 mg PO qd. The dose should be increased in 7 mg increments to 28 mg once daily. The minimum recommended interval between dose increases is one week, and only if the previous dose has been well tolerated. The maximum recommended dose is 28 mg once daily.
- Memantine can be taken with or without food. Memantine capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed. The entire contents of each Memantine capsule should be consumed; the dose should not be divided.
Except when opened and sprinkled on applesauce, as described above, Memantine should be swallowed whole. Memantine capsules should not be divided, chewed, or crushed.
Switching from Memantine Tablets to Memantine Capsules
- Patients treated with Memantine tablets may be switched to Memantine capsules as follows:
- It is recommended that a patient who is on a regimen of 10 mg twice daily of Memantine tablets be switched to Memantine 28 mg once daily capsules the day following the last dose of a 10 mg Memantine tablet. There is no study addressing the comparative efficacy of these 2 regimens.
- In a patient with severe renal impairment, it is recommended that a patient who is on a regimen of 5 mg twice daily of NAMENDA tablets be switched to Memantine 14 mg once daily capsules the day following the last dose of a 5 mg NAMENDA tablet.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Memantine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Memantine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of memantine in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Memantine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Memantine in pediatric patients.
# Contraindications
Memantine is contraindicated in patients with known hypersensitivity to memantine hydrochloride or to any excipients used in the formulation.
# Warnings
### Genitourinary Conditions
Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine.
### Seizures
Memantine has not been systematically evaluated in patients with a seizure disorder. In clinical trials of memantine, seizures occurred in 0.3% of patients treated with memantine and 0.6% of patients treated with placebo.
# Adverse Reactions
## Clinical Trials Experience
### Clinical Trial Data Sources
Memantine was evaluated in a double-blind placebo-controlled trial treating a total of 676 patients with moderate to severe dementia of the Alzheimer's type (341 patients treated with Memantine 28 mg/day dose and 335 patients treated with placebo) for a treatment period up to 24 weeks.
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.
### Adverse Reactions Leading to Discontinuation
In the placebo-controlled clinical trial of Memantine , which treated a total of 676 patients, the proportion of patients in the Memantine 28 mg/day dose and placebo groups who discontinued treatment due to adverse events were 10.0% and 6.3%, respectively. The most common adverse reaction in the Memantine treated group that led to treatment discontinuation in this study was dizziness at a rate of 1.5%.
### Most Common Adverse Reactions
The most commonly observed adverse reactions seen in patients administered Memantine in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the Memantine group and at a higher frequency than placebo were headache, diarrhea and dizziness.
Table 1 lists treatment-emergent adverse reactions that were observed at an incidence of ≥ 2% in the Memantine treated group and occurred at a rate greater than placebo.
### Vital Sign Changes
Memantine and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, diastolic blood pressure, and weight) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. There were no clinically important changes in vital signs in patients treated with Memantine. A comparison of supine and standing vital sign measures for Memantine and placebo in Alzheimer's patients indicated that Memantine treatment is not associated with orthostatic changes.
### Laboratory Changes
Memantine and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Memantine treatment.
### ECG Changes
Memantine and placebo groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in ECG parameters associated with Memantine treatment.
### Other Adverse Reactions Observed During Clinical Trials of Memantine
Following is a list of treatment-emergent adverse reactions reported from 750 patients treated with Memantine for periods up to 52 weeks in double-blind or open-label clinical trials. The listing does not include those events already listed in Table 1, those events for which a drug cause was remote, those events for which descriptive terms were so lacking in specificity as to be uninformative, and those events reported only once which did not have a substantial probability of being immediately life threatening. Events are categorized by body system.
Blood and Lymphatic System Disorders: anemia.
Cardiac Disorders: bradycardia, myocardial infarction.
Gastrointestinal Disorders: fecal incontinence, nausea.
General Disorders: asthenia, fatigue, gait disturbance, irritability, peripheral edema, pyrexia.
Infections and Infestations: bronchitis, nasopharyngitis, pneumonia, upper respiratory tract infection, urinary tract infection.
Injury, Poisoning and Procedural Complications: fall.
Investigations: weight decreased.
Metabolism and Nutrition Disorders: anorexia, dehydration, decreased appetite, hyperglycemia.
Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity.
Nervous System Disorders: convulsion, Alzheimer's disease, syncope, tremor.
Psychiatric Disorders: agitation, confusional state, delirium, delusion, disorientation, hallucination, insomnia, restlessness.
Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnea.
### Memantine Immediate Release Clinical Trial and Post Marketing Spontaneous Reports
The following additional adverse reactions have been identified from previous worldwide experience with memantine (immediate release) use. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to memantine and have not been listed elsewhere in labeling. However, because some of these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship between their occurrence and the administration of memantine. These events include:
Blood and Lymphatic System Disorders: agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia and thrombotic thrombocytopenic purpura.
Cardiac Disorders: atrial fibrillation, atrioventricular block (including 2nd and 3rd degree block), cardiac failure, orthostatic hypotension, and torsades de pointes.
Endocrine Disorders: Syndrome of inappropriate antidiuretic hormone.
Gastrointestinal disorders: colitis, pancreatitis.
General disorders and administration site conditions: malaise, sudden death.
Hepatobiliary Disorders: hepatitis (including abnormal hepatic function test, cytolytic and cholestatic hepatitis ), hepatic failure.
Infections and infestations: sepsis.
Investigations: electrocardiogram QT prolonged, international normalized ratio increased.
Metabolism and Nutrition Disorders: hypoglycaemia, hyponatraemia.
Nervous System Disorders: convulsions (including grand mal), cerebrovascular accident, dyskinesia, extrapyramidal disorder, hypertonia, loss of consciousness, neuroleptic malignant syndrome, Parkinsonism, tardive dyskinesia, transient ischemic attack.
Psychiatric Disorders: hallucinations (both visual and auditory), restlessness, suicidal ideation.
Renal and Urinary Disorders:acute renal failure (including abnormal renal function test), urinary retention.
Skin Disorders: rash, Stevens Johnson syndrome.
Vascular Disorders: pulmonary embolism, thrombophlebitis, deep venous thrombosis.
The following adverse events have been reported to be temporally associated with memantine treatment and are not described elsewhere in the product labeling: aspiration pneumonia, bone fracture, carpal tunnel syndrome, cerebral infarction, chest pain, cholelithiasis, claudication, depressed level of consciousness (including rare reports of coma), dysphagia, encephalopathy, gastritis, gastroesophageal reflux, intracranial hemorrhage, hyperglycemia, hyperlipidemia, ileus, impotence, lethargy, myoclonus, supraventricular tachycardia, and tachycardia. However, there is again no evidence that any of these additional adverse events are caused by memantine.
## Postmarketing Experience
FDA Package Insert for Memantine contains no information regarding postmarketing experience.
# Drug Interactions
No drug-drug interaction studies have been conducted with Memantine, specifically.
## Use with other N-methyl-D-aspartate (NMDA) Antagonists
The combined use of Memantine with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.
## Effect of Memantine on the Metabolism of Other Drugs
In vitro studies conducted with marker substrates of CYP450 enzymes (CYP1A2, -2A6, -2C9, -2D6, -2E1, -3A4) showed minimal inhibition of these enzymes by memantine. In addition, in vitro studies indicate that at concentrations exceeding those associated with efficacy, memantine does not induce the cytochrome P450 isozymes CYP1A2, -2C9, -2E1 and -3A4/5. No pharmacokinetic interactions with drugs metabolized by these enzymes are expected.
Pharmacokinetic studies evaluated the potential of memantine for interaction with donepezil and bupropion. Coadministration of memantine with the AChE inhibitor donepezil HCl does not affect the pharmacokinetics of either compound. Memantine did not affect the pharmacokinetics of the CYP2B6 substrate bupropion or its metabolite hydroxybupropion.
## Effect of Other Drugs on Memantine
Memantine is predominantly renally eliminated, and drugs that are substrates and/or inhibitors of the CYP450 system are not expected to alter the pharmacokinetics of memantine. A clinical drug-drug interaction study indicated that bupropion did not affect the pharmacokinetics of memantine.
## Drugs Eliminated via Renal Mechanisms
Because memantine is eliminated in part by tubular secretion, coadministration of drugs that use the same renal cationic system, including hydrochlorothiazide (HCTZ), triamterene (TA), metformin, cimetidine, ranitidine, quinidine, and nicotine, could potentially result in altered plasma levels of both agents. However, coadministration of memantine and HCTZ/TA did not affect the bioavailability of either memantine or TA, and the bioavailability of HCTZ decreased by 20%. In addition, coadministration of memantine with the antihyperglycemic drug Glucovance® (glyburide and metformin HCl) did not affect the pharmacokinetics of memantine, metformin and glyburide. Furthermore, memantine did not modify the serum glucose lowering effect of Glucovance®, indicating the absence of a pharmacodynamic interaction.
## Drugs That Make the Urine Alkaline
The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate ) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions.
## Drugs Highly Bound to Plasma Proteins
Because the plasma protein binding of memantine is low (45%), an interaction with drugs that are highly bound to plasma proteins, such as warfarin and digoxin, is unlikely.
## Use with Cholinesterase Inhibitors
Coadministration of memantine with the AChE inhibitor donepezil HCl did not affect the pharmacokinetics of either compound. In a 24-week controlled clinical study in patients with moderate to severe Alzheimer's disease, the adverse event profile observed with a combination of memantine immediate-release and donepezil was similar to that of donepezil alone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled studies of Memantine in pregnant women. Memantine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 6 and 21 times, respectively, the maximum recommended human dose [MRHD] on a mg/m2 basis).
Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Memantine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Memantine during labor and delivery.
### Nursing Mothers
It is not known whether memantine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when memantine is administered to a nursing mother.
### Pediatric Use
The safety and effectiveness of memantine in pediatric patients have not been established.
Memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric patients aged 6-12 years with autism spectrum disorders (ASD), including autism, Asperger's disorder, and Pervasive Development Disorder - Not Otherwise Specified (PDD-NOS). Memantine has not been studied in pediatric patients under 6 years of age or over 12 years of age. Memantine treatment was initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6. Oral doses of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20-39 kg, 40-59 kg and ≥ 60 kg, respectively.
In a randomized, 12-week double-blind, placebo-controlled parallel study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53). In a 12-week responder-enriched randomized withdrawal study (Study B) in 471 patients with ASD, there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo (n=158).
The overall safety profile of memantine in pediatric patients was generally consistent with the known safety profile in adults.
In Study A, the treatment emergent adverse events in the memantine group (n=56) that were reported in at least 5% of patients and twice that in the placebo group (N=58) are listed in Table 2:
The treatment emergent adverse events that were reported in at least 5% of patients in the 12-48 week open-label study to identify responders to enroll in Study B are listed in Table 3:
In the randomized withdrawal study (Study B), the treatment emergent adverse event in patients randomized to placebo (n=160) and reported in at least 5% of patients and twice that of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%).
In a juvenile animal study, male and female juvenile rats were administered memantine (15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 14 through PND 70. Body weights were reduced at 45 mg/kg/day. Delays in sexual maturation were noted in male and female rats at doses ≥ 30 mg/kg/day. Memantine induced neuronal lesions in several areas of the brain on PND 15 and 17 at doses ≥ 30 mg/kg/day. Behavioral toxicity (decrease percent of auditory startle habituation) was noted for animals in the 45 mg/kg/day dose group. The 15 mg/kg/day dose was considered the No-Observed-Adverse-Effect-Level (NOAEL) for this study.
In a second juvenile rat toxicity study, male and female juvenile rats were administered memantine (1, 3, 8, 15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 7 through PND 70. Due to early memantine-related mortality, the 30 and 45 mg/kg/day dose groups were terminated without further evaluation. Memantine induced apoptosis or neuronal degeneration in several areas of the brain on PND 8, 10, and 17 at a dose of 15 mg/kg/day. The NOAEL for apoptosis and neuronal degeneration was 8 mg/kg/day. Behavioral toxicity (effects on motor activity, auditory startle habituation, and learning and memory) was noted at doses ≥ 3 mg/kg/day during treatment, but was not seen after drug discontinuation. Therefore, the 1 mg/kg/day dose was considered the NOAEL for the neurobehavioral effect in this study.
### Geriatic Use
There is no FDA guidance on the use of Memantine in geriatric settings.
### Gender
There is no FDA guidance on the use of Memantine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Memantine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Memantine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Memantine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Memantine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Memantine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Monitor your patient if :
- If the patient have, or ever had seizures.
- If the patient have, or ever had difficulty passing urine.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
Signs and symptoms most often accompanying overdosage with other formulations of memantine in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness. The largest known ingestion of memantine worldwide was 2 grams in an individual who took memantine in conjunction with unspecified antidiabetic medications. This person experienced coma, diplopia, and agitation, but subsequently recovered.
One patient participating in a Memantine clinical trial unintentionally took 112 mg of Memantine daily for 31 days and experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count.
No fatalities have been noted with overdoses of memantine alone. A fatal outcome has very rarely been reported when memantine has been ingested as part of overdosing with multiple drugs; in those instances, the relationship between memantine and a fatal outcome has been unclear.
Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug. As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic. Elimination of memantine can be enhanced by acidification of urine.
# Pharmacology
## Mechanism of Action
Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease. Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels. There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.
## Structure
Memantine is an orally active NMDA receptor antagonist. The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula:
The molecular formula is C12H21N•HCl and the molecular weight is 215.76. Memantine HCl occurs as a fine white to off-white powder and is soluble in water.
NAMENDA XR capsules are supplied for oral administration as 7, 14, 21 and 28 mg capsules. Each capsule contains extended release beads with the labeled amount of memantine HCl and the following inactive ingredients: sugar spheres, polyvinylpyrrolidone, hypromellose, talc, polyethylene glycol, ethylcellulose, ammonium hydroxide, oleic acid, and medium chain triglycerides in hard gelatin capsules.
## Pharmacodynamics
Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+ or K+ channels. Memantine also showed antagonistic effects at the 5HT3 receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.
In vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine.
## Pharmacokinetics
Memantine is well absorbed after oral administration and has linear pharmacokinetics over the therapeutic dose range. It is excreted predominantly unchanged in urine and has a terminal elimination half-life of about 60-80 hours. In a study comparing 28 mg once daily NAMENDA XR to 10 mg twice daily NAMENDA Cmax and AUC0-24 values were 48% and 33% higher for the XR dosage regimen, respectively.
### Absorption
After multiple dose administration of Memantine, memantine peak concentrations occur around 9-12 hours postdose. There is no difference in the absorption of Memantine when the capsule is taken intact or when the contents are sprinkled on applesauce.
There is no difference in memantine exposure, based on Cmax or AUC, for Memantine whether that drug product is administered with food or on an empty stomach. However, peak plasma concentrations are achieved about 18 hours after administration with food versus approximately 25 hours after administration on an empty stomach.
### Distribution
The mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%).
### Metabolism
Memantine undergoes partial hepatic metabolism. The hepatic microsomal CYP450 enzyme system does not play a significant role in the metabolism of memantine.
### Elimination
Memantine is excreted predominantly in the urine, unchanged, and has a terminal elimination half-life of about 60-80 hours. About 48% of administered drug is excreted unchanged in urine; the remainder is converted primarily to three polar metabolites which possess minimal NMDA receptor antagonistic activity: the N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine. A total of 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption.
## Pharmacokinetics in Special Populations
### Hepatic Impairment
Memantine pharmacokinetics were evaluated following the administration of single oral doses of 20 mg in 8 subjects with moderate hepatic impairment (Child-Pugh Class B,score 7-9) and 8 subjects who were age-, gender-, and weight-matched to the hepatically-impaired subjects. There was no change in memantine exposure (based on Cmax and AUC) in subjects with moderate hepatic impairment as compared with healthy subjects. However, terminal elimination half-life increased by about 16% in subjects with moderate hepatic impairment as compared with healthy subjects. No dose adjustment is recommended for patients with mild and moderate hepatic impairment. Memantine should be administered with caution to patients with severe hepatic impairment as the pharmacokinetics of memantine have not been evaluated in that population.
### Renal Impairment
Memantine pharmacokinetics were evaluated following single oral administration of 20 mg memantine HCl in 8 subjects with mild renal impairment (creatinine clearance, CLcr, > 50 – 80 mL/min), 8 subjects with moderate renal impairment (CLcr 30 – 49 mL/min), 7 subjects with severe renal impairment (CLcr 5 – 29 mL/min) and 8 healthy subjects (CLcr > 80 mL/min) matched as closely as possible by age, weight and gender to the subjects with renal impairment. Mean AUC0-∞ increased by 4%, 60%, and 115% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects. The terminal elimination half-life increased by 18%, 41%, and 95% in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects.
No dosage adjustment is recommended for patients with mild and moderate renal impairment. Dosage should be reduced in patients with severe renal impairment.
### Gender
Following multiple dose administration of memantine HCl 20 mg daily, females had about 45% higher exposure than males, but there was no difference in exposure when body weight was taken into account.
### Elderly
The pharmacokinetics of memantine in young and elderly subjects are similar.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (7 times the maximum recommended human dose [MRHD] on a mg/m2 basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (14 and 7 times the MRHD on a mg/m2 basis, respectively) through 128 weeks.
Memantine produced no evidence of genotoxic potential when evaluated in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, an in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.
No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (6 times the MRHD on a mg/m2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.
## Animal Toxicology
Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 4 times the maximum recommended human dose (MRHD of 28 mg/day) on a mg/m2 basis.
In a neurotoxicity study, female rats were given oral doses of memantine (3, 10, 30, 60 mg/kg/day) alone or in combination with donepezil (3, 10 mg/kg/day) for 28 days. When administered alone, memantine induced neurodegeneration only at 60 mg/kg/day; however, when administered in combination with 10 mg/kg/day donepezil, memantine induced neurodegeneration at doses of 30 and 60 mg/kg/day. When 60 mg/kg/day memantine and 10 mg/kg/day donepezil were administered in combination, the incidence and severity of neurodegeneration was increased compared to that with 60 mg/kg/day memantine alone or with 30 mg/kg/day memantine in combination with 10 mg/kg/day donepezil. In addition, the combination of 60 mg/kg/day memantine and 10 mg/kg/day donepezil was associated with widespread neurodegeneration in cortical areas (perirhinal, temporal, entorhinal, frontal, insular, piriform) and in olfactory nucleus and subiculum, whereas in the other affected groups, there was limited cortical (entorhinal, retrosplenial) involvement. At the no-effect level of the combination (10 mg/kg/day memantine + 10 mg/kg/day donepezil), plasma exposures of memantine were similar to (AUC) or two times (Cmax) those expected in humans at the MRHD; plasma exposures of donepezil were 3 (AUC) or 6 (Cmax) times those in humans at the MRHD of donepezil (10 mg/day). In a published study, similar donepezil-mediated exacerbation of memantine-induced neurodegeneration was observed in female rats given single doses of memantine in combination with donepezil, both administered by intraperitoneal injection.
The potential for induction of central neurodegenerative lesions by NMDA receptor antagonists in humans is unknown.
# Clinical Studies
The effectiveness of Memantine as a treatment for patients with moderate to severe Alzheimer's disease was based on the results of a double-blind, placebo-controlled trial.
## 24-week Study of Memantine Capsules
This was a randomized double-blind clinical investigation in outpatients with moderate to severe Alzheimer's disease (diagnosed by DSM-IV criteria and NINCDS-ADRDA criteria for AD with a Mini Mental State Examination (MMSE) score ≥ 3 and ≤ 14 at Screening and Baseline) receiving acetylcholinesterase inhibitor (AChEI) therapy at a stable dose for 3 months prior to screening. The mean age of patients participating in this trial was 76.5 years with a range of 49-97 years. Approximately 72% of patients were female and 94% were Caucasian.
## Study Outcome Measures
The effectiveness of Memantine was evaluated in this study using the co-primary efficacy parameters of Severe Impairment Battery (SIB) and the Clinician's Interview-Based Impression of Change (CIBIC-Plus).
The ability of Memantine to improve cognitive performance was assessed with the Severe Impairment Battery (SIB), a multi-item instrument that has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB examines selected aspects of cognitive performance, including elements of attention, orientation, language, memory, visuospatial ability, construction, praxis, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
The ability of Memantine to produce an overall clinical effect was assessed using a Clinician's Interview Based Impression of Change that required the use of caregiver information, the CIBIC-Plus. The CIBIC-Plus is not a single instrument and is not a standardized instrument like the ADCS-ADL or SIB. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC-Plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-Plus evaluations from other clinical trials. The CIBIC-Plus used in this trial was a structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. It represents the assessment of a skilled clinician using validated scales based on his/her observation during an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-Plus is scored as a seven point categorical rating, ranging from a score of 1, indicating “marked improvement” to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening.” The CIBIC-Plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.
## Study Results
In this study, 677 patients were randomized to one of the following 2 treatments: Memantine 28 mg/day or placebo while still receiving an AChEI (either donepezil, galantamine, or rivastigmine).
Effects on Severe Impairment Battery (SIB)
Figure 1 shows the time course for the change from baseline in SIB score for the two treatment groups completing the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the SIB change scores for the Memantine 28 mg/AChEI-treated (combination therapy) patients compared to the patients on placebo/AChEI (monotherapy) was 2.6 units. Using an LOCF analysis, Memantine 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.
Figure 2 shows the cumulative percentages of patients from each treatment group who had attained at least the measure of improvement in SIB score shown on the X axis. The curves show that both patients assigned to Memantine 28 mg/AChEI and placebo/AChEI have a wide range of responses, but that the Memantine 28 mg/AChEI group is more likely to show an improvement or a smaller decline.
Figure 3 shows the time course for the CIBIC-Plus score for patients in the two treatment groups completing the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the CIBIC-Plus scores for the Memantine 28 mg/AChEI-treated patients compared to the patients on placebo/AChEI was 0.3 units. Using an LOCF analysis, Memantine 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.
Figure 4 is a histogram of the percentage distribution of CIBIC-Plus scores attained by patients assigned to each of the treatment groups who completed 24 weeks of treatment.
# How Supplied
‘’‘7 mg Capsule:’‘’
Yellow opaque capsule, with “FLI 7 mg” black imprint.
Bottle of 30: NDC# 0456-3407-33
’‘’14 mg Capsule:‘’‘
Yellow cap and dark green opaque capsule with “FLI 14 mg” black imprint on the yellow cap.
Bottle of 30: NDC# 0456-3414-33
Bottle of 90: NDC# 0456-3414-90
10 x 10 Unit Dose: NDC# 0456-3414-63
‘’‘21 mg Capsule:’‘’
White to off-white cap and dark green opaque capsule, with “FLI 21 mg” black imprint on the white to off-white cap.
Bottle of 30: NDC# 0456-3421-33
‘’‘28 mg Capsule:‘’‘
Dark green opaque capsule, with “FLI 28 mg” white imprint.
Bottle of 30: NDC# 0456-3428-33
Bottle of 90: NDC# 0456-3428-90
10 x 10 Unit Dose: NDC# 0456-3428-63
’‘’Titration Pack:‘’‘
NDC# 0456-3400-29
Contains 28 capsules (7 x 7 mg, 7 x 14 mg, 7 x 21 mg, 7 x 28 mg)
## Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
See FDA-approved patient labeling.
To assure safe and effective use of Memantine, the information and instructions provided in the patient information section should be discussed with patients and caregivers.
Patients and caregivers should be instructed to take Memantine only once per day, as prescribed.
Patients and caregivers should be instructed that Memantine capsules be swallowed whole. Alternatively, Memantine capsules may be opened and sprinkled on applesauce and the entire contents should be consumed. The capsules should not be divided, chewed or crushed.
Patients and caregivers should be advised that the product may cause headache, diarrhea and dizziness.
Manufactured for:Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045
Manufactured by:
Forest Laboratories Ireland Ltd
Licensed from Merz Pharmaceuticals GmbH
PATIENT INFORMATION
NAMENDA XR [Nuh-MEN-dah Eks-Are]
(memantine hydrochloride) Extended Release Capsules
What is NAMENDA XR and what is it used for?
NAMENDA XR belongs to a class of substances called NMDA antagonists. It is used for the treatment of patients with Alzheimer's disease.
Do not take NAMENDA XR in the following cases:
If you know that you are allergic (hyper-sensitive) to NAMENDA XR (the active substance in NAMENDA XR) or to any of the other ingredients of NAMENDA XR.
Take special care with NAMENDA XR if:
You have, or ever had seizures.
You have, or ever had difficulty passing urine.
If any of these apply to you, your doctor may need to monitor you more closely while you are on this medicine.
NAMENDA XR with food and drink:
NAMENDA XR may be taken with or without food. NAMENDA XR capsules may be opened and sprinkled on applesauce before swallowing, but the contents of the entire capsule should be taken and the dose should not be divided. Except when opened and sprinkled on applesauce, NAMENDA XR capsules must be swallowed whole and never crushed, divided or chewed.
NAMENDA XR and older people:
NAMENDA XR can be used by patients over the age of 65, as well as by patients with Alzheimer's Disease who are aged 65 years or younger.
NAMENDA XR and children:
The use of NAMENDA XR in children is not recommended.
Pregnant women:
Tell your doctor if you are pregnant or planning to become pregnant. In the event of pregnancy, the benefits of NAMENDA XR must be assessed against the possible effects on your unborn child. Ask your doctor or pharmacist for advice before taking any medicine during pregnancy.
Breast-feeding mothers:
You should not breast-feed during treatment with NAMENDA XR. Ask your doctor or pharmacist for advice before taking any medicine while you are breast-feeding.
Taking other medicines:
Tell your doctor or pharmacist about any other medicines you are taking or have recently taken, including any you have taken without a prescription.
How to use NAMENDA XR:
Follow all instructions given to you by your doctor carefully, even if they differ from the ones given in this leaflet.
How to start treatment:
Treatment begins at a low dose (7 mg, once a day) and is gradually increased until the target dose (28 mg, once a day) is reached. To be effective, NAMENDA XR must be taken correctly, according to the following schedule:
Week 1: Start on Day 1
Take one 7 mg capsule each day.
Week 2: Start on Day 8
Take one 14 mg capsule each day.
Week 3: Start on Day 15
Take one 21 mg capsule each day.
Week 4: Start on Day 22
Take one 28 mg capsule each day.
Once the target dose (28 mg, once a day) has been reached, you can continue with that daily schedule unless told otherwise by your healthcare professional. (For patients with severe renal impairment, 14 mg once a day is the recommended dose.)
During the course of treatment, your healthcare professional may change the dose to suit your individual needs.
If you are currently taking another formulation of NAMENDA XR, talk to your healthcare professional about how to switch to NAMENDA XR.
What to do if you take more NAMENDA XR capsules than you should:
If you accidentally take more NAMENDA XR capsules than you should, inform your healthcare professional that you have accidentally taken more NAMENDA XR than you should have. You may require medical attention. Some people who have accidentally taken too much NAMENDA XR have experienced dizziness, unsteadiness, weakness, tiredness, confusion, as well as other symptoms.
If you forget to take NAMENDA XR:
If you forget to take one dose of NAMENDA XR, do not double-up on your next dose. Take only your next dose as scheduled.
If you have forgotten to take NAMENDA XR for several days, do not take the next dose until you have talked to your healthcare professional.
Possible side effects:
Like all medicines, NAMENDA XR can cause side effects, although not everyone gets them.
Do not be alarmed by this list of possible side effects. You may not experience any of them.
The most common side effects in patients taking NAMENDA XR were headache, diarrhea and dizziness.
How to store NAMENDA XR:
Do not use NAMENDA XR after the expiration date shown on the carton and bottle.
Store at 25°C (77°F).
Do not use any capsules of NAMENDA XR that are damaged or show signs of tampering.
Keep NAMENDA XR out of the reach and sight of children and pets.
Manufactured for:Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045
Manufactured by:
Forest Laboratories Ireland Ltd
Licensed from Merz Pharmaceuticals GmbH
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 7 MG BOTTLE LABEL
Rx Only
NDC 0456-3407-33
30 capsules
Once-Daily
Namenda XR™
(memantine HCl) extended release capsules
7 mg
FOREST PHARMACEUTICALS, INC.
# Precautions with Alcohol
Signs and symptoms most often accompanying overdosage with other formulations of memantine in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol.
# Brand Names
NAMENDA XR
# Look-Alike Drug Names
There is limited information regarding Memantine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Memantine | |
1cd017ebc7aa412db35a74c5747012f31ab9149f | wikidoc | Menadione | Menadione
# 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.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Menadione is a polycyclic aromatic ketone that is FDA approved for the treatment of joint pains, bruising, fatigue, abdominal discomfort, diarrhea, and hay fever.. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For temporary relief of joint pains, bruising, fatigue, abdominal discomfort, diarrhea, and hay fever.
- Dosage: 1-10 drops under the tongue, 3 times a day
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Menadione in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Menadione in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Consult a physician for use in children under 12 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Menadione in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Menadione in pediatric patients.
# Contraindications
There is limited information regarding Menadione Contraindications in the drug label.
# Warnings
- If pregnant or breast-feeding, ask a health care professional before use.
- Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.
- Do not use if tamper evident seal is broken or missing. Store in a cool, dry place.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Menadione Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Menadione Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Menadione Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Menadione in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Menadione in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Menadione during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Menadione in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Menadione in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Menadione in geriatric settings.
### Gender
There is no FDA guidance on the use of Menadione with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Menadione with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Menadione in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Menadione in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Menadione in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Menadione in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Menadione Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Menadione and IV administrations.
# Overdosage
There is limited information regarding Menadione overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Menadione Mechanism of Action in the drug label.
## Structure
There is limited information regarding Menadione Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Menadione Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Menadione Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Menadione Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Menadione Clinical Studies in the drug label.
# How Supplied
Menadione 1 FL OZ (30 ml)
## Storage
There is limited information regarding Menadione Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Menadione Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Menadione interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Menadione
# Look-Alike Drug Names
There is limited information regarding Menadione Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Menadione
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Menadione is a polycyclic aromatic ketone that is FDA approved for the treatment of joint pains, bruising, fatigue, abdominal discomfort, diarrhea, and hay fever.. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For temporary relief of joint pains, bruising, fatigue, abdominal discomfort, diarrhea, and hay fever.
- Dosage: 1-10 drops under the tongue, 3 times a day
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Menadione in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Menadione in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Consult a physician for use in children under 12 years of age.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Menadione in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Menadione in pediatric patients.
# Contraindications
There is limited information regarding Menadione Contraindications in the drug label.
# Warnings
- If pregnant or breast-feeding, ask a health care professional before use.
- Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.
- Do not use if tamper evident seal is broken or missing. Store in a cool, dry place.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Menadione Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Menadione Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Menadione Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Menadione in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Menadione in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Menadione during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Menadione in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Menadione in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Menadione in geriatric settings.
### Gender
There is no FDA guidance on the use of Menadione with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Menadione with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Menadione in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Menadione in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Menadione in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Menadione in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Menadione Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Menadione and IV administrations.
# Overdosage
There is limited information regarding Menadione overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Menadione Mechanism of Action in the drug label.
## Structure
There is limited information regarding Menadione Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Menadione Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Menadione Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Menadione Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Menadione Clinical Studies in the drug label.
# How Supplied
Menadione 1 FL OZ (30 ml)
## Storage
There is limited information regarding Menadione Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Menadione Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Menadione interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Menadione [2]
# Look-Alike Drug Names
There is limited information regarding Menadione Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Menadione | |
06fdd324300f6f302900d97f6e58a2ddaf1250b6 | wikidoc | Vitamin K | Vitamin K
# Overview
Vitamin K denotes a group of lipophilic, and hydrophobic, vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation. Chemically they are 2-methyl-1,4-naphthoquinone derivatives.
Vitamin K2 (menaquinone, menatetrenone) is normally produced by bacteria in the intestines, and dietary deficiency is extremely rare unless the intestines are heavily damaged.
# Chemical structure
Vitamin K ("Koagulation" in German) is a group name for a number of related compounds, which have in common a methylated naphthoquinone ring structure, and which vary in the aliphatic side chain attached at the 3-position (see figure 1). Phylloquinone (also known as vitamin K1) invariably contains in its side chain four isoprenoid residues, one of which is unsaturated.
Menaquinones have side chains composed of a variable number of unsaturated isoprenoid residues; generally they are designated as MK-n, where n specifies the number of isoprenoids.
It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur.
# Physiology
Vitamin K is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate residues (abbreviated Gla-residues). Gla-residues are usually involved in binding calcium. The Gla-residues are essential for the biological activity of all known Gla-proteins.
At this time 14 human Gla-proteins have been discovered, and they play key roles in the regulation of three physiological processes: blood coagulation, bone metabolism and vascular biology.
### Blood Coagulation
- Vitamin K plays a role in blood coagulation through the activation of blood coagulation and anticoagulation pathways. In fact vitamin K is involved in the gamma carboxylation of glutamate residues of prothrombin (factor II), factors VII, IX, X, protein C, protein S and protein Z.
- Vitamin K is transformed into its active form by the enzyme vitamin K epoxide reductase.
### Bone Metabolism
- Vitamin K is involved in bone mineralization through the gamma carboxylation of vitamin K dependent proteins osteocalcin, a protein synthesized by osteoblasts , and matrix gla protein (MGP) which is a protein found in cartilage.
- Vitamin K affects calcium balance by regulating the synthesis and excretion of nephrocalcin and interleukin 1 and 6.
- High dose vitamin K2 and low dose vitamin K1 were shown to increase bone density in osteoporosis and decrease fracture rates. In fact, vitamin K's effect on bone is synergistic with co-administration of vitamin D.
### Vascular Biology
- Matrix gla protein (MGP) is not only found in cartilage but also in vessels and it plays a role in preventing atherosclerosis and in decreasing age related arterial stiffness.
# Recommended amounts
The U.S. Dietary Reference Intake (DRI) for an Adequate Intake (AI) for a 25-year old male for Vitamin K is 120 micrograms/day. No Tolerable Upper Intake Level (UL) has been set.
The human body stores Vitamin K, so it is not necessary to take Vitamin K daily.
# Sources of Vitamin K
Vitamin K is found in leafy green vegetables such as spinach and lettuce; Brassica vegetables such as kale, cabbage, cauliflower, broccoli, and Brussels sprouts; wheat bran; organ meats; cereals; some fruits, such as avocado, kiwifruit and bananas; meats; cow milk and other dairy products; eggs; and other soy products. Two tablespoons of parsley contains 153% of the recommended daily amount of vitamin K.
Phylloquinone (vitamin K1) is the major dietary form of vitamin K. Vitamin K1 is found in chicken egg yolk, butter, cow liver, most cheeses, and products. It is also found in some types of mayonnaise.
# Vitamin K deficiency
- Poor dietary intake (malnutrition, starvation, fasting, post-chemotherapy induced anorexia, total parenteral nutrition)
- Malabsorption (celiac disease)
- Antibiotics
# Role in disease
Vitamin K-deficiency may occur by disturbed intestinal uptake (such as would occur in a bile duct obstruction), by therapeutic or accidental intake of vitamin K-antagonists or, very rarely, by nutritional vitamin K-deficiency. As a result of the acquired vitamin K-deficiency, Gla-residues are not or incompletely formed and hence the Gla-proteins are inactive. Lack of control of the three processes mentioned above may lead to the following: risk of massive, uncontrolled internal bleeding, cartilage calcification and severe malformation of developing bone, or deposition of insoluble calcium salts in the arterial vessel walls.
# Vitamin K indications
## Warfarin overdose
For detailed description of role of vitamin K in warfarin overdose click here
## Superwarfarin toxicity
- Superwarfarins are long-acting rat poisons that are 100 times more potent than warfarin
- Market name: Brodifacoum, bromadiolone, coumafuryl, difenacoum
- Increased risks of superwarfarin poisoning can be seen in:
Occupational hazard
Drug addicts
Accidental exposure
Suicide cases
- Occupational hazard
- Drug addicts
- Accidental exposure
- Suicide cases
- Presentation
Bleeding
- Bleeding
- Diagnosis
Superwarfarin assays
Abnormal coagulation profile (↑ PT, aPTT, INR)
- Superwarfarin assays
- Abnormal coagulation profile (↑ PT, aPTT, INR)
- Treatment - High doses of vitamin K for longer durations (may be weeks to months)
## Use on newborn babies
In some countries, injections of Vitamin K are routinely given to newborn babies. Vitamin K is used as prophylactic measure to prevent late-onset haemorrhagic disease (HDN). However, HDN is a relatively rare problem, and many parents now choose for their babies not to have such an injection.
## Vitamin K: route of administration in patients with warfarin overanticoagulation
In patients with warfarin overanticoagulation, vitamin K administration can decrease the risks of bleeding. Oral and intravenous routes of vitamin K administration are found to be more effective than subcutaneous routes. Also, oral routes are preferred over intravenous routes, due to ease of administration and absence of anaphylaxsis seen with oral routes .
# Biochemistry
## Discovery
In the late 1920s, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet. After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that - together with the cholesterol - a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy (of Saint Louis University) did much of the research that led to the discovery of the structure and chemical nature of Vitamin K. Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on Vitamin K. Several laboratories synthesized the compound in 1939.
For several decades the vitamin K-deficient chick model was the only method of quantitating of vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content.
The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 at the University of Iowa Department of Pathology by Drs. Harry Pratt Smith, Emory Warner, Kenneth Brinkhous, and Walter Seegers.
## Function in the cell
The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al., Nelsestuen et al., and Magnusson et al.) isolated the vitamin K-dependent coagulation factor prothrombin (Factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that while warfarin-treated cows had a form of prothrombin that contained 10 glutamate amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues which were chemically identified as gamma-carboxyglutamate, or Gla. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.
The biochemistry of how Vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world. Within the cell, Vitamin K undergoes electron reduction to a reduced form of Vitamin K (called Vitamin K hydroquinone) by the enzyme Vitamin K epoxide reductase (or VKOR). Another enzyme then oxidizes Vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase or the Vitamin K-dependent carboxylase. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize Vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. Vitamin K epoxide is then re-converted to Vitamin K by the Vitamin K epoxide reductase. These two enzymes comprise the so-called Vitamin K cycle. One of the reasons why Vitamin K is rarely deficient in a human diet is because Vitamin K is continually recycled in our cells.
Warfarin and other coumadin drugs block the action of the Vitamin K epoxide reductase. This results in decreased concentrations of Vitamin K and Vitamin K hydroquinone in the tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with a greatly diminished or a complete absence of Gla. Without Gla on the amino termini of these factors, they no longer stablely bind to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As administration of Warfarin to a patient suppresses the clotting response, it must be carefully monitored to avoid over-dosing. See Warfarin.
## Gla-proteins
At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting protein Z. The bone Gla-protein osteocalcin, the calcification inhibiting matrix gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown. Gas6 can function as a growth factor that activates the Axl receptor tyrosine kinase and stimulates cell proliferation or prevents apoptosis in some cells. In all cases in which their function was known, the presence of the Gla-residues in these proteins turned out to be essential for functional activity.
Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.
Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus. These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2-5 Gla residues.
## Function in Bacteria
Many bacteria, such as Escherichia coli found in the large intestine, can synthesize Vitamin K2 (menaquinone), but not Vitamin K1 (phylloquinone). In these bacteria, menaquinone will transfer two electrons between two different small molecules, in a process called anaerobic respiration. For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, will pass two electrons to a menaquinone. The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate will convert the molecule to succinate or nitrite + water, repectively. Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except that the final electron acceptor is not molecular oxygen, but say fumarate or nitrate (In aerobic respiration, the final oxidant is molecular oxygen (O2) , which accepts four electrons from an electron donor such as NADH to be converted to water.) Escherichia coli can carry out aerobic respiration and menaquninone-mediated anaerobic respiration.
# Further reading
- Dam, H., Researches in Vitamin K, In: Pespectives in Biological Chemistry (RE Olson, ed.), Marcel Dekker, 1970. The Nobel Prize winner recounts the history of the discovery of Vitamin K.
- Suttie, J.W., Vitamin K, In: Handbook of Lipid research: The fat-soluble vitamins (HF DeLuca, ed.), Plenum Press, 1978. Outstanding review of Vitamin K research from 1930-1978 by one of the leaders in the field.
- David A. Bender, Nutritional biochemistry of the vitamins, Cambridge University Press, 2003
- G. F. M. Ball, Vitamins: their role in the human body, Blackwell Science, 2004
- Gerald F. Combs, The vitamins: fundamental aspects in nutrition and health, Academic Press, 1998 | Vitamin K
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
# Overview
Vitamin K denotes a group of lipophilic, and hydrophobic, vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation. Chemically they are 2-methyl-1,4-naphthoquinone derivatives.
Vitamin K2 (menaquinone, menatetrenone) is normally produced by bacteria in the intestines, and dietary deficiency is extremely rare unless the intestines are heavily damaged.
# Chemical structure
Vitamin K ("Koagulation" in German) is a group name for a number of related compounds, which have in common a methylated naphthoquinone ring structure, and which vary in the aliphatic side chain attached at the 3-position (see figure 1). Phylloquinone (also known as vitamin K1) invariably contains in its side chain four isoprenoid residues, one of which is unsaturated.
Menaquinones have side chains composed of a variable number of unsaturated isoprenoid residues; generally they are designated as MK-n, where n specifies the number of isoprenoids.
It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur.
# Physiology
Vitamin K is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate residues (abbreviated Gla-residues). Gla-residues are usually involved in binding calcium. The Gla-residues are essential for the biological activity of all known Gla-proteins.[1]
At this time 14 human Gla-proteins have been discovered, and they play key roles in the regulation of three physiological processes: blood coagulation[2], bone metabolism[3] and vascular biology[4].
### Blood Coagulation
- Vitamin K plays a role in blood coagulation through the activation of blood coagulation and anticoagulation pathways. In fact vitamin K is involved in the gamma carboxylation of glutamate residues of prothrombin (factor II), factors VII, IX, X, protein C, protein S and protein Z.[2]
- Vitamin K is transformed into its active form by the enzyme vitamin K epoxide reductase.
### Bone Metabolism
- Vitamin K is involved in bone mineralization through the gamma carboxylation of vitamin K dependent proteins osteocalcin, a protein synthesized by osteoblasts , and matrix gla protein (MGP) which is a protein found in cartilage.[3][5]
- Vitamin K affects calcium balance by regulating the synthesis and excretion of nephrocalcin and interleukin 1 and 6.[6]
- High dose vitamin K2 and low dose vitamin K1 were shown to increase bone density in osteoporosis and decrease fracture rates. In fact, vitamin K's effect on bone is synergistic with co-administration of vitamin D.[5]
### Vascular Biology
- Matrix gla protein (MGP) is not only found in cartilage but also in vessels and it plays a role in preventing atherosclerosis and in decreasing age related arterial stiffness.[4][7]
# Recommended amounts
The U.S. Dietary Reference Intake (DRI) for an Adequate Intake (AI) for a 25-year old male for Vitamin K is 120 micrograms/day. No Tolerable Upper Intake Level (UL) has been set.
The human body stores Vitamin K, so it is not necessary to take Vitamin K daily.
# Sources of Vitamin K
Vitamin K is found in leafy green vegetables such as spinach and lettuce; Brassica vegetables such as kale, cabbage, cauliflower, broccoli, and Brussels sprouts; wheat bran; organ meats; cereals; some fruits, such as avocado, kiwifruit and bananas; meats; cow milk and other dairy products; eggs; and other soy products. Two tablespoons of parsley contains 153% of the recommended daily amount of vitamin K.[8]
Phylloquinone (vitamin K1) is the major dietary form of vitamin K. Vitamin K1 is found in chicken egg yolk, butter, cow liver, most cheeses, and products. It is also found in some types of mayonnaise.
# Vitamin K deficiency
- Poor dietary intake (malnutrition, starvation, fasting, post-chemotherapy induced anorexia, total parenteral nutrition)
- Malabsorption (celiac disease)
- Antibiotics
# Role in disease
Vitamin K-deficiency may occur by disturbed intestinal uptake (such as would occur in a bile duct obstruction), by therapeutic or accidental intake of vitamin K-antagonists or, very rarely, by nutritional vitamin K-deficiency. As a result of the acquired vitamin K-deficiency, Gla-residues are not or incompletely formed and hence the Gla-proteins are inactive. Lack of control of the three processes mentioned above may lead to the following: risk of massive, uncontrolled internal bleeding, cartilage calcification and severe malformation of developing bone, or deposition of insoluble calcium salts in the arterial vessel walls.
# Vitamin K indications
## Warfarin overdose
For detailed description of role of vitamin K in warfarin overdose click here
## Superwarfarin toxicity
- Superwarfarins are long-acting rat poisons that are 100 times more potent than warfarin
- Market name: Brodifacoum, bromadiolone, coumafuryl, difenacoum
- Increased risks of superwarfarin poisoning can be seen in:
Occupational hazard
Drug addicts
Accidental exposure
Suicide cases
- Occupational hazard
- Drug addicts
- Accidental exposure
- Suicide cases
- Presentation
Bleeding
- Bleeding
- Diagnosis
Superwarfarin assays
Abnormal coagulation profile (↑ PT, aPTT, INR)
- Superwarfarin assays
- Abnormal coagulation profile (↑ PT, aPTT, INR)
- Treatment - High doses of vitamin K for longer durations (may be weeks to months)
## Use on newborn babies
In some countries, injections of Vitamin K are routinely given to newborn babies. Vitamin K is used as prophylactic measure to prevent late-onset haemorrhagic disease (HDN). However, HDN is a relatively rare problem, and many parents now choose for their babies not to have such an injection.
## Vitamin K: route of administration in patients with warfarin overanticoagulation
In patients with warfarin overanticoagulation, vitamin K administration can decrease the risks of bleeding. Oral and intravenous routes of vitamin K administration are found to be more effective than subcutaneous routes. Also, oral routes are preferred over intravenous routes, due to ease of administration and absence of anaphylaxsis seen with oral routes [9].
# Biochemistry
## Discovery
In the late 1920s, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet.[10] After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that - together with the cholesterol - a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy (of Saint Louis University) did much of the research that led to the discovery of the structure and chemical nature of Vitamin K.[11] Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on Vitamin K. Several laboratories synthesized the compound in 1939.[12]
For several decades the vitamin K-deficient chick model was the only method of quantitating of vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content.
The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 at the University of Iowa Department of Pathology by Drs. Harry Pratt Smith, Emory Warner, Kenneth Brinkhous, and Walter Seegers.[13]
## Function in the cell
The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al.[14], Nelsestuen et al.[15], and Magnusson et al.[16]) isolated the vitamin K-dependent coagulation factor prothrombin (Factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that while warfarin-treated cows had a form of prothrombin that contained 10 glutamate amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues which were chemically identified as gamma-carboxyglutamate, or Gla. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.
The biochemistry of how Vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world. Within the cell, Vitamin K undergoes electron reduction to a reduced form of Vitamin K (called Vitamin K hydroquinone) by the enzyme Vitamin K epoxide reductase (or VKOR).[17] Another enzyme then oxidizes Vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase[18][19] or the Vitamin K-dependent carboxylase. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize Vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. Vitamin K epoxide is then re-converted to Vitamin K by the Vitamin K epoxide reductase. These two enzymes comprise the so-called Vitamin K cycle.[20] One of the reasons why Vitamin K is rarely deficient in a human diet is because Vitamin K is continually recycled in our cells.
Warfarin and other coumadin drugs block the action of the Vitamin K epoxide reductase.[21] This results in decreased concentrations of Vitamin K and Vitamin K hydroquinone in the tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with a greatly diminished or a complete absence of Gla. Without Gla on the amino termini of these factors, they no longer stablely bind to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As administration of Warfarin to a patient suppresses the clotting response, it must be carefully monitored to avoid over-dosing. See Warfarin.
## Gla-proteins
At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting protein Z. The bone Gla-protein osteocalcin, the calcification inhibiting matrix gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown. Gas6 can function as a growth factor that activates the Axl receptor tyrosine kinase and stimulates cell proliferation or prevents apoptosis in some cells. In all cases in which their function was known, the presence of the Gla-residues in these proteins turned out to be essential for functional activity.
Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.
Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus.[22] These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2-5 Gla residues.[23]
## Function in Bacteria
Many bacteria, such as Escherichia coli found in the large intestine, can synthesize Vitamin K2 (menaquinone),[24] but not Vitamin K1 (phylloquinone). In these bacteria, menaquinone will transfer two electrons between two different small molecules, in a process called anaerobic respiration.[25] For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, will pass two electrons to a menaquinone. The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate will convert the molecule to succinate or nitrite + water, repectively. Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except that the final electron acceptor is not molecular oxygen, but say fumarate or nitrate (In aerobic respiration, the final oxidant is molecular oxygen (O2) , which accepts four electrons from an electron donor such as NADH to be converted to water.) Escherichia coli can carry out aerobic respiration and menaquninone-mediated anaerobic respiration.
# Further reading
- Dam, H., Researches in Vitamin K, In: Pespectives in Biological Chemistry (RE Olson, ed.), Marcel Dekker, 1970. The Nobel Prize winner recounts the history of the discovery of Vitamin K.
- Suttie, J.W., Vitamin K, In: Handbook of Lipid research: The fat-soluble vitamins (HF DeLuca, ed.), Plenum Press, 1978. Outstanding review of Vitamin K research from 1930-1978 by one of the leaders in the field.
- David A. Bender, Nutritional biochemistry of the vitamins, Cambridge University Press, 2003
- G. F. M. Ball, Vitamins: their role in the human body, Blackwell Science, 2004
- Gerald F. Combs, The vitamins: fundamental aspects in nutrition and health, Academic Press, 1998
# External links
- Template:Pauling
- Vitamin K: Another Reason to Eat Your Greens
- Vitamin K: Signs of Deficiency
- Vitamin K Deficiency - from the Merck Manual
- An Alternative Perspective on Vitamin K Prophylaxis
- Vitamin K Content - USDA National Nutrient Database for Standard Reference, Release 19 | https://www.wikidoc.org/index.php/Menaquinone |
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