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d3f86412f3580497c43beb4cbb89c44b380bfdfa	wikidoc	Oscillopsia	Oscillopsia # Overview Oscillopsia is a visual disturbance in which objects in the visual field appear to oscillate. The severity of the effect may range from a mild blurring to rapid and periodic jumping. # Differential diagnosis of causes of Oscillopsia: Oscillopsia may be caused by loss of the vestibulo-ocular reflex, involuntary eye movements such as nystagmus, or impaired coordination in the visual cortex (especially due to toxins). # Associated signs and symptoms Sufferers may experience dizziness and nausea. Oscillopsia can also be used as a quantitative test to document aminoglycoside toxicity.	Oscillopsia Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Oscillopsia is a visual disturbance in which objects in the visual field appear to oscillate. The severity of the effect may range from a mild blurring to rapid and periodic jumping. # Differential diagnosis of causes of Oscillopsia: Oscillopsia may be caused by loss of the vestibulo-ocular reflex, involuntary eye movements such as nystagmus, or impaired coordination in the visual cortex (especially due to toxins). # Associated signs and symptoms Sufferers may experience dizziness and nausea. Oscillopsia can also be used as a quantitative test to document aminoglycoside toxicity. # External links - Fuzzy Vision Template:Skin and subcutaneous tissue symptoms and signs Template:Nervous and musculoskeletal system symptoms and signs Template:Urinary system symptoms and signs Template:Cognition, perception, emotional state and behaviour symptoms and signs Template:Speech and voice symptoms and signs Template:General symptoms and signs Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Oscillopsia
f661404155d51dec2b2063ee80ae20d09ce1be32	wikidoc	Oseltamivir	Oseltamivir # 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 Oseltamivir is a antiviral that is FDA approved for the treatment of influenza A and influenza B (flu) virus. Common adverse reactions include rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, hepatitis, liver function tests abnormal, arrhythmia, gastrointestinal bleeding, hemorrhagic colitis, seizure, aggravation of diabetes, psychiatric conditions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Treatment of Influenza - Ostelmavir is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days. ### Prophylaxis of Influenza - TAMIFLU is indicated for the prophylaxis of influenza in patients 1 year and older. ### Limitations of Use The following points should be considered before initiating treatment or prophylaxis with oseltamivir. - Efficacy of oseltamivir in patients who begin treatment after 48 hours of symptoms has not been established. - Oseltamivir is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention - Advisory Committee on Immunization Practices. - There is no evidence for efficacy of oseltamivir in any illness caused by agents other than influenza viruses types A and B. - Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. - Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use oseltamivir. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oseltamivir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oseltamivir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and efficacy of TAMIFLU in pediatric patients younger than 1 year of age have not been studied. TAMIFLU is not indicated for either treatment or prophylaxis of influenza in pediatric patients younger than 1 year of age because of the unknown clinical significance of nonclinical animal toxicology data for human infants. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oseltamivir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oseltamivir in pediatric patients. # Contraindications - TAMIFLU is contraindicated in patients with known serious hypersensitivity to oseltamivir or any component of the product. Severe allergic reactions have included anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme. # Warnings ### Serious Skin/Hypersensitivity Reactions - Cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme have been reported in postmarketing experience with TAMIFLU. TAMIFLU should be stopped and appropriate treatment instituted if an allergic-like reaction occurs or is suspected. ### Neuropsychiatric Events - Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. - There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving TAMIFLU. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on TAMIFLU usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of TAMIFLU to these events has not been established. Closely monitor patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing treatment for each patient. ### Bacterial Infections - Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. TAMIFLU has not been shown to prevent such complications. - Limitations of Populations Studied Efficacy of TAMIFLU in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization. - Efficacy of TAMIFLU for treatment or prophylaxis of influenza has not been established in immunocompromised patients. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Oseltamivir Clinical Trials Experience in the drug label. ## Postmarketing Experience - The following adverse reactions have been identified during postapproval use of TAMIFLU. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to TAMIFLU exposure. - Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme. Hepatitis, liver function tests abnormal. - Arrhythmia - Gastrointestinal bleeding, hemorrhagic colitis - Seizure - Aggravation of diabetes - Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions # Drug Interactions - The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of TAMIFLU, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of TAMIFLU. - Overall Drug Interaction Profile for Oseltamivir - Information derived from pharmacology and pharmacokinetic studies of oseltamivir suggests that clinically significant drug interactions are unlikely. - Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, located predominantly in the liver. Drug interactions involving competition for esterases have not been extensively reported in literature. Low protein binding of oseltamivir and oseltamivir carboxylate suggests that the probability of drug displacement interactions is low. - In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases. - Clinically important drug interactions involving competition for renal tubular secretion are unlikely due to the known safety margin for most of these drugs, the elimination characteristics of oseltamivir carboxylate (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. Coadministration of probenecid results in an approximate two-fold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However, due to the safety margin of oseltamivir carboxylate, no dose adjustments are required when coadministering with probenecid. - No pharmacokinetic interactions have been observed when coadministering oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), or warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are insufficient human data upon which to base an evaluation of risk of TAMIFLU to the pregnant woman or developing fetus. - Studies for effects on embryo-fetal development were conducted in rats (50, 250, and 1500 mg/kg/day) and rabbits (50, 150, and 500 mg/kg/day) by the oral route. Relative exposures at these doses were, respectively, 2, 13, and 100 times human exposure in the rat and 4, 8, and 50 times human exposure in the rabbit. - Pharmacokinetic studies indicated that fetal exposure was seen in both species. In the rat study, minimal maternal toxicity was reported in the 1500 mg/kg/day group. In the rabbit study, slight and marked maternal toxicities were observed, respectively, in the 150 and 500 mg/kg/day groups. There was a dose-dependent increase in the incidence rates of a variety of minor skeletal abnormalities and variants in the exposed offspring in these studies. However, the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied. - Because animal reproductive studies may not be predictive of human response and there are no adequate and well-controlled studies in pregnant women, TAMIFLU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oseltamivir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Oseltamivir during labor and delivery. ### Nursing Mothers - In lactating rats, oseltamivir and oseltamivir carboxylate are excreted in the milk. It is not known whether oseltamivir or oseltamivir carboxylate is excreted in human milk. TAMIFLU should, therefore, be used only if the potential benefit for the lactating mother justifies the potential risk to the breast-fed infant. ### Pediatric Use There is no FDA guidance on the use of Oseltamivir in pediatric settings. ### Geriatic Use - Of the total number of subjects in clinical studies of TAMIFLU for the treatment of influenza, 19% were 65 and over, while 7% were 75 and over. Of the total number of patients in clinical studies of TAMIFLU for the prophylaxis of influenza, 25% were 65 and over, while 18% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. - The safety of TAMIFLU in geriatric subjects has been established in clinical studies that enrolled 741 subjects (374 received placebo and 362 received TAMIFLU). Some seasonal variability was noted in the clinical efficacy outcomes. - Safety and efficacy have been demonstrated in elderly residents of nursing homes who took TAMIFLU for up to 42 days for the prevention of influenza. Many of these individuals had cardiac and/or respiratory disease, and most had received vaccine that season. ### Gender There is no FDA guidance on the use of Oseltamivir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Oseltamivir with respect to specific racial populations. ### Renal Impairment - Dose adjustment is recommended for patients with a serum creatinine clearance between 10 and 30 mL/min. No recommended dosing regimens are available for patients with end-stage renal disease undergoing routine hemodialysis or continuous peritoneal dialysis treatment. ### Hepatic Impairment - No dosage adjustment is required in patients with mild to moderate hepatic impairment. The safety and pharmacokinetics in patients with severe hepatic impairment have not been evaluated. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Oseltamivir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Oseltamivir in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Oseltamivir Administration in the drug label. ### Monitoring There is limited information regarding Oseltamivir Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Oseltamivir and IV administrations. # Overdosage - At present, there has been no experience with overdose. Single doses of up to 1000 mg of TAMIFLU have been associated with nausea and/or vomiting. # Pharmacology ## Mechanism of Action Oseltamivir is an antiviral drug ## Structure - TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate, and as a powder for oral suspension, which when constituted with water as directed contains 6 mg/mL oseltamivir base. - In addition to the active ingredient, each capsule contains pregelatinized starch, talc, povidone K30, croscarmellose sodium, and sodium stearyl fumarate. - The 30 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and red iron oxide. The 45 mg capsule shell contains gelatin, titanium dioxide, and black iron oxide. The 75 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and red iron oxide. - Each capsule is printed with blue ink, which includes FD&C Blue No. 2 as the colorant. In addition to the active ingredient, the powder for oral suspension contains sorbitol, monosodium citrate, xanthan gum, titanium dioxide, tutti-frutti flavoring, sodium benzoate, and saccharin sodium. - Oseltamivir phosphate is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate. The chemical formula is C16H28N2O4 (free base). The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt ## Pharmacodynamics There is limited information regarding Oseltamivir Pharmacodynamics in the drug label. ## Pharmacokinetics - Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted predominantly by hepatic esterases to oseltamivir carboxylate. - At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate. Exposure to oseltamivir is less than 5% of the total exposure after oral dosing. - Plasma concentrations of oseltamivir carboxylate are proportional to doses up to 500 mg given twice daily. - Coadministration with food has no significant effect on the peak plasma concentration (551 ng/mL under fasted conditions and 441 ng/mL under fed conditions) and the area under the plasma concentration time curve (6218 ng∙h/mL under fasted conditions and 6069 ng∙h/mL under fed conditions) of oseltamivir carboxylate. - The volume of distribution (Vss) of oseltamivir carboxylate, following intravenous administration in 24 subjects, ranged between 23 and 26 liters. - The binding of oseltamivir carboxylate to human plasma protein is low (3%). - The binding of oseltamivir to human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions. - Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms. - Absorbed oseltamivir is primarily (>90%) eliminated by conversion to oseltamivir carboxylate. Plasma concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral administration. - Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. Plasma concentrations of oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects after oral administration. - Oseltamivir carboxylate is eliminated entirely (>99%) by renal excretion. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h), indicating that tubular secretion occurs in addition to glomerular filtration. Less than 20% of an oral radiolabeled dose is eliminated in feces. - Renal Impairment Administration of 100 mg of oseltamivir phosphate twice daily for 5 days to patients with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal function. - In clinical studies oseltamivir carboxylate exposure was not altered in patients with mild or moderate hepatic impairment. - The pharmacokinetics of oseltamivir and oseltamivir carboxylate have been evaluated in a single-dose pharmacokinetic study in pediatric patients aged 5 to 16 years (n=18) and in a small number of pediatric patients aged 3 to 12 years (n=5) enrolled in a clinical trial. - Younger pediatric patients cleared both the prodrug and the active metabolite faster than adult patients resulting in a lower exposure for a given mg/kg dose. For oseltamivir carboxylate, apparent total clearance decreases linearly with increasing age (up to 12 years). - The pharmacokinetics of oseltamivir in pediatric patients over 12 years of age are similar to those in adult patients. - Exposure to oseltamivir carboxylate at steady-state was 25% to 35% higher in geriatric patients (age range 65 to 78 years) compared to young adults given comparable doses of oseltamivir. Half-lives observed in the geriatric patients were similar to those seen in young adults. - Based on drug exposure and tolerability, dose adjustments are not required for geriatric patients for either treatment or prophylaxis. ## Nonclinical Toxicology - In 2-year carcinogenicity studies in mice and rats given daily oral doses of the prodrug oseltamivir phosphate up to 400 mg/kg and 500 mg/kg, respectively, the prodrug and the active form oseltamivir carboxylate induced no statistically significant increases in tumors over controls. - The mean maximum daily exposures to the prodrug in mice and rats were approximately 130- and 320-fold, respectively, greater than those in humans at the proposed clinical dose based on AUC comparisons. - The respective safety margins of the exposures to the active oseltamivir carboxylate were 15- and 50-fold. - Oseltamivir was found to be non-mutagenic in the Ames test and the human lymphocyte chromosome assay with and without enzymatic activation and negative in the mouse micronucleus test. - It was found to be positive in a Syrian Hamster Embryo (SHE) cell transformation test. Oseltamivir carboxylate was non-mutagenic in the Ames test and the L5178Y mouse lymphoma assay with and without enzymatic activation and negative in the SHE cell transformation test. - In a fertility and early embryonic development study in rats, doses of oseltamivir at 50, 250, and 1500 mg/kg/day were administered to females for 2 weeks before mating, during mating and until day 6 of pregnancy. Males were dosed for 4 weeks before mating, during mating, and for 2 weeks after mating. - There were no effects on fertility, mating performance or early embryonic development at any dose level. The highest dose was approximately 100 times the human systemic exposure (AUC0-24h) of oseltamivir carboxylate. - Animal Toxicology and/or Pharmacology Single, oral administration of ≥657 mg/kg oseltamivir resulted in toxicity, including death, in juvenile 7 day old rats, but had no effect on adult rats. - No toxicity was observed after repeated administration of up to 500 mg/kg oseltamivir to developing juvenile rats 7 to 21 days old. This 500 mg/kg dose was approximately 280 and 14 times the human systemic exposure (AUC0-24h) of oseltamivir and oseltamivir carboxylate, respectively. - Clinical relevance of the juvenile rat study finding for young infants is unknown. # Clinical Studies - Two placebo-controlled double-blind clinical trials were conducted: one in the U.S. and one outside the U.S. Subjects were eligible for these trials if they had fever >100ºF, accompanied by at least one respiratory symptom (cough, nasal symptoms, or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue, or headache) and influenza virus was known to be circulating in the community. - In addition, all subjects enrolled in the trials were allowed to take fever-reducing medications. - Of 1355 subjects enrolled in these two trials, 849 (63%) subjects were influenza-infected (age range 18 to 65 years; median age 34 years; 52% male; 90% Caucasian; 31% smokers). Of the 849 influenza-infected subjects, 95% were infected with influenza A, 3% with influenza B, and 2% with influenza of unknown type. - TAMIFLU was started within 40 hours of onset of symptoms. Subjects participating in the trials were required to self-assess the influenza-associated symptoms as "none," "mild," "moderate," or "severe." - Time to improvement was calculated from the time of treatment initiation to the time when all symptoms (nasal congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats) were assessed as "none" or "mild." - In both studies, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1.3 day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to subjects receiving placebo. - Subgroup analyses of these studies by gender showed no differences in the treatment effect of TAMIFLU in men and women. - In the treatment of influenza, no increased efficacy was demonstrated in subjects receiving treatment of 150 mg TAMIFLU twice daily for 5 days. - Three double-blind placebo-controlled treatment trials were conducted in subjects ≥65 years of age in three consecutive seasons. - The enrollment criteria were similar to that of adult trials with the exception of fever being defined as >97.5°F. Of 741 subjects enrolled, 476 (65%) subjects were influenza-infected. - Of the 476 influenza-infected subjects, 95% were infected with influenza type A and 5% with influenza type B. - In the pooled analysis, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1-day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to those receiving placebo (p=NS). However, the magnitude of treatment effect varied between studies. - One double-blind placebo-controlled treatment trial was conducted in pediatric subjects aged 1 to 12 years (median age 5 years), who had fever (>100°F) plus one respiratory symptom (cough or coryza) when influenza virus was known to be circulating in the community. - Of 698 subjects enrolled in this trial, 452 (65%) were influenza-infected (50% male; 68% Caucasian). - Of the 452 influenza-infected subjects, 67% were infected with influenza A and 33% with influenza B. - The primary endpoint in this study was the time to freedom from illness, a composite endpoint that required 4 individual conditions to be met. - These were: alleviation of cough, alleviation of coryza, resolution of fever, and parental opinion of a return to normal health and activity. TAMIFLU treatment of 2 mg/kg twice daily, started within 48 hours of onset of symptoms, significantly reduced the total composite time to freedom from illness by 1.5 days compared to placebo. - Subgroup analyses of this study by gender showed no differences in the treatment effect of TAMIFLU in male and female pediatric subjects. - The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis studies and a postexposure prophylaxis study in households. - The primary efficacy parameter for all these studies was the incidence of laboratory-confirmed clinical influenza. - Laboratory-confirmed clinical influenza was defined as oral temperature ≥99.0°F/37.2°C plus at least one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats), all recorded within 24 hours, plus either a positive virus isolation or a four-fold increase in virus antibody titers from baseline. - In a pooled analysis of two seasonal prophylaxis studies in healthy unvaccinated adults (aged 13 to 65 years), TAMIFLU 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory-confirmed clinical influenza from 5% (25/519) for the placebo group to 1% (6/520) for the TAMIFLU group. - In a seasonal prophylaxis study in elderly residents of skilled nursing homes, TAMIFLU 75 mg once daily taken for 42 days reduced the incidence of laboratory-confirmed clinical influenza from 4% (12/272) for the placebo group to <1% (1/276) for the TAMIFLU group. About 80% of this elderly population were vaccinated, 14% of subjects had chronic airway obstructive disorders, and 43% had cardiac disorders. - In a study of postexposure prophylaxis in household contacts (aged ≥13 years) of an index case, TAMIFLU 75 mg once daily administered within 2 days of onset of symptoms in the index case and continued for 7 days reduced the incidence of laboratory-confirmed clinical influenza from 12% (24/200) in the placebo group to 1% (2/205) for the TAMIFLU group. - Index cases did not receive TAMIFLU in the study. - The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in a randomized, open-label, postexposure prophylaxis study in households that included children aged 1 to 12 years, both as index cases and as family contacts. - All index cases in this study received treatment. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the household. - Laboratory-confirmed clinical influenza was defined as oral temperature ≥100°F/37.8°C plus cough and/or coryza recorded within 48 hours, plus either a positive virus isolation or a four-fold or greater increase in virus antibody titers from baseline or at illness visits. - Among household contacts 1 to 12 years of age not already shedding virus at baseline, TAMIFLU for oral suspension 30 mg to 60 mg taken once daily for 10 days reduced the incidence of laboratory-confirmed clinical influenza from 17% (18/106) in the group not receiving prophylaxis to 3% (3/95) in the group receiving prophylaxis. - A double-blind, placebo-controlled study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised subjects (including 18 pediatric subjects 1 to 12 years of age) who had received solid organ (n=388; liver, kidney, liver and kidney) or hematopoietic stem cell transplants (n=87). - Median time since transplant for solid organ transplant recipients was 1105 days for the placebo group and 1379 days for the oseltamivir group. - Median time since transplant for hematopoietic stem cell transplant recipients was 424 days for the placebo group and 367 days for the oseltamivir group. - Approximately 40% of subjects received influenza vaccine prior to entering the study. - The primary efficacy endpoint for this study was the incidence of confirmed, clinical influenza, defined as oral temperature >99.0°F/37.2°C plus cough and/or coryza, all recorded within 24 hours, plus either a positive virus culture or a four-fold increase in virus antibody titers from baseline. - The incidence of confirmed clinical influenza was 3% (7/238) in the group not receiving TAMIFLU compared with 2% (5/237) in the group receiving TAMIFLU; this difference was not statistically significant. A secondary analysis was performed using the same clinical symptoms and RT-PCR for laboratory confirmation of influenza. - Among subjects who were not already shedding virus at baseline, the incidence of RT-PCR-confirmed clinical influenza was 3% (7/231) in the group not receiving TAMIFLU and <1% (1/232) in the group receiving TAMIFLU. # How Supplied - 75-mg capsules (75 mg free base equivalent of the phosphate salt): grey/light yellow hard gelatin capsules. "ROCHE" is printed in blue ink on the grey body and "75 mg" is printed in blue ink on the light yellow cap. Available in blister packages of 10 (NDC 42254-001-10). ## Storage - Store the capsules at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). - TAMIFLU for Oral Suspension - Supplied as a white powder blend in a glass bottle. After constitution, the powder blend produces a white tutti-frutti–flavored oral suspension. - After constitution with 55 mL of water, each bottle delivers a usable volume of 60 mL of oral suspension equivalent to 360 mg oseltamivir base (6 mg/mL). - Each bottle is supplied with a bottle adapter and a 10 mL oral dispenser (NDC 0004-0820-09). - Store dry powder at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). - Store constituted suspension under refrigeration for up to 17 days at 2° to 8°C (36° to 46°F). Do not freeze. - Alternatively, store constituted suspension for up to 10 days at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients and/or caregivers should be advised of the risk of severe allergic reactions (including anaphylaxis) or serious skin reactions and should stop TAMIFLU and seek immediate medical attention if an allergic-like reaction occurs or is suspected. - Patients and/or caregivers should be advised of the risk of neuropsychiatric events in patients with influenza and should contact their physician if they experience signs of abnormal behavior while receiving TAMIFLU. Their physician will determine if TAMIFLU treatment should be continued. - Instruct patients to begin treatment with TAMIFLU as soon as possible from the first appearance of flu symptoms. Similarly, prevention should begin as soon as possible after exposure, at the recommendation of a physician. - Instruct patients to take any missed doses as soon as they remember, except if it is near the next scheduled dose (within 2 hours), and then continue to take TAMIFLU at the usual times. - TAMIFLU is not a substitute for a flu vaccination. Patients should continue receiving an annual flu vaccination according to guidelines on immunization practices. - A bottle of TAMIFLU for oral suspension contains approximately 11 g sorbitol. One dose of 75 mg TAMIFLU for oral suspension delivers 2 g sorbitol. For patients with hereditary fructose intolerance, this is above the daily maximum limit of sorbitol and may cause dyspepsia and diarrhea. # Precautions with Alcohol Alcohol-Oseltamivir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TAMIFLU # Look-Alike Drug Names There is limited information regarding Oseltamivir Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Oseltamivir 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. # Overview Oseltamivir is a antiviral that is FDA approved for the treatment of influenza A and influenza B (flu) virus. Common adverse reactions include rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, hepatitis, liver function tests abnormal, arrhythmia, gastrointestinal bleeding, hemorrhagic colitis, seizure, aggravation of diabetes, psychiatric conditions. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Treatment of Influenza - Ostelmavir is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days. ### Prophylaxis of Influenza - TAMIFLU is indicated for the prophylaxis of influenza in patients 1 year and older. ### Limitations of Use The following points should be considered before initiating treatment or prophylaxis with oseltamivir. - Efficacy of oseltamivir in patients who begin treatment after 48 hours of symptoms has not been established. - Oseltamivir is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention * Advisory Committee on Immunization Practices. - There is no evidence for efficacy of oseltamivir in any illness caused by agents other than influenza viruses types A and B. - Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. - Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use oseltamivir. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oseltamivir in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oseltamivir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - The safety and efficacy of TAMIFLU in pediatric patients younger than 1 year of age have not been studied. TAMIFLU is not indicated for either treatment or prophylaxis of influenza in pediatric patients younger than 1 year of age because of the unknown clinical significance of nonclinical animal toxicology data for human infants. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oseltamivir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oseltamivir in pediatric patients. # Contraindications - TAMIFLU is contraindicated in patients with known serious hypersensitivity to oseltamivir or any component of the product. Severe allergic reactions have included anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme. # Warnings ### Serious Skin/Hypersensitivity Reactions - Cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme have been reported in postmarketing experience with TAMIFLU. TAMIFLU should be stopped and appropriate treatment instituted if an allergic-like reaction occurs or is suspected. ### Neuropsychiatric Events - Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. - There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving TAMIFLU. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on TAMIFLU usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of TAMIFLU to these events has not been established. Closely monitor patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing treatment for each patient. ### Bacterial Infections - Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. TAMIFLU has not been shown to prevent such complications. - Limitations of Populations Studied Efficacy of TAMIFLU in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization. - Efficacy of TAMIFLU for treatment or prophylaxis of influenza has not been established in immunocompromised patients. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Oseltamivir Clinical Trials Experience in the drug label. ## Postmarketing Experience - The following adverse reactions have been identified during postapproval use of TAMIFLU. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to TAMIFLU exposure. - Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme. Hepatitis, liver function tests abnormal. - Arrhythmia - Gastrointestinal bleeding, hemorrhagic colitis - Seizure - Aggravation of diabetes - Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions # Drug Interactions - The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of TAMIFLU, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of TAMIFLU. - Overall Drug Interaction Profile for Oseltamivir - Information derived from pharmacology and pharmacokinetic studies of oseltamivir suggests that clinically significant drug interactions are unlikely. - Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, located predominantly in the liver. Drug interactions involving competition for esterases have not been extensively reported in literature. Low protein binding of oseltamivir and oseltamivir carboxylate suggests that the probability of drug displacement interactions is low. - In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases. - Clinically important drug interactions involving competition for renal tubular secretion are unlikely due to the known safety margin for most of these drugs, the elimination characteristics of oseltamivir carboxylate (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. Coadministration of probenecid results in an approximate two-fold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However, due to the safety margin of oseltamivir carboxylate, no dose adjustments are required when coadministering with probenecid. - No pharmacokinetic interactions have been observed when coadministering oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), or warfarin. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are insufficient human data upon which to base an evaluation of risk of TAMIFLU to the pregnant woman or developing fetus. - Studies for effects on embryo-fetal development were conducted in rats (50, 250, and 1500 mg/kg/day) and rabbits (50, 150, and 500 mg/kg/day) by the oral route. Relative exposures at these doses were, respectively, 2, 13, and 100 times human exposure in the rat and 4, 8, and 50 times human exposure in the rabbit. - Pharmacokinetic studies indicated that fetal exposure was seen in both species. In the rat study, minimal maternal toxicity was reported in the 1500 mg/kg/day group. In the rabbit study, slight and marked maternal toxicities were observed, respectively, in the 150 and 500 mg/kg/day groups. There was a dose-dependent increase in the incidence rates of a variety of minor skeletal abnormalities and variants in the exposed offspring in these studies. However, the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied. - Because animal reproductive studies may not be predictive of human response and there are no adequate and well-controlled studies in pregnant women, TAMIFLU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oseltamivir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Oseltamivir during labor and delivery. ### Nursing Mothers - In lactating rats, oseltamivir and oseltamivir carboxylate are excreted in the milk. It is not known whether oseltamivir or oseltamivir carboxylate is excreted in human milk. TAMIFLU should, therefore, be used only if the potential benefit for the lactating mother justifies the potential risk to the breast-fed infant. ### Pediatric Use There is no FDA guidance on the use of Oseltamivir in pediatric settings. ### Geriatic Use - Of the total number of subjects in clinical studies of TAMIFLU for the treatment of influenza, 19% were 65 and over, while 7% were 75 and over. Of the total number of patients in clinical studies of TAMIFLU for the prophylaxis of influenza, 25% were 65 and over, while 18% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. - The safety of TAMIFLU in geriatric subjects has been established in clinical studies that enrolled 741 subjects (374 received placebo and 362 received TAMIFLU). Some seasonal variability was noted in the clinical efficacy outcomes. - Safety and efficacy have been demonstrated in elderly residents of nursing homes who took TAMIFLU for up to 42 days for the prevention of influenza. Many of these individuals had cardiac and/or respiratory disease, and most had received vaccine that season. ### Gender There is no FDA guidance on the use of Oseltamivir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Oseltamivir with respect to specific racial populations. ### Renal Impairment - Dose adjustment is recommended for patients with a serum creatinine clearance between 10 and 30 mL/min. No recommended dosing regimens are available for patients with end-stage renal disease undergoing routine hemodialysis or continuous peritoneal dialysis treatment. ### Hepatic Impairment - No dosage adjustment is required in patients with mild to moderate hepatic impairment. The safety and pharmacokinetics in patients with severe hepatic impairment have not been evaluated. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Oseltamivir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Oseltamivir in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Oseltamivir Administration in the drug label. ### Monitoring There is limited information regarding Oseltamivir Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Oseltamivir and IV administrations. # Overdosage - At present, there has been no experience with overdose. Single doses of up to 1000 mg of TAMIFLU have been associated with nausea and/or vomiting. # Pharmacology ## Mechanism of Action Oseltamivir is an antiviral drug ## Structure - TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate, and as a powder for oral suspension, which when constituted with water as directed contains 6 mg/mL oseltamivir base. - In addition to the active ingredient, each capsule contains pregelatinized starch, talc, povidone K30, croscarmellose sodium, and sodium stearyl fumarate. - The 30 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and red iron oxide. The 45 mg capsule shell contains gelatin, titanium dioxide, and black iron oxide. The 75 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and red iron oxide. - Each capsule is printed with blue ink, which includes FD&C Blue No. 2 as the colorant. In addition to the active ingredient, the powder for oral suspension contains sorbitol, monosodium citrate, xanthan gum, titanium dioxide, tutti-frutti flavoring, sodium benzoate, and saccharin sodium. - Oseltamivir phosphate is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate. The chemical formula is C16H28N2O4 (free base). The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt ## Pharmacodynamics There is limited information regarding Oseltamivir Pharmacodynamics in the drug label. ## Pharmacokinetics - Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted predominantly by hepatic esterases to oseltamivir carboxylate. - At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate. Exposure to oseltamivir is less than 5% of the total exposure after oral dosing. - Plasma concentrations of oseltamivir carboxylate are proportional to doses up to 500 mg given twice daily. - Coadministration with food has no significant effect on the peak plasma concentration (551 ng/mL under fasted conditions and 441 ng/mL under fed conditions) and the area under the plasma concentration time curve (6218 ng∙h/mL under fasted conditions and 6069 ng∙h/mL under fed conditions) of oseltamivir carboxylate. - The volume of distribution (Vss) of oseltamivir carboxylate, following intravenous administration in 24 subjects, ranged between 23 and 26 liters. - The binding of oseltamivir carboxylate to human plasma protein is low (3%). - The binding of oseltamivir to human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions. - Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms. - Absorbed oseltamivir is primarily (>90%) eliminated by conversion to oseltamivir carboxylate. Plasma concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral administration. - Oseltamivir carboxylate is not further metabolized and is eliminated in the urine. Plasma concentrations of oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects after oral administration. - Oseltamivir carboxylate is eliminated entirely (>99%) by renal excretion. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h), indicating that tubular secretion occurs in addition to glomerular filtration. Less than 20% of an oral radiolabeled dose is eliminated in feces. - Renal Impairment Administration of 100 mg of oseltamivir phosphate twice daily for 5 days to patients with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal function. - In clinical studies oseltamivir carboxylate exposure was not altered in patients with mild or moderate hepatic impairment. - The pharmacokinetics of oseltamivir and oseltamivir carboxylate have been evaluated in a single-dose pharmacokinetic study in pediatric patients aged 5 to 16 years (n=18) and in a small number of pediatric patients aged 3 to 12 years (n=5) enrolled in a clinical trial. - Younger pediatric patients cleared both the prodrug and the active metabolite faster than adult patients resulting in a lower exposure for a given mg/kg dose. For oseltamivir carboxylate, apparent total clearance decreases linearly with increasing age (up to 12 years). - The pharmacokinetics of oseltamivir in pediatric patients over 12 years of age are similar to those in adult patients. - Exposure to oseltamivir carboxylate at steady-state was 25% to 35% higher in geriatric patients (age range 65 to 78 years) compared to young adults given comparable doses of oseltamivir. Half-lives observed in the geriatric patients were similar to those seen in young adults. - Based on drug exposure and tolerability, dose adjustments are not required for geriatric patients for either treatment or prophylaxis. ## Nonclinical Toxicology - In 2-year carcinogenicity studies in mice and rats given daily oral doses of the prodrug oseltamivir phosphate up to 400 mg/kg and 500 mg/kg, respectively, the prodrug and the active form oseltamivir carboxylate induced no statistically significant increases in tumors over controls. - The mean maximum daily exposures to the prodrug in mice and rats were approximately 130- and 320-fold, respectively, greater than those in humans at the proposed clinical dose based on AUC comparisons. - The respective safety margins of the exposures to the active oseltamivir carboxylate were 15- and 50-fold. - Oseltamivir was found to be non-mutagenic in the Ames test and the human lymphocyte chromosome assay with and without enzymatic activation and negative in the mouse micronucleus test. - It was found to be positive in a Syrian Hamster Embryo (SHE) cell transformation test. Oseltamivir carboxylate was non-mutagenic in the Ames test and the L5178Y mouse lymphoma assay with and without enzymatic activation and negative in the SHE cell transformation test. - In a fertility and early embryonic development study in rats, doses of oseltamivir at 50, 250, and 1500 mg/kg/day were administered to females for 2 weeks before mating, during mating and until day 6 of pregnancy. Males were dosed for 4 weeks before mating, during mating, and for 2 weeks after mating. * There were no effects on fertility, mating performance or early embryonic development at any dose level. The highest dose was approximately 100 times the human systemic exposure (AUC0-24h) of oseltamivir carboxylate. - Animal Toxicology and/or Pharmacology Single, oral administration of ≥657 mg/kg oseltamivir resulted in toxicity, including death, in juvenile 7 day old rats, but had no effect on adult rats. * No toxicity was observed after repeated administration of up to 500 mg/kg oseltamivir to developing juvenile rats 7 to 21 days old. This 500 mg/kg dose was approximately 280 and 14 times the human systemic exposure (AUC0-24h) of oseltamivir and oseltamivir carboxylate, respectively. - Clinical relevance of the juvenile rat study finding for young infants is unknown. # Clinical Studies - Two placebo-controlled double-blind clinical trials were conducted: one in the U.S. and one outside the U.S. Subjects were eligible for these trials if they had fever >100ºF, accompanied by at least one respiratory symptom (cough, nasal symptoms, or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue, or headache) and influenza virus was known to be circulating in the community. - In addition, all subjects enrolled in the trials were allowed to take fever-reducing medications. - Of 1355 subjects enrolled in these two trials, 849 (63%) subjects were influenza-infected (age range 18 to 65 years; median age 34 years; 52% male; 90% Caucasian; 31% smokers). Of the 849 influenza-infected subjects, 95% were infected with influenza A, 3% with influenza B, and 2% with influenza of unknown type. - TAMIFLU was started within 40 hours of onset of symptoms. Subjects participating in the trials were required to self-assess the influenza-associated symptoms as "none," "mild," "moderate," or "severe." - Time to improvement was calculated from the time of treatment initiation to the time when all symptoms (nasal congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats) were assessed as "none" or "mild." - In both studies, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1.3 day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to subjects receiving placebo. - Subgroup analyses of these studies by gender showed no differences in the treatment effect of TAMIFLU in men and women. - In the treatment of influenza, no increased efficacy was demonstrated in subjects receiving treatment of 150 mg TAMIFLU twice daily for 5 days. - Three double-blind placebo-controlled treatment trials were conducted in subjects ≥65 years of age in three consecutive seasons. - The enrollment criteria were similar to that of adult trials with the exception of fever being defined as >97.5°F. Of 741 subjects enrolled, 476 (65%) subjects were influenza-infected. - Of the 476 influenza-infected subjects, 95% were infected with influenza type A and 5% with influenza type B. - In the pooled analysis, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1-day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to those receiving placebo (p=NS). However, the magnitude of treatment effect varied between studies. - One double-blind placebo-controlled treatment trial was conducted in pediatric subjects aged 1 to 12 years (median age 5 years), who had fever (>100°F) plus one respiratory symptom (cough or coryza) when influenza virus was known to be circulating in the community. - Of 698 subjects enrolled in this trial, 452 (65%) were influenza-infected (50% male; 68% Caucasian). - Of the 452 influenza-infected subjects, 67% were infected with influenza A and 33% with influenza B. - The primary endpoint in this study was the time to freedom from illness, a composite endpoint that required 4 individual conditions to be met. - These were: alleviation of cough, alleviation of coryza, resolution of fever, and parental opinion of a return to normal health and activity. TAMIFLU treatment of 2 mg/kg twice daily, started within 48 hours of onset of symptoms, significantly reduced the total composite time to freedom from illness by 1.5 days compared to placebo. - Subgroup analyses of this study by gender showed no differences in the treatment effect of TAMIFLU in male and female pediatric subjects. - The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis studies and a postexposure prophylaxis study in households. - The primary efficacy parameter for all these studies was the incidence of laboratory-confirmed clinical influenza. - Laboratory-confirmed clinical influenza was defined as oral temperature ≥99.0°F/37.2°C plus at least one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats), all recorded within 24 hours, plus either a positive virus isolation or a four-fold increase in virus antibody titers from baseline. - In a pooled analysis of two seasonal prophylaxis studies in healthy unvaccinated adults (aged 13 to 65 years), TAMIFLU 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory-confirmed clinical influenza from 5% (25/519) for the placebo group to 1% (6/520) for the TAMIFLU group. - In a seasonal prophylaxis study in elderly residents of skilled nursing homes, TAMIFLU 75 mg once daily taken for 42 days reduced the incidence of laboratory-confirmed clinical influenza from 4% (12/272) for the placebo group to <1% (1/276) for the TAMIFLU group. About 80% of this elderly population were vaccinated, 14% of subjects had chronic airway obstructive disorders, and 43% had cardiac disorders. - In a study of postexposure prophylaxis in household contacts (aged ≥13 years) of an index case, TAMIFLU 75 mg once daily administered within 2 days of onset of symptoms in the index case and continued for 7 days reduced the incidence of laboratory-confirmed clinical influenza from 12% (24/200) in the placebo group to 1% (2/205) for the TAMIFLU group. - Index cases did not receive TAMIFLU in the study. - The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in a randomized, open-label, postexposure prophylaxis study in households that included children aged 1 to 12 years, both as index cases and as family contacts. - All index cases in this study received treatment. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the household. - Laboratory-confirmed clinical influenza was defined as oral temperature ≥100°F/37.8°C plus cough and/or coryza recorded within 48 hours, plus either a positive virus isolation or a four-fold or greater increase in virus antibody titers from baseline or at illness visits. - Among household contacts 1 to 12 years of age not already shedding virus at baseline, TAMIFLU for oral suspension 30 mg to 60 mg taken once daily for 10 days reduced the incidence of laboratory-confirmed clinical influenza from 17% (18/106) in the group not receiving prophylaxis to 3% (3/95) in the group receiving prophylaxis. - A double-blind, placebo-controlled study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised subjects (including 18 pediatric subjects 1 to 12 years of age) who had received solid organ (n=388; liver, kidney, liver and kidney) or hematopoietic stem cell transplants (n=87). - Median time since transplant for solid organ transplant recipients was 1105 days for the placebo group and 1379 days for the oseltamivir group. - Median time since transplant for hematopoietic stem cell transplant recipients was 424 days for the placebo group and 367 days for the oseltamivir group. - Approximately 40% of subjects received influenza vaccine prior to entering the study. - The primary efficacy endpoint for this study was the incidence of confirmed, clinical influenza, defined as oral temperature >99.0°F/37.2°C plus cough and/or coryza, all recorded within 24 hours, plus either a positive virus culture or a four-fold increase in virus antibody titers from baseline. - The incidence of confirmed clinical influenza was 3% (7/238) in the group not receiving TAMIFLU compared with 2% (5/237) in the group receiving TAMIFLU; this difference was not statistically significant. A secondary analysis was performed using the same clinical symptoms and RT-PCR for laboratory confirmation of influenza. - Among subjects who were not already shedding virus at baseline, the incidence of RT-PCR-confirmed clinical influenza was 3% (7/231) in the group not receiving TAMIFLU and <1% (1/232) in the group receiving TAMIFLU. # How Supplied - 75-mg capsules (75 mg free base equivalent of the phosphate salt): grey/light yellow hard gelatin capsules. "ROCHE" is printed in blue ink on the grey body and "75 mg" is printed in blue ink on the light yellow cap. Available in blister packages of 10 (NDC 42254-001-10). ## Storage - Store the capsules at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). - TAMIFLU for Oral Suspension - Supplied as a white powder blend in a glass bottle. After constitution, the powder blend produces a white tutti-frutti–flavored oral suspension. - After constitution with 55 mL of water, each bottle delivers a usable volume of 60 mL of oral suspension equivalent to 360 mg oseltamivir base (6 mg/mL). - Each bottle is supplied with a bottle adapter and a 10 mL oral dispenser (NDC 0004-0820-09). - Store dry powder at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). - Store constituted suspension under refrigeration for up to 17 days at 2° to 8°C (36° to 46°F). Do not freeze. - Alternatively, store constituted suspension for up to 10 days at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients and/or caregivers should be advised of the risk of severe allergic reactions (including anaphylaxis) or serious skin reactions and should stop TAMIFLU and seek immediate medical attention if an allergic-like reaction occurs or is suspected. - Patients and/or caregivers should be advised of the risk of neuropsychiatric events in patients with influenza and should contact their physician if they experience signs of abnormal behavior while receiving TAMIFLU. Their physician will determine if TAMIFLU treatment should be continued. - Instruct patients to begin treatment with TAMIFLU as soon as possible from the first appearance of flu symptoms. Similarly, prevention should begin as soon as possible after exposure, at the recommendation of a physician. - Instruct patients to take any missed doses as soon as they remember, except if it is near the next scheduled dose (within 2 hours), and then continue to take TAMIFLU at the usual times. - TAMIFLU is not a substitute for a flu vaccination. Patients should continue receiving an annual flu vaccination according to guidelines on immunization practices. - A bottle of TAMIFLU for oral suspension contains approximately 11 g sorbitol. One dose of 75 mg TAMIFLU for oral suspension delivers 2 g sorbitol. For patients with hereditary fructose intolerance, this is above the daily maximum limit of sorbitol and may cause dyspepsia and diarrhea. # Precautions with Alcohol Alcohol-Oseltamivir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - TAMIFLU[2] # Look-Alike Drug Names There is limited information regarding Oseltamivir Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Oseltamivir
a0ce4bb6ce242682227ce5be0500315376f870ed	wikidoc	Osimertinib	Osimertinib Patient Selection - Confirm the presence of a T790M EGFR mutation in tumor or, in the absence of tumor, plasma specimens prior to initiation of treatment with Osimertinib. Testing for the presence of the mutation in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If this mutation is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. Information on FDA-approved tests for the detection of T790M mutations is available at HTTP. Recommended Dosage Regimen - The recommended dose of Osimertinib is 80 mg tablet once a day until disease progression or unacceptable toxicity. Osimertinib can be taken with or without food. - If a dose of Osimertinib is missed, do not make up the missed dose and take the next dose as scheduled. Administration to Patients Who Have Difficulty Swallowing Solids - Disperse tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces) of water and immediately drink. - If administration via naso-gastric tube is required, disperse the tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL). Dosage Modification - Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 3.3% (n=27) of Osimertinib treated patients (n=813); 0.5% (n=4) were fatal. - Withhold Osimertinib and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue Osimertinib if ILD is confirmed. QTc Interval Prolongation - The heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with Osimertinib. Of the 411 patients in Study 1 and Study 2, one patient (0.2%) was found to have a QTc greater than 500 msec, and 11 patients (2.7%) had an increase from baseline QTc greater than 60 msec. - In Study 1 and 2, patients with baseline QTc of 470 msec or greater were excluded. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue Osimertinib in patients who develop QTc intervalprolongation with signs/symptoms of life-threatening arrhythmia. Cardiomyopathy - Across clinical trials, cardiomyopathy (defined as cardiac failure, pulmonary edema, ejection fraction decreased or stress cardiomyopathy) occurred in 1.4% (n=11) of Osimertinib treated patients (n=813); 0.2% (n=2) were fatal. - In Study 1 and Study 2, Left Ventricular Ejection Fraction (LVEF) decline >10% and a drop to <50% occurred in 2.4% (9/375) of patients who had baseline and at least one follow-up LVEF assessment. - Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of Osimertinib and then at 3 month intervals while on treatment. Withhold treatment with Osimertinib if ejection fraction decreases by 10% from pretreatment values and is less than 50%. For symptomatic congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue Osimertinib. Embryo-Fetal Toxicity - Based on data from animal studies and its mechanism of action, Osimertinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended human dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5-times those observed in patients at the 80 mg dose level. Advise pregnant women of the potential risk to a fetus. - Advise females of reproductive potential to use effective contraception during treatment with Osimertinib and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose - 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 data described below reflect exposure to Osimertinib(80 mg daily) in 411 patients with EGFR T790M mutation-positive non-small cell lung cancer who received prior EGFR TKI therapy, in two single-arm studies, Study 1 and Study 2. Patients with a past medical history of ILD or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 ms were excluded from Study 1 and Study 2. Baseline patient and disease characteristics were: median age 63 years, 13% of patients were ≥75 years old, female (68%), White (36%), Asian (60%), metastatic (96%), sites of brain metastases (39%), World Health Organization (WHO) performance status of 0 (37%) or 1 (63%), 1 prior line of therapy , 2 or more prior lines of therapy (69%). Of the 411 patients, 333 patients were exposed to Osimertinib for at least 6 months; 97 patients were exposed for at least 9 months; however, no patient was exposed to Osimertinib for 12 months. - In Studies 1 and 2, the most common (>20%) adverse reactions (all grades) observed in Osimertinib-treated patients were diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). Dose reductions occurred in 4.4% of patients treated with Osimertinib. The most frequent adverse reactions that led to dose reductions or interruptions were: electrocardiogram QTc prolonged (2.2%) and neutropenia (1.9%). Serious adverse reactions reported in 2% or more patients were pneumonia and pulmonary embolus. There were 4 patients (1%) treated with Osimertinib who developed fatal adverse reactions of ILD/pneumonitis. Other fatal adverse reactions occurring in more than 1 patient included pneumonia (4 patients) and CVA/cerebral hemorrhage (2 patients). Discontinuation of therapy due to adverse reactions occurred in 5.6% of patients treated with Osimertinib. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis and cerebrovascular accidents/infarctions. Tables 2 and 3 summarize the common adverse reactions and laboratory abnormalities observed in Osimertinib-treated patients. Adverse reactions Laboratory abormalities - Strong CYP3A Inducers Coadministering Osimertinib with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering Osimertinib alone. Decreased osimertinib exposure may lead to reduced efficacy. - Avoid coadministering Osimertinib with strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, St. John’s Wort) . Increase the Osimertinib dosage when coadministering with a strong CYP3A4 inducer if concurrent use is unavoidable. No dose adjustments are required when Osimertinib is used with moderate and/or weak CYP3A inducers. Effect of Osimertinib on Other Drugs - Coadministering Osimertinib with a BCRP substrate increased the exposure of the BCRP substrate compared to administering the BCRP substrate alone. Increased BCRP substrate exposure may increase the risk of exposure-related toxicity. - Monitor for adverse reactions of the BCRP substrate (e.g., rosuvastatin, sulfasalazine, topotecan), unless otherwise instructed in its approved labeling, when coadministered with Osimertinib. Drug Interactions Effect of Other Drugs on Osimertinib in Clinical Pharmacokinetic Studies Strong CYP3A Inducers - The steady-state AUC of osimertinib was reduced by 78% in patients when coadministered with rifampin (600 mg daily for 21 days) in a clinical pharmacokinetic study. Strong CYP3A Inhibitors: - Coadministering Osimertinib with 200 mg itraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on the exposure of osimertinib (AUC increased by 24% and Cmax decreased by 20%). Gastric Acid Reducing Agents: The exposure of osimertinib was not affected by concurrent administration of a single 80 mg Osimertinib tablet following 40 mg omeprazole administration for 5 days. Effect of Osimertinib on Other Drugs in Clinical Pharmacokinetic Studies BCRP substrates: Coadministering Osimertinib with rosuvastatin (a BCRP substrate) increased rosuvastatin AUC by 35% and Cmax by 72% in a clinical pharmacokinetic study. CYP3A4 substrates: Coadministering Osimertinib with simvastatin (a CYP3A4 substrate) had no clinically significant effect on the exposure of simvastatin in a clinical pharmacokinetic study. In Vitro Studies CYP450 Metabolic Pathways: Osimertinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1. Osimertinib induced CYP1A2 enzymes. Transporter Systems: Osimertinib is a substrate of P-glycoprotein and BCRP and is not a substrate of OATP1B1 and OATP1B3. Osimertinib is an inhibitor of BCRP and does not inhibit P-glycoprotein, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, MATE2K and OCT2. - Based on data from animal studies and its mechanism of action, Osimertinib can cause fetal harm when administered to a pregnant woman. There are no available data on Osimertinib use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended human dose. Advise pregnant women of the potential risk to a fetus. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1-times the AUC observed in patients at the recommended dose of 80 mg), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6. .Females - Advise females of reproductive potential to use effective contraception during treatment with Osimertinib and for 6 weeks after the final dose. Males - Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of Osimertinib. Infertility - Based on animal studies, Osimertinib may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are rever - If a dose of Osimertinib is missed, do not make up the missed dose and take the next dose as scheduled. - The QTc interval prolongation potential of osimertinib was assessed in 210 patients who received Osimertinib 80 mg daily in Study 2. A central tendency analysis of the QTcF data at steady-state demonstrated that the maximum mean change from baseline was 16.2 msec (upper bound of two-sided 90% confidence interval (CI) 17.6 msec). A pharmacokinetic/pharmacodynamic analysis in Study 2 suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of Osimertinib 80 mg. - The area under the plasma concentration-time curve (AUC) and maximal plasma concentration (Cmax) of osimertinib increased dose proportionally over 20 to 240 mg dose range (i.e., 0.25 to 3 times the recommended dosage) after oral administration and exhibited linear pharmacokinetics (PK). Administration of Osimertinib orally once daily resulted in approximately 3-fold accumulation with steady state exposures achieved after 15 days of dosing. At steady state, the Cmax to Cmin (minimal concentration) ratio was 1.6-fold. Absorption - The median time to Cmax of osimertinib was 6 hours (range 3-24 hours). - Following administration of a 20 mg Osimertinib tablet with a high-fat, high-calorie meal (containing approximately 58 grams of fat and 1000 calories), the Cmax and AUC of osimertinib were comparable to that under fasting conditions. Distribution - The mean volume of distribution at steady-state (Vss/F) of osimertinib was 986 L. Plasma protein binding of osimertinib is likely high based on its physiochemical properties. Elimination - Osimertinib plasma concentrations decreased with time and a population estimated mean half-life of osimertinib was 48 hours, and oral clearance (CL/F) was 14.2 (L/h). Metabolism - The main metabolic pathways of osimertinib were oxidation (predominantly CYP3A) and dealkylation in vitro. Two pharmacologically active metabolites (AZ7550 and AZ5104) have been identified in the plasma after Osimertinib oral administration. The geometric mean exposure (AUC) of each metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of osimertinib at steady-state. Excretion - Osimertinib is primarily eliminated in the feces (68%) and to a lesser extent in the urine (14%). Unchanged osimertinib accounted for approximately 2% of the elimination. Specific Populations - No clinically significant differences in the pharmacokinetics of osimertinib were observed based on age, sex, ethnicity, body weight, smoking status, mild (CLcr 60-89 mL/min, as estimated by C-G) or moderate (CLcr 30-59 mL/min, as estimated by C-G) renal impairment, or mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN or total bilirubin between 1 to 1.5 times ULN and any AST). The pharmacokinetics of osimertinib in patients with severe renal impairment (CLcr less than 30 mL/min) or with moderate to severe hepatic impairment (moderate: total bilirubin between 1.5 to 3 times ULN and any AST, and severe: total bilirubin between 3 to 10 times ULN and any AST) are unknown. Carcinogenicity studies have not been performed with osimertinib. Osimertinib did not cause genetic damage in in vitro and in vivo assays. Based on studies in animals, male fertility may be impaired by treatment with Osimertinib. Degenerative changes were present in the testes in rats and dogs exposed to osimertinib for 1 month or more with evidence of reversibility in the rat. Following administration of osimertinib to rats for approximately 10 weeks at a dose of 40 mg/kg, at exposures 0.5-times the AUC observed in patients at the recommended dose of 80 mg, there was a reduction in male fertility, demonstrated by increased pre-implantation loss in untreated females mated to treated males. Based on studies in animals, female fertility may be impaired by treatment with Osimertinib. In repeat dose toxicity studies, histological evidence of anestrus, corpora lutea degeneration in the ovaries and epithelial thinning in the uterus and vagina were seen in rats exposed to osimertinib for 1 month or more at exposures 0.3-times the AUC observed in patients at the recommended dose of 80 mg. Findings in the ovaries seen following 1 month of dosing exhibited evidence of reversibility. In a female fertility study in rats, administration of osimertinib from 2 weeks prior to mating through Day 8 of gestation at a dose of 20 mg/kg/day (approximately 1.5-times the human Cmax at the recommended dose of 80 mg/day) had no effects on oestrus cycling or the number of females becoming pregnant, but caused early embryonic deaths. These findings showed evidence of reversibility when females were mated 1 month after treatment discontinuation. - Study 1 population characteristics were: median age 62 years (range 37 to 89), female (66%), White (38%), Asian (58%), never smoker (67%), WHO performance status 0 (34%) or 1 (66%), adenocarcinoma histology (97%), 1 prior line of therapy (30%), 2 or more prior lines of therapy (70%). Sites of extra-thoracic metastasis included liver (32%), bone (51%), and brain (37%). Somatic EGFR mutations in addition to T790M were exon 19 deletion (71%), L858R (25%), G719X (2%), and S768I (2%). Study 2 population characteristics were: - Median age 64 years (range 35 to 88), female (70%), White (34%), Asian (63%), never smoker (76%), WHO performance status 0 (40%) or 1 (60%), adenocarcinoma histology (95%), 1 prior line of therapy (32%), 2 or more prior lines of therapy (68%). Sites of extra-thoracic metastasis included liver (26%), bone (43%), and brain (41%). Somatic EGFR mutations in addition to T790M were exon 19 deletion (65%), L858R (32%), G719X (2%), and S768I (1%). Efficacy results by BICR from Study 1 and Study 2 - The majority (96%) of patients with confirmed objective responses had ongoing responses ranging from 1.1 to 5.6 months after a median duration of follow-up of 4.2 months for Study 1 and 4.0 months for Study 2. 40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1349-30). - Interstitial Lung Disease/Pneumonitis Inform patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms. - QTc Interval Prolongation Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications. Cardiomyopathy - Osimertinib can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider. Embryo-Fetal Toxicity - Osimertinib can cause fetal harm if taken during pregnancy. Advise pregnant women of the potential risk to a fetus. - Advise females to inform their healthcare provider if they become pregnant or if pregnancy is suspected, while taking Osimertinib. Females and Males of Reproductive Potential - Advise females of reproductive potential to use effective contraception during treatment with Osimertinib and for 6 weeks after the final dose - Advise males to use effective contraception during treatment and for 4 months after the final dose of Osimertinib. Lactation - Advise women not to breastfeed during treatment with Osimertinib and for 2 weeks after the final dose - ↑ "Tagrisso (osimertinib) Tablet, for Oral Use. Full Prescribing Information" (PDF). AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Retrieved 16 November 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}	Osimertinib Patient Selection - Confirm the presence of a T790M EGFR mutation in tumor or, in the absence of tumor, plasma specimens prior to initiation of treatment with Osimertinib. Testing for the presence of the mutation in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If this mutation is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. Information on FDA-approved tests for the detection of T790M mutations is available at HTTP://WWW.FDA.GOV/COMPANIONDIAGNOSTICS. Recommended Dosage Regimen - The recommended dose of Osimertinib is 80 mg tablet once a day until disease progression or unacceptable toxicity. Osimertinib can be taken with or without food. - If a dose of Osimertinib is missed, do not make up the missed dose and take the next dose as scheduled. Administration to Patients Who Have Difficulty Swallowing Solids - Disperse tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces) of water and immediately drink. - If administration via naso-gastric tube is required, disperse the tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL). Dosage Modification - Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 3.3% (n=27) of Osimertinib treated patients (n=813); 0.5% (n=4) were fatal. - Withhold Osimertinib and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue Osimertinib if ILD is confirmed. QTc Interval Prolongation - The heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with Osimertinib. Of the 411 patients in Study 1 and Study 2, one patient (0.2%) was found to have a QTc greater than 500 msec, and 11 patients (2.7%) had an increase from baseline QTc greater than 60 msec. - In Study 1 and 2, patients with baseline QTc of 470 msec or greater were excluded. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue Osimertinib in patients who develop QTc intervalprolongation with signs/symptoms of life-threatening arrhythmia. Cardiomyopathy - Across clinical trials, cardiomyopathy (defined as cardiac failure, pulmonary edema, ejection fraction decreased or stress cardiomyopathy) occurred in 1.4% (n=11) of Osimertinib treated patients (n=813); 0.2% (n=2) were fatal. - In Study 1 and Study 2, Left Ventricular Ejection Fraction (LVEF) decline >10% and a drop to <50% occurred in 2.4% (9/375) of patients who had baseline and at least one follow-up LVEF assessment. - Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of Osimertinib and then at 3 month intervals while on treatment. Withhold treatment with Osimertinib if ejection fraction decreases by 10% from pretreatment values and is less than 50%. For symptomatic congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue Osimertinib. Embryo-Fetal Toxicity - Based on data from animal studies and its mechanism of action, Osimertinib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended human dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5-times those observed in patients at the 80 mg dose level. Advise pregnant women of the potential risk to a fetus. - Advise females of reproductive potential to use effective contraception during treatment with Osimertinib and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose - 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 data described below reflect exposure to Osimertinib(80 mg daily) in 411 patients with EGFR T790M mutation-positive non-small cell lung cancer who received prior EGFR TKI therapy, in two single-arm studies, Study 1 and Study 2. Patients with a past medical history of ILD or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 ms were excluded from Study 1 and Study 2. Baseline patient and disease characteristics were: median age 63 years, 13% of patients were ≥75 years old, female (68%), White (36%), Asian (60%), metastatic (96%), sites of brain metastases (39%), World Health Organization (WHO) performance status of 0 (37%) or 1 (63%), 1 prior line of therapy [EGFR-TKI treatment only, second line, chemotherapy-naïve (31%)], 2 or more prior lines of therapy (69%). Of the 411 patients, 333 patients were exposed to Osimertinib for at least 6 months; 97 patients were exposed for at least 9 months; however, no patient was exposed to Osimertinib for 12 months. - In Studies 1 and 2, the most common (>20%) adverse reactions (all grades) observed in Osimertinib-treated patients were diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). Dose reductions occurred in 4.4% of patients treated with Osimertinib. The most frequent adverse reactions that led to dose reductions or interruptions were: electrocardiogram QTc prolonged (2.2%) and neutropenia (1.9%). Serious adverse reactions reported in 2% or more patients were pneumonia and pulmonary embolus. There were 4 patients (1%) treated with Osimertinib who developed fatal adverse reactions of ILD/pneumonitis. Other fatal adverse reactions occurring in more than 1 patient included pneumonia (4 patients) and CVA/cerebral hemorrhage (2 patients). Discontinuation of therapy due to adverse reactions occurred in 5.6% of patients treated with Osimertinib. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis and cerebrovascular accidents/infarctions. Tables 2 and 3 summarize the common adverse reactions and laboratory abnormalities observed in Osimertinib-treated patients. Adverse reactions Laboratory abormalities - Strong CYP3A Inducers Coadministering Osimertinib with a strong CYP3A4 inducer decreased the exposure of osimertinib compared to administering Osimertinib alone. Decreased osimertinib exposure may lead to reduced efficacy. - Avoid coadministering Osimertinib with strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, St. John’s Wort) [note: effect of St. John’s Wort varies widely and is preparation-dependent]. Increase the Osimertinib dosage when coadministering with a strong CYP3A4 inducer if concurrent use is unavoidable. No dose adjustments are required when Osimertinib is used with moderate and/or weak CYP3A inducers. Effect of Osimertinib on Other Drugs - Coadministering Osimertinib with a BCRP substrate increased the exposure of the BCRP substrate compared to administering the BCRP substrate alone. Increased BCRP substrate exposure may increase the risk of exposure-related toxicity. - Monitor for adverse reactions of the BCRP substrate (e.g., rosuvastatin, sulfasalazine, topotecan), unless otherwise instructed in its approved labeling, when coadministered with Osimertinib. Drug Interactions Effect of Other Drugs on Osimertinib in Clinical Pharmacokinetic Studies Strong CYP3A Inducers - The steady-state AUC of osimertinib was reduced by 78% in patients when coadministered with rifampin (600 mg daily for 21 days) in a clinical pharmacokinetic study. Strong CYP3A Inhibitors: - Coadministering Osimertinib with 200 mg itraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on the exposure of osimertinib (AUC increased by 24% and Cmax decreased by 20%). Gastric Acid Reducing Agents: The exposure of osimertinib was not affected by concurrent administration of a single 80 mg Osimertinib tablet following 40 mg omeprazole administration for 5 days. Effect of Osimertinib on Other Drugs in Clinical Pharmacokinetic Studies BCRP substrates: Coadministering Osimertinib with rosuvastatin (a BCRP substrate) increased rosuvastatin AUC by 35% and Cmax by 72% in a clinical pharmacokinetic study. CYP3A4 substrates: Coadministering Osimertinib with simvastatin (a CYP3A4 substrate) had no clinically significant effect on the exposure of simvastatin in a clinical pharmacokinetic study. In Vitro Studies CYP450 Metabolic Pathways: Osimertinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1. Osimertinib induced CYP1A2 enzymes. Transporter Systems: Osimertinib is a substrate of P-glycoprotein and BCRP and is not a substrate of OATP1B1 and OATP1B3. Osimertinib is an inhibitor of BCRP and does not inhibit P-glycoprotein, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, MATE2K and OCT2. - Based on data from animal studies and its mechanism of action, Osimertinib can cause fetal harm when administered to a pregnant woman. There are no available data on Osimertinib use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended human dose. Advise pregnant women of the potential risk to a fetus. - In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1-times the AUC observed in patients at the recommended dose of 80 mg), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6. .Females - Advise females of reproductive potential to use effective contraception during treatment with Osimertinib and for 6 weeks after the final dose. Males - Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of Osimertinib. Infertility - Based on animal studies, Osimertinib may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are rever - If a dose of Osimertinib is missed, do not make up the missed dose and take the next dose as scheduled. - The QTc interval prolongation potential of osimertinib was assessed in 210 patients who received Osimertinib 80 mg daily in Study 2. A central tendency analysis of the QTcF data at steady-state demonstrated that the maximum mean change from baseline was 16.2 msec (upper bound of two-sided 90% confidence interval (CI) 17.6 msec). A pharmacokinetic/pharmacodynamic analysis in Study 2 suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of Osimertinib 80 mg. - The area under the plasma concentration-time curve (AUC) and maximal plasma concentration (Cmax) of osimertinib increased dose proportionally over 20 to 240 mg dose range (i.e., 0.25 to 3 times the recommended dosage) after oral administration and exhibited linear pharmacokinetics (PK). Administration of Osimertinib orally once daily resulted in approximately 3-fold accumulation with steady state exposures achieved after 15 days of dosing. At steady state, the Cmax to Cmin (minimal concentration) ratio was 1.6-fold. Absorption - The median time to Cmax of osimertinib was 6 hours (range 3-24 hours). - Following administration of a 20 mg Osimertinib tablet with a high-fat, high-calorie meal (containing approximately 58 grams of fat and 1000 calories), the Cmax and AUC of osimertinib were comparable to that under fasting conditions. Distribution - The mean volume of distribution at steady-state (Vss/F) of osimertinib was 986 L. Plasma protein binding of osimertinib is likely high based on its physiochemical properties. Elimination - Osimertinib plasma concentrations decreased with time and a population estimated mean half-life of osimertinib was 48 hours, and oral clearance (CL/F) was 14.2 (L/h). Metabolism - The main metabolic pathways of osimertinib were oxidation (predominantly CYP3A) and dealkylation in vitro. Two pharmacologically active metabolites (AZ7550 and AZ5104) have been identified in the plasma after Osimertinib oral administration. The geometric mean exposure (AUC) of each metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of osimertinib at steady-state. Excretion - Osimertinib is primarily eliminated in the feces (68%) and to a lesser extent in the urine (14%). Unchanged osimertinib accounted for approximately 2% of the elimination. Specific Populations - No clinically significant differences in the pharmacokinetics of osimertinib were observed based on age, sex, ethnicity, body weight, smoking status, mild (CLcr 60-89 mL/min, as estimated by C-G) or moderate (CLcr 30-59 mL/min, as estimated by C-G) renal impairment, or mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN or total bilirubin between 1 to 1.5 times ULN and any AST). The pharmacokinetics of osimertinib in patients with severe renal impairment (CLcr less than 30 mL/min) or with moderate to severe hepatic impairment (moderate: total bilirubin between 1.5 to 3 times ULN and any AST, and severe: total bilirubin between 3 to 10 times ULN and any AST) are unknown. Carcinogenicity studies have not been performed with osimertinib. Osimertinib did not cause genetic damage in in vitro and in vivo assays. Based on studies in animals, male fertility may be impaired by treatment with Osimertinib. Degenerative changes were present in the testes in rats and dogs exposed to osimertinib for 1 month or more with evidence of reversibility in the rat. Following administration of osimertinib to rats for approximately 10 weeks at a dose of 40 mg/kg, at exposures 0.5-times the AUC observed in patients at the recommended dose of 80 mg, there was a reduction in male fertility, demonstrated by increased pre-implantation loss in untreated females mated to treated males. Based on studies in animals, female fertility may be impaired by treatment with Osimertinib. In repeat dose toxicity studies, histological evidence of anestrus, corpora lutea degeneration in the ovaries and epithelial thinning in the uterus and vagina were seen in rats exposed to osimertinib for 1 month or more at exposures 0.3-times the AUC observed in patients at the recommended dose of 80 mg. Findings in the ovaries seen following 1 month of dosing exhibited evidence of reversibility. In a female fertility study in rats, administration of osimertinib from 2 weeks prior to mating through Day 8 of gestation at a dose of 20 mg/kg/day (approximately 1.5-times the human Cmax at the recommended dose of 80 mg/day) had no effects on oestrus cycling or the number of females becoming pregnant, but caused early embryonic deaths. These findings showed evidence of reversibility when females were mated 1 month after treatment discontinuation. - Study 1 population characteristics were: median age 62 years (range 37 to 89), female (66%), White (38%), Asian (58%), never smoker (67%), WHO performance status 0 (34%) or 1 (66%), adenocarcinoma histology (97%), 1 prior line of therapy [EGFR-TKI treatment only, second line, chemotherapy-naïve] (30%), 2 or more prior lines of therapy (70%). Sites of extra-thoracic metastasis included liver (32%), bone (51%), and brain (37%). Somatic EGFR mutations in addition to T790M were exon 19 deletion (71%), L858R (25%), G719X (2%), and S768I (2%). Study 2 population characteristics were: - Median age 64 years (range 35 to 88), female (70%), White (34%), Asian (63%), never smoker (76%), WHO performance status 0 (40%) or 1 (60%), adenocarcinoma histology (95%), 1 prior line of therapy [EGFR-TKI treatment only, second line, chemotherapy-naïve] (32%), 2 or more prior lines of therapy (68%). Sites of extra-thoracic metastasis included liver (26%), bone (43%), and brain (41%). Somatic EGFR mutations in addition to T790M were exon 19 deletion (65%), L858R (32%), G719X (2%), and S768I (1%). Efficacy results by BICR from Study 1 and Study 2 - The majority (96%) of patients with confirmed objective responses had ongoing responses ranging from 1.1 to 5.6 months after a median duration of follow-up of 4.2 months for Study 1 and 4.0 months for Study 2. 40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1349-30). . - Interstitial Lung Disease/Pneumonitis Inform patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms. - QTc Interval Prolongation Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications. Cardiomyopathy - Osimertinib can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider. Embryo-Fetal Toxicity - Osimertinib can cause fetal harm if taken during pregnancy. Advise pregnant women of the potential risk to a fetus. - Advise females to inform their healthcare provider if they become pregnant or if pregnancy is suspected, while taking Osimertinib. Females and Males of Reproductive Potential - Advise females of reproductive potential to use effective contraception during treatment with Osimertinib and for 6 weeks after the final dose - Advise males to use effective contraception during treatment and for 4 months after the final dose of Osimertinib. Lactation - Advise women not to breastfeed during treatment with Osimertinib and for 2 weeks after the final dose - ↑ "Tagrisso (osimertinib) Tablet, for Oral Use. Full Prescribing Information" (PDF). AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Retrieved 16 November 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/Osimertinib
bf3e97ad824f2298c7d28e6274fa1c0f55e9c7b4	wikidoc	Osteocalcin	Osteocalcin Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a noncollagenous protein hormone found in bone and dentin. Because it has gla domains, its synthesis is vitamin K dependent. In humans, the osteocalcin is encoded by the BGLAP gene. Its receptor is GPRC6A. # Function Osteocalcin is secreted solely by osteoblasts and thought to play a role in the body's metabolic regulation and is pro-osteoblastic, or bone-building, by nature. It is also implicated in bone mineralization and calcium ion homeostasis. Osteocalcin acts as a hormone in the body, causing beta cells in the pancreas to release more insulin, and at the same time directing fat cells to release the hormone adiponectin, which increases sensitivity to insulin. Osteocalcin acts on Leydig cells of the testis to stimulate testosterone biosynthesis and therefore affect male fertility. Osteocalcin also acts on myocytes to promote energy availability and utilization and in this manner favors exercise capacity. # Use as a biochemical marker for bone formation As osteocalcin is produced by osteoblasts, it is often used as a marker for the bone formation process. It has been observed that higher serum-osteocalcin levels are relatively well correlated with increases in bone mineral density (BMD) during treatment with anabolic bone formation drugs for osteoporosis, such as Teriparatide. In many studies, osteocalcin is used as a preliminary biomarker on the effectiveness of a given drug on bone formation. For instance, one study which aimed to study the effectiveness of a glycoprotein called lactoferrin on bone formation used osteocalcin as a measure of osteoblast activity.	Osteocalcin Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a noncollagenous protein hormone found in bone and dentin. Because it has gla domains, its synthesis is vitamin K dependent. In humans, the osteocalcin is encoded by the BGLAP gene.[1][2] Its receptor is GPRC6A.[3] # Function Osteocalcin is secreted solely by osteoblasts and thought to play a role in the body's metabolic regulation and is pro-osteoblastic, or bone-building, by nature.[4] It is also implicated in bone mineralization and calcium ion homeostasis. Osteocalcin acts as a hormone in the body, causing beta cells in the pancreas to release more insulin, and at the same time directing fat cells to release the hormone adiponectin, which increases sensitivity to insulin.[4] Osteocalcin acts on Leydig cells of the testis to stimulate testosterone biosynthesis and therefore affect male fertility.[5] Osteocalcin also acts on myocytes to promote energy availability and utilization and in this manner favors exercise capacity.[6] # Use as a biochemical marker for bone formation As osteocalcin is produced by osteoblasts, it is often used as a marker for the bone formation process. It has been observed that higher serum-osteocalcin levels are relatively well correlated with increases in bone mineral density (BMD) during treatment with anabolic bone formation drugs for osteoporosis, such as Teriparatide. In many studies, osteocalcin is used as a preliminary biomarker on the effectiveness of a given drug on bone formation. For instance, one study which aimed to study the effectiveness of a glycoprotein called lactoferrin on bone formation used osteocalcin as a measure of osteoblast activity.[7]	https://www.wikidoc.org/index.php/Osteocalcin
cb7916a88f31a6cb082f31c0847794b50e1df854	wikidoc	Osteoglycin	Osteoglycin Osteoglycin (also called mimecan), encoded by the OGN gene, is a human protein. This gene encodes a protein which induces ectopic bone formation in conjunction with transforming growth factor beta. This protein is a small proteoglycan which contains tandem leucine-rich repeats (LRR). The gene expresses three transcript variants. The level of expression of this gene has been correlated with enlarged hearts and more specifically left ventricular hypertrophy.	Osteoglycin Osteoglycin (also called mimecan), encoded by the OGN gene, is a human protein.[1] This gene encodes a protein which induces ectopic bone formation in conjunction with transforming growth factor beta. This protein is a small proteoglycan which contains tandem leucine-rich repeats (LRR). The gene expresses three transcript variants.[1] The level of expression of this gene has been correlated with enlarged hearts and more specifically left ventricular hypertrophy.[2][3]	https://www.wikidoc.org/index.php/Osteoglycin
8e9ea79e149622773d2c5170ac4f7d5e6ab03baf	wikidoc	Osteonectin	Osteonectin Osteonectin (ON) also known as secreted protein acidic and rich in cysteine (SPARC) or basement-membrane protein 40 (BM-40) is a protein that in humans is encoded by the SPARC gene. Osteonectin is a glycoprotein in the bone that binds calcium. It is secreted by osteoblasts during bone formation, initiating mineralization and promoting mineral crystal formation. Osteonectin also shows affinity for collagen in addition to bone mineral calcium. A correlation between osteonectin over-expression and ampullary cancers and chronic pancreatitis has been found. # Gene The human SPARC gene is 26.5 kb long, and contains 10 exons and 9 introns and is located on chromosome 5q31-q33. # Structure Osteonectin is a 40 kD acidic and cysteine-rich glycoprotein consisting of a single polypeptide chain that can be broken into 4 domains: 1) a Ca++ binding domain near the glutamic acid-rich region at the amino terminus (domain I), 2) a cysteine-rich domain (II), 3) a hydrophilic region (domain III), and 4) an EF hand motif at the carboxy terminus region (domain IV). # Function Osteonectin is an acidic extracellular matrix glycoprotein that plays a vital role in bone mineralization, cell-matrix interactions, and collagen binding. Osteonectin also increases the production and activity of matrix metalloproteinases, a function important to invading cancer cells within bone. Additional functions of osteonectin beneficial to tumor cells include angiogenesis, proliferation and migration. Overexpression of osteonectin is reported in many human cancers such as breast, prostate and colon. This molecule has been implicated in several biological functions, including mineralization of bone and cartilage, inhibiting mineralization, modulation of cell proliferation, facilitation of acquisition of differentiated phenotype and promotion of cell attachment and spreading. A number of phosphoproteins and glycoproteins are found in bone. The phosphate is bound to the protein backbone through phosphorylated serine or threonine amino acid residues. The best characterized of these bone proteins is osteonectin. It binds collagen and hydroxyapatite in separate domains, is found in relatively large amounts in immature bone, and promotes mineralization of collagen. # Tissue distribution Fibroblasts, including periodontal fibroblasts, synthesize osteonectin. This protein is synthesized by macrophages at sites of wound repair and platelet degranulation, so it may play an important role in wound healing. SPARC does not support cell attachment, and like thrombospondin and tenascin, is anti-adhesive and an inhibitor of cell spreading. It disrupts focal adhesions in fibroblasts. It also regulates the proliferation of some cells, especially endothelial cells, mediated by its ability to bind to cytokines and growth factors. Osteonectin has also been found to decrease DNA synthesis in cultured bone. High levels of immunodetectable osteonectin are found in active osteoblasts and marrow progenitor cells, odontoblasts, periodontal ligament and gingival cells, and some chondrocytes and hypertrophic chondrocytes. Osteonectin is also detectable in osteoid, bone matrix proper, and dentin. Osteonectin has been localized in a variety of tissues, but is found in greatest abundance in osseous tissue, tissues characterized by high turnover (such as intestinal epithelium), basement membranes, and certain neoplasms. Osteonectin is expressed by a wide variety of cells, including chondrocytes, fibroblasts, platelets, endothelial cells, epithelial cells, Leydig cells, Sertoli cells, luteal cells, adrenal cortical cells, and numerous neoplastic cell lines (such as SaOS-2 cells from human osteosarcoma). # Model organisms Model organisms have been used in the study of SPARC function. A conditional knockout mouse line, called Sparctm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and six significant abnormalities were observed. Homozygous mutant animals had unusually white incisors, decreased bone mineral density, abnormal lens morphology, cataracts and a decreased length of long bones.	Osteonectin Osteonectin (ON) also known as secreted protein acidic and rich in cysteine (SPARC) or basement-membrane protein 40 (BM-40) is a protein that in humans is encoded by the SPARC gene. Osteonectin is a glycoprotein in the bone that binds calcium. It is secreted by osteoblasts during bone formation, initiating mineralization and promoting mineral crystal formation. Osteonectin also shows affinity for collagen in addition to bone mineral calcium. A correlation between osteonectin over-expression and ampullary cancers and chronic pancreatitis has been found. # Gene The human SPARC gene is 26.5 kb long, and contains 10 exons and 9 introns and is located on chromosome 5q31-q33. # Structure Osteonectin is a 40 kD acidic and cysteine-rich glycoprotein consisting of a single polypeptide chain that can be broken into 4 domains: 1) a Ca++ binding domain near the glutamic acid-rich region at the amino terminus (domain I), 2) a cysteine-rich domain (II), 3) a hydrophilic region (domain III), and 4) an EF hand motif at the carboxy terminus region (domain IV).[1] # Function Osteonectin is an acidic extracellular matrix glycoprotein that plays a vital role in bone mineralization, cell-matrix interactions, and collagen binding. Osteonectin also increases the production and activity of matrix metalloproteinases, a function important to invading cancer cells within bone. Additional functions of osteonectin beneficial to tumor cells include angiogenesis, proliferation and migration. Overexpression of osteonectin is reported in many human cancers such as breast, prostate and colon.[2] This molecule has been implicated in several biological functions, including mineralization of bone and cartilage, inhibiting mineralization, modulation of cell proliferation, facilitation of acquisition of differentiated phenotype and promotion of cell attachment and spreading. A number of phosphoproteins and glycoproteins are found in bone. The phosphate is bound to the protein backbone through phosphorylated serine or threonine amino acid residues. The best characterized of these bone proteins is osteonectin. It binds collagen and hydroxyapatite in separate domains, is found in relatively large amounts in immature bone, and promotes mineralization of collagen. # Tissue distribution Fibroblasts, including periodontal fibroblasts, synthesize osteonectin.[3] This protein is synthesized by macrophages at sites of wound repair and platelet degranulation, so it may play an important role in wound healing. SPARC does not support cell attachment, and like thrombospondin and tenascin, is anti-adhesive and an inhibitor of cell spreading. It disrupts focal adhesions in fibroblasts. It also regulates the proliferation of some cells, especially endothelial cells, mediated by its ability to bind to cytokines and growth factors.[4] Osteonectin has also been found to decrease DNA synthesis in cultured bone.[5] High levels of immunodetectable osteonectin are found in active osteoblasts and marrow progenitor cells, odontoblasts, periodontal ligament and gingival cells, and some chondrocytes and hypertrophic chondrocytes. Osteonectin is also detectable in osteoid, bone matrix proper, and dentin. Osteonectin has been localized in a variety of tissues, but is found in greatest abundance in osseous tissue, tissues characterized by high turnover (such as intestinal epithelium), basement membranes, and certain neoplasms. Osteonectin is expressed by a wide variety of cells, including chondrocytes, fibroblasts, platelets, endothelial cells, epithelial cells, Leydig cells, Sertoli cells, luteal cells, adrenal cortical cells, and numerous neoplastic cell lines (such as SaOS-2 cells from human osteosarcoma). # Model organisms Model organisms have been used in the study of SPARC function. A conditional knockout mouse line, called Sparctm1a(EUCOMM)Wtsi[14][15] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[16][17][18] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[12][19] Twenty six tests were carried out on mutant mice and six significant abnormalities were observed.[12] Homozygous mutant animals had unusually white incisors, decreased bone mineral density, abnormal lens morphology, cataracts and a decreased length of long bones.[12]	https://www.wikidoc.org/index.php/Osteonectin
203b37feaaedda6010c86f30a0e15a5e95f25cb9	wikidoc	Osteopontin	Osteopontin Osteopontin (OPN), also known as bone sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric), is a protein that in humans is encoded by the SPP1 gene (secreted phosphoprotein 1). The murine ortholog is Spp1. Osteopontin is a SIBLING (glycoprotein) that was first identified in 1986 in osteoblasts. The prefix osteo- indicates that the protein is expressed in bone, although it is also expressed in other tissues. The suffix -pontin is derived from "pons," the Latin word for bridge, and signifies osteopontin's role as a linking protein. Osteopontin is an extracellular structural protein and therefore an organic component of bone. Synonyms for this protein include sialoprotein I and 44K BPP (bone phosphoprotein). The gene has 7 exons, spans 5 kilobases in length and in humans it is located on the long arm of chromosome 4 region 22 (4q1322.1). The protein is composed of ~300 amino acids residues and has ~30 carbohydrate residues attached including 10 sialic acid residues, which are attached to the protein during post-translational modification in the Golgi apparatus. The protein is rich in acidic residues: 30-36% are either aspartic or glutamic acid. # Structure ## General structure OPN is a highly negatively charged, extracellular matrix protein that lacks an extensive secondary structure. It is composed of about 300 amino acids (297 in mouse; 314 in human) and is expressed as a 33-kDa nascent protein; there are also functionally important cleavage sites. OPN can go through posttranslational modifications, which increase its apparent molecular weight to about 44 kDa. The OPN gene is composed of 7 exons, 6 of which containing coding sequence. The first two exons contain the 5' untranslated region (5' UTR). Exons 2, 3, 4, 5, 6, and 7 code for 17, 13, 27, 14, 108 and 134 amino acids, respectively. All intron-exon boundaries are of the phase 0 type, thus alternative exon splicing maintains the reading frame of the OPN gene. ## Isoforms Full-length OPN (OPN-FL) can be modified by thrombin cleavage, which exposes a cryptic sequence, SVVYGLR on the cleaved form of the protein known as OPN-R (Fig. 1). This thrombin-cleaved OPN (OPN-R) exposes an epitope for integrin receptors of α4β1, α9β1, and α9β4. These integrin receptors are present on a number of immune cells such as mast cells, neutrophils, and T cells. It is also expressed by monocytes and macrophages. Upon binding these receptors, cells use several signal transduction pathways to elicit immune responses in these cells. OPN-R can be further cleaved by Carboxypeptidase B (CPB) by removal of C-terminal arginine and become OPN-L. The function of OPN-L is largely unknown. It appears an intracellular variant of OPN (iOPN) is involved in a number of cellular processes including migration, fusion and motility. Intracellular OPN is generated using an alternative translation start site on the same mRNA species used to generate the extracellular isoform. This alternative translation start site is downstream of the N-terminal endoplasmic reticulum-targeting signal sequence, thus allowing cytoplasmic translation of OPN. Various human cancers, including breast cancer, have been observed to express splice variants of OPN. The cancer-specific splice variants are osteopontin-a, osteopontin-b, and osteopontin-c. Exon 5 is lacking from osteopontin-b, whereas osteopontin-c lacks exon 4. Osteopontin-c has been suggested to facilitate the anchorage-independent phenotype of some human breast cancer cells due to its inability to associate with the extracellular matrix. # Biosynthesis Osteopontin is biosynthesized by a variety of tissue types including cardiac fibroblasts, preosteoblasts, osteoblasts, osteocytes, odontoblasts, some bone marrow cells, hypertrophic chondrocytes, dendritic cells, macrophages, smooth muscle, skeletal muscle myoblasts, endothelial cells, and extraosseous (non-bone) cells in the inner ear, brain, kidney, deciduum, and placenta. Synthesis of osteopontin is stimulated by calcitriol (1,25-dihydroxy-vitamin D3). ## Regulation Regulation of the osteopontin gene is incompletely understood. Different cell types may differ in their regulatory mechanisms of the OPN gene. OPN expression in bone predominantly occurs by osteoblasts and osteocyctes (bone-forming cells) as well as osteoclasts (bone-resorbing cells). Runx2 (aka Cbfa1) and osterix (Osx) transcription factors are required for the expression of OPN Runx2 and Osx bind promoters of osteoblast-specific genes such as Col1α1, Bsp, and Opn and upregulate transcription. Hypocalcemia and hypophosphatemia (instances that stimulate kidney proximal tubule cells to produce calcitriol (1α,25-dihydroxyvitamin D3)) lead to increases in OPN transcription, translation and secretion. This is due to the presence of a high-specificity vitamin D response element (VDRE) in the OPN gene promoter. Extracellular inorganic phosphate (ePi) has also been identified as a modulator of OPN expression. Stimulation of OPN expression also occurs upon exposure of cells to pro-inflammatory cytokines, classical mediators of acute inflammation (e.g. tumour necrosis factor α , infterleukin-1β ), angiotensin II, transforming growth factor β (TGFβ) and parathyroid hormone (PTH), although a detailed mechanistic understanding of these regulatory pathways are not yet known. Hyperglycemia and hypoxia are also known to increase OPN expression. # Biological function ## Role in biomineralization OPN belongs to a family of secreted acidic proteins whose members have an abundance of negatively charged amino acids such as Asp and Glu. OPN also has a large number of consensus sequence sites for post-translational phosphorylation of Ser residues to form phosphoserine, providing additional negative charge. Contiguous stretches of high negative charge in OPN have been identified and named the polyAsp motif (poly-aspartic acid) and the ASARM motif (acidic serine- and aspartate-rich motif), with the latter sequence having multiple phosphorylation sites. This overall negative charge of OPN, along with its specific acidic motifs and the fact that OPN is an intrinsically disordered protein allowing for open and flexible structures, permit OPN to bind strongly to calcium atoms available at crystal surfaces in various biominerals. Such binding of OPN to various types of calcium-based biominerals ‒ such as calcium-phosphate mineral in bones and teeth, calcium-carbonate mineral in inner ear otoconia and avian eggshells, and calcium-oxalate mineral in kidney stones – acts as a mineralization inhibitor to regulate crystal growth. OPN is a substrate protein for a number of enzymes whose actions may modulate the mineralization-inhibiting function of OPN. PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) is one such enzyme, which extensively degrades OPN, and whose inactivating gene mutations (in X-linked hypophosphatemia, XLH) lead to altered processing of OPN such that inhibitory OPN cannot be degraded and accumulates in the bone (and tooth) extracellular matrix, likely contributing locally to the osteomalacia (soft hypomineralized bones) characteristic of XLH. Along with its role in the regulation of normal mineralization within the extracellular matrices of bones and teeth, OPN is also upregulated at sites of pathologic, ectopic calcification – such as for example, in urolithiasis and vascular calcification ‒ presumably at least in part to inhibit debilitating mineralization in these soft tissues. ## Role in bone remodeling Osteopontin has been implicated as an important factor in bone remodeling. Specifically, research suggests it plays a role in anchoring osteoclasts to the mineral matrix of bones. The organic part of bone is about 20% of the dry weight, and counts in, other than osteopontin, collagen type I, osteocalcin, osteonectin, bone sialo protein, and alkaline phosphatase. Collagen type I counts for 90% of the protein mass. The inorganic part of bone is the mineral hydroxyapatite, Ca10(PO4)6(OH)2. Loss of this mineral may lead to osteoporosis, as the bone is depleted for calcium if this is not supplied in the diet. OPN serves to initiate the process by which osteoclasts develop their ruffled borders to begin bone resorption. It is also found in urine, where it inhibits kidney stone formation. ## Role in immune functions As discussed, OPN binds to several integrin receptors including α4β1, α9β1, and α9β4 expressed by leukocytes. These receptors have been well-established to function in cell adhesion, migration, and survival in these cells. Therefore, recent research efforts have focused on the role of OPN in mediating such responses. Osteopontin (OPN) is expressed in a range of immune cells, including macrophages, neutrophils, dendritic cells, and T and B cells, with varying kinetics. OPN is reported to act as an immune modulator in a variety of manners. Firstly, it has chemotactic properties, which promote cell recruitment to inflammatory sites. It also functions as an adhesion protein, involved in cell attachment and wound healing. In addition, OPN mediates cell activation and cytokine production, as well as promoting cell survival by regulating apoptosis. The following examples are found. ### Role in Heart OPN expression increases under a variety of conditions of the heart, and is associated with increased myocyte apoptosis and myocardial dysfunction. ### Chemotaxis OPN plays an important role in neutrophil recruitment in alcoholic liver disease. OPN is important for the migration of neutrophil in vitro. In addition, OPN recruits inflammatory cells to arthritis joints in the collagen-induced arthritis model of rheumatoid arthritis. A recent in vitro study in 2008 has found that OPN plays a role in mast cell migration. Here OPN knock-out mast cells were cultured and they observed a decreased level of chemotaxis in these cells compared to wildtype mast cells. OPN was also found to act as a macrophage chemotactic factor. In this study, researchers looked at the accumulation of macrophages in the brain of rhesus monkeys and found that OPN prevented macrophages from leaving the accumulation site, indicating an increased level of chemotaxis. ### Cell activation Activated T cells are promoted by IL-12 to differentiate towards the Th1 type, producing cytokines including IL-12 and IFNγ. OPN inhibits production of the Th2 cytokine IL-10, which leads to enhanced Th1 response. OPN influences cell-mediated immunity and has Th1 cytokine functions. It enhances B cell immunoglobulin production and proliferation. Recent studies in 2008 suggest that OPN also induces mast cell degranulation. The researchers here observed that IgE-mediated anaphylaxis was significantly reduced in OPN knock-out mice compared to wild-type mice. The role of OPN in activation of macrophages has also been implicated in a cancer study, when researchers discovered that OPN-producing tumors were able to induce macrophage activation compared to OPN-deficient tumors. ### Apoptosis OPN is an important anti-apoptotic factor in many circumstances. OPN blocks the activation-induced cell death of macrophages and T cells as well as fibroblasts and endothelial cells exposed to harmful stimuli. OPN prevents non-programmed cell death in inflammatory colitis. # Potential clinical application The fact that OPN interacts with multiple cell surface receptors that are ubiquitously expressed makes it an active player in many physiological and pathological processes including wound healing, bone turnover, tumorigenesis, inflammation, ischemia, and immune responses1. Therefore, manipulation of plasma (or local) OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, bone (and tooth) mineralization diseases, osteoporosis, and some forms of stress. ## Role in autoimmune diseases OPN has been implicated in pathogenesis of rheumatoid arthritis. For instance, researchers found that OPN-R, the thrombin-cleaved form of OPN, was elevated in the rheumatoid arthritis joint. However, the role of OPN in rheumatoid arthritis is still unclear. One group found that OPN knock-out mice were protected against arthritis. while others were not able to reproduce this observation. OPN has been found to play a role in other autoimmune diseases including autoimmune hepatitis, allergic airway disease, and multiple sclerosis. ## Role in cancers and inflammatory diseases It has been shown that OPN drives IL-17 production; OPN is overexpressed in a variety of cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer, ovarian cancer, papillary thyroid carcinoma, melanoma and pleural mesothelioma; OPN contributes both glomerulonephritis and tubulointerstitial nephritis; and OPN is found in atheromatous plaques within arteries. Thus, manipulation of plasma OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, osteoporosis and some forms of stress. Research has implicated osteopontin in excessive scar-forming and a gel has been developed to inhibit its effect. ## Role in colitis Opn is up-regulated in inflammatory bowel disease (IBD). Opn expression is highly up-regulated in intestinal immune and non-immune cells and in the plasma of patients with Crohn’s disease (CD) and ulcerative colitis (UC), as well as in the colon and plasma of mice with experimental colitis. Increased plasma Opn levels are related to the severity of CD inflammation, and certain Opn gene (Spp1) haplotypes are modifiers of CD susceptibility. Opn has also a proinflammatory role in TNBS- and dextran sulfate sodium (DSS)-induced colitis, which are mouse models for IBD. Opn was found highly expressed by a specific dendritic cell (DC) subset derived from murine mesenteric lymph nodes (MLNs)and is highly proinflammatory for colitis. Dendritic cells are important for the development of intestinal inflammation in humans with IBD and in mice with experimental colitis. Opn expression by this inflammatory MLN DC subset is crucial for their pathogenic action during colitis. ## Role in allergy and asthma Osteopontin has recently been associated with allergic inflammation and asthma. Expression of Opn is significantly increased in lung epithelial and subepithelial cells of asthmatic patients in comparison to healthy subjects. Opn expression is also upregulated in lungs of mice with allergic airway inflammation. The secreted form of Opn (Opn-s) plays a proinflammatory role during allergen sensitization (OVA/Alum), as neutralization of Opn-s during that phase results in significantly milder allergic airway inflammation. In contrast, neutralization of Opn-s during antigenic challenge exacerbates allergic airway disease. These effects of Opn-s are mainly mediated by the regulation of Th2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and Th2-promoting conventional DCs during secondary antigenic challenge. OPN deficiency was also reported to protect against remodeling and bronchial hyperresponsiveness (BHR), again using a chronic allergen-challenge model of airway remodeling. Furthermore, it was recently demonstrated that OPN expression is upregulated in human asthma, is associated with remodeling changes and its subepithelial expression correlates to disease severity. OPN has also been reported to be increased in the sputum supernatant of smoking asthmatics, as well as the BALF and bronchial tissue of smoking controls and asthmatics. ## Role in muscle disease and injury Evidence is accumulating that suggests that osteopontin plays a number of roles in diseases of skeletal muscle, such as Duchenne muscular dystrophy. Osteopontin has been described as a component of the inflammatory environment of dystrophic and injured muscles, and has also been shown to increase scarring of diaphragm muscles of aged dystrophic mice. A recent study has identified osteopontin as a determinant of disease severity in patients with Duchenne muscular dystrophy. This study found that a mutation in the osteopontin gene promoter, known to cause low levels of osteopontin expression, is associated with a decrease in age to loss of ambulation and muscle strength in patients with Duchenne muscular dystrophy. ## Role in hip osteoarthritis An increase in Plasma OPN levels has been observed in patients with idiopathic hip OA. Furthermore, a correlation between OPN plasma levels and the severity of the disease has been noted. # Role in implantation OPN is expressed in endometrial cells during implantation. Due to the production of progesterone by the ovaries, OPN is up-regulated immensely to aid in this process. The endometrium must undergo decidualization, the process in which the endometrium undergoes changes to prepare for implantation, which will lead to the attachment of the embryo. The endometrium houses stromal cells that will differentiate to produce an optimal environment for the embryo to attach (decidualization). OPN is a vital protein for stromal cell proliferation and differentiation as well as it binds to the receptor αvβ3 to assist with adhesion. OPN along with decidualization ultimately encourages the successful implantation of the early embryo. A OPN gene knock-out results in attachment instability at the maternal-fetal interface.	Osteopontin Osteopontin (OPN), also known as bone sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), secreted phosphoprotein 1 (SPP1), 2ar and Rickettsia resistance (Ric),[1] is a protein that in humans is encoded by the SPP1 gene (secreted phosphoprotein 1). The murine ortholog is Spp1. Osteopontin is a SIBLING (glycoprotein) that was first identified in 1986 in osteoblasts. The prefix osteo- indicates that the protein is expressed in bone, although it is also expressed in other tissues. The suffix -pontin is derived from "pons," the Latin word for bridge, and signifies osteopontin's role as a linking protein. Osteopontin is an extracellular structural protein and therefore an organic component of bone. Synonyms for this protein include sialoprotein I and 44K BPP (bone phosphoprotein). The gene has 7 exons, spans 5 kilobases in length and in humans it is located on the long arm of chromosome 4 region 22 (4q1322.1). The protein is composed of ~300 amino acids residues and has ~30 carbohydrate residues attached including 10 sialic acid residues, which are attached to the protein during post-translational modification in the Golgi apparatus. The protein is rich in acidic residues: 30-36% are either aspartic or glutamic acid. # Structure ## General structure OPN is a highly negatively charged, extracellular matrix protein that lacks an extensive secondary structure.[2] It is composed of about 300 amino acids (297 in mouse; 314 in human) and is expressed as a 33-kDa nascent protein; there are also functionally important cleavage sites. OPN can go through posttranslational modifications, which increase its apparent molecular weight to about 44 kDa.[3] The OPN gene is composed of 7 exons, 6 of which containing coding sequence.[4][5] The first two exons contain the 5' untranslated region (5' UTR).[6] Exons 2, 3, 4, 5, 6, and 7 code for 17, 13, 27, 14, 108 and 134 amino acids, respectively.[6] All intron-exon boundaries are of the phase 0 type, thus alternative exon splicing maintains the reading frame of the OPN gene. ## Isoforms Full-length OPN (OPN-FL) can be modified by thrombin cleavage, which exposes a cryptic sequence, SVVYGLR on the cleaved form of the protein known as OPN-R (Fig. 1). This thrombin-cleaved OPN (OPN-R) exposes an epitope for integrin receptors of α4β1, α9β1, and α9β4.[7][8] These integrin receptors are present on a number of immune cells such as mast cells,[9] neutrophils,[10] and T cells. It is also expressed by monocytes and macrophages.[11] Upon binding these receptors, cells use several signal transduction pathways to elicit immune responses in these cells. OPN-R can be further cleaved by Carboxypeptidase B (CPB) by removal of C-terminal arginine and become OPN-L. The function of OPN-L is largely unknown. It appears an intracellular variant of OPN (iOPN) is involved in a number of cellular processes including migration, fusion and motility.[12][13][14][15] Intracellular OPN is generated using an alternative translation start site on the same mRNA species used to generate the extracellular isoform.[16] This alternative translation start site is downstream of the N-terminal endoplasmic reticulum-targeting signal sequence, thus allowing cytoplasmic translation of OPN. Various human cancers, including breast cancer, have been observed to express splice variants of OPN.[17][18] The cancer-specific splice variants are osteopontin-a, osteopontin-b, and osteopontin-c. Exon 5 is lacking from osteopontin-b, whereas osteopontin-c lacks exon 4.[17] Osteopontin-c has been suggested to facilitate the anchorage-independent phenotype of some human breast cancer cells due to its inability to associate with the extracellular matrix.[17] # Biosynthesis Osteopontin is biosynthesized by a variety of tissue types including cardiac fibroblasts,[19] preosteoblasts, osteoblasts, osteocytes, odontoblasts, some bone marrow cells, hypertrophic chondrocytes, dendritic cells, macrophages,[20] smooth muscle,[21] skeletal muscle myoblasts,[22] endothelial cells, and extraosseous (non-bone) cells in the inner ear, brain, kidney, deciduum, and placenta. Synthesis of osteopontin is stimulated by calcitriol (1,25-dihydroxy-vitamin D3). ## Regulation Regulation of the osteopontin gene is incompletely understood. Different cell types may differ in their regulatory mechanisms of the OPN gene. OPN expression in bone predominantly occurs by osteoblasts and osteocyctes (bone-forming cells) as well as osteoclasts (bone-resorbing cells).[23] Runx2 (aka Cbfa1) and osterix (Osx) transcription factors are required for the expression of OPN [24] Runx2 and Osx bind promoters of osteoblast-specific genes such as Col1α1, Bsp, and Opn and upregulate transcription.[25] Hypocalcemia and hypophosphatemia (instances that stimulate kidney proximal tubule cells to produce calcitriol (1α,25-dihydroxyvitamin D3)) lead to increases in OPN transcription, translation and secretion.[26] This is due to the presence of a high-specificity vitamin D response element (VDRE) in the OPN gene promoter.[27][28][29] Extracellular inorganic phosphate (ePi) has also been identified as a modulator of OPN expression.[30] Stimulation of OPN expression also occurs upon exposure of cells to pro-inflammatory cytokines,[31] classical mediators of acute inflammation (e.g. tumour necrosis factor α [TNFα], infterleukin-1β [IL-1β]), angiotensin II, transforming growth factor β (TGFβ) and parathyroid hormone (PTH),[32][33] although a detailed mechanistic understanding of these regulatory pathways are not yet known. Hyperglycemia and hypoxia are also known to increase OPN expression.[32][34][35] # Biological function ## Role in biomineralization OPN belongs to a family of secreted acidic proteins whose members have an abundance of negatively charged amino acids such as Asp and Glu.[36] OPN also has a large number of consensus sequence sites for post-translational phosphorylation of Ser residues to form phosphoserine, providing additional negative charge.[37] Contiguous stretches of high negative charge in OPN have been identified and named the polyAsp motif (poly-aspartic acid) and the ASARM motif (acidic serine- and aspartate-rich motif), with the latter sequence having multiple phosphorylation sites.[38][39][40][41] This overall negative charge of OPN, along with its specific acidic motifs and the fact that OPN is an intrinsically disordered protein[42][43] allowing for open and flexible structures, permit OPN to bind strongly to calcium atoms available at crystal surfaces in various biominerals.[41][44][45] Such binding of OPN to various types of calcium-based biominerals ‒ such as calcium-phosphate mineral in bones and teeth,[46] calcium-carbonate mineral in inner ear otoconia[47] and avian eggshells,[48] and calcium-oxalate mineral in kidney stones[49][50][51] – acts as a mineralization inhibitor to regulate crystal growth.[52] OPN is a substrate protein for a number of enzymes whose actions may modulate the mineralization-inhibiting function of OPN. PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) is one such enzyme, which extensively degrades OPN, and whose inactivating gene mutations (in X-linked hypophosphatemia, XLH) lead to altered processing of OPN such that inhibitory OPN cannot be degraded and accumulates in the bone (and tooth) extracellular matrix, likely contributing locally to the osteomalacia (soft hypomineralized bones) characteristic of XLH.[53][54][55] Along with its role in the regulation of normal mineralization within the extracellular matrices of bones and teeth,[56] OPN is also upregulated at sites of pathologic, ectopic calcification[57][58] – such as for example, in urolithiasis and vascular calcification ‒ presumably at least in part to inhibit debilitating mineralization in these soft tissues. ## Role in bone remodeling Osteopontin has been implicated as an important factor in bone remodeling.[59] Specifically, research suggests it plays a role in anchoring osteoclasts to the mineral matrix of bones.[9] The organic part of bone is about 20% of the dry weight, and counts in, other than osteopontin, collagen type I, osteocalcin, osteonectin, bone sialo protein, and alkaline phosphatase. Collagen type I counts for 90% of the protein mass. The inorganic part of bone is the mineral hydroxyapatite, Ca10(PO4)6(OH)2. Loss of this mineral may lead to osteoporosis, as the bone is depleted for calcium if this is not supplied in the diet. OPN serves to initiate the process by which osteoclasts develop their ruffled borders to begin bone resorption. It is also found in urine, where it inhibits kidney stone formation. ## Role in immune functions As discussed, OPN binds to several integrin receptors including α4β1, α9β1, and α9β4 expressed by leukocytes. These receptors have been well-established to function in cell adhesion, migration, and survival in these cells. Therefore, recent research efforts have focused on the role of OPN in mediating such responses. Osteopontin (OPN) is expressed in a range of immune cells, including macrophages, neutrophils, dendritic cells, and T and B cells, with varying kinetics. OPN is reported to act as an immune modulator in a variety of manners.[2] Firstly, it has chemotactic properties, which promote cell recruitment to inflammatory sites. It also functions as an adhesion protein, involved in cell attachment and wound healing. In addition, OPN mediates cell activation and cytokine production, as well as promoting cell survival by regulating apoptosis.[2] The following examples are found.[2] ### Role in Heart OPN expression increases under a variety of conditions of the heart, and is associated with increased myocyte apoptosis and myocardial dysfunction.[60] ### Chemotaxis OPN plays an important role in neutrophil recruitment in alcoholic liver disease.[10][61] OPN is important for the migration of neutrophil in vitro.[62] In addition, OPN recruits inflammatory cells to arthritis joints in the collagen-induced arthritis model of rheumatoid arthritis.[63][64] A recent in vitro study in 2008 has found that OPN plays a role in mast cell migration.[65] Here OPN knock-out mast cells were cultured and they observed a decreased level of chemotaxis in these cells compared to wildtype mast cells. OPN was also found to act as a macrophage chemotactic factor.[66] In this study, researchers looked at the accumulation of macrophages in the brain of rhesus monkeys and found that OPN prevented macrophages from leaving the accumulation site, indicating an increased level of chemotaxis. ### Cell activation Activated T cells are promoted by IL-12 to differentiate towards the Th1 type, producing cytokines including IL-12 and IFNγ. OPN inhibits production of the Th2 cytokine IL-10, which leads to enhanced Th1 response. OPN influences cell-mediated immunity and has Th1 cytokine functions. It enhances B cell immunoglobulin production and proliferation.[2] Recent studies in 2008 suggest that OPN also induces mast cell degranulation.[65] The researchers here observed that IgE-mediated anaphylaxis was significantly reduced in OPN knock-out mice compared to wild-type mice. The role of OPN in activation of macrophages has also been implicated in a cancer study, when researchers discovered that OPN-producing tumors were able to induce macrophage activation compared to OPN-deficient tumors.[67] ### Apoptosis OPN is an important anti-apoptotic factor in many circumstances. OPN blocks the activation-induced cell death of macrophages and T cells as well as fibroblasts and endothelial cells exposed to harmful stimuli.[68][69] OPN prevents non-programmed cell death in inflammatory colitis.[70] # Potential clinical application The fact that OPN interacts with multiple cell surface receptors that are ubiquitously expressed makes it an active player in many physiological and pathological processes including wound healing, bone turnover, tumorigenesis, inflammation, ischemia, and immune responses1. Therefore, manipulation of plasma (or local) OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, bone (and tooth) mineralization diseases, osteoporosis, and some forms of stress.[2] ## Role in autoimmune diseases OPN has been implicated in pathogenesis of rheumatoid arthritis. For instance, researchers found that OPN-R, the thrombin-cleaved form of OPN, was elevated in the rheumatoid arthritis joint. However, the role of OPN in rheumatoid arthritis is still unclear. One group found that OPN knock-out mice were protected against arthritis.[71] while others were not able to reproduce this observation.[72] OPN has been found to play a role in other autoimmune diseases including autoimmune hepatitis, allergic airway disease, and multiple sclerosis.[73] ## Role in cancers and inflammatory diseases It has been shown that OPN drives IL-17 production;[74] OPN is overexpressed in a variety of cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer, ovarian cancer, papillary thyroid carcinoma, melanoma and pleural mesothelioma; OPN contributes both glomerulonephritis and tubulointerstitial nephritis; and OPN is found in atheromatous plaques within arteries. Thus, manipulation of plasma OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, osteoporosis and some forms of stress.[2] Research has implicated osteopontin in excessive scar-forming and a gel has been developed to inhibit its effect.[75] ## Role in colitis Opn is up-regulated in inflammatory bowel disease (IBD).[76] Opn expression is highly up-regulated in intestinal immune and non-immune cells and in the plasma of patients with Crohn’s disease (CD) and ulcerative colitis (UC), as well as in the colon and plasma of mice with experimental colitis.[76][77][78] Increased plasma Opn levels are related to the severity of CD inflammation, and certain Opn gene (Spp1) haplotypes are modifiers of CD susceptibility. Opn has also a proinflammatory role in TNBS- and dextran sulfate sodium (DSS)-induced colitis, which are mouse models for IBD. Opn was found highly expressed by a specific dendritic cell (DC) subset derived from murine mesenteric lymph nodes (MLNs)and is highly proinflammatory for colitis.[79] Dendritic cells are important for the development of intestinal inflammation in humans with IBD and in mice with experimental colitis. Opn expression by this inflammatory MLN DC subset is crucial for their pathogenic action during colitis.[79] ## Role in allergy and asthma Osteopontin has recently been associated with allergic inflammation and asthma. Expression of Opn is significantly increased in lung epithelial and subepithelial cells of asthmatic patients in comparison to healthy subjects.[80] Opn expression is also upregulated in lungs of mice with allergic airway inflammation.[80] The secreted form of Opn (Opn-s) plays a proinflammatory role during allergen sensitization (OVA/Alum), as neutralization of Opn-s during that phase results in significantly milder allergic airway inflammation.[80] In contrast, neutralization of Opn-s during antigenic challenge exacerbates allergic airway disease.[80] These effects of Opn-s are mainly mediated by the regulation of Th2-suppressing plasmacytoid dendritic cells (DCs) during primary sensitization and Th2-promoting conventional DCs during secondary antigenic challenge.[80] OPN deficiency was also reported to protect against remodeling and bronchial hyperresponsiveness (BHR), again using a chronic allergen-challenge model of airway remodeling.[81] Furthermore, it was recently demonstrated that OPN expression is upregulated in human asthma, is associated with remodeling changes and its subepithelial expression correlates to disease severity.[82] OPN has also been reported to be increased in the sputum supernatant of smoking asthmatics,[83] as well as the BALF and bronchial tissue of smoking controls and asthmatics.[84] ## Role in muscle disease and injury Evidence is accumulating that suggests that osteopontin plays a number of roles in diseases of skeletal muscle, such as Duchenne muscular dystrophy. Osteopontin has been described as a component of the inflammatory environment of dystrophic and injured muscles,[22][85][86][87] and has also been shown to increase scarring of diaphragm muscles of aged dystrophic mice.[88] A recent study has identified osteopontin as a determinant of disease severity in patients with Duchenne muscular dystrophy.[89] This study found that a mutation in the osteopontin gene promoter, known to cause low levels of osteopontin expression, is associated with a decrease in age to loss of ambulation and muscle strength in patients with Duchenne muscular dystrophy. ## Role in hip osteoarthritis An increase in Plasma OPN levels has been observed in patients with idiopathic hip OA. Furthermore, a correlation between OPN plasma levels and the severity of the disease has been noted.[90] # Role in implantation OPN is expressed in endometrial cells during implantation. Due to the production of progesterone by the ovaries, OPN is up-regulated immensely to aid in this process. The endometrium must undergo decidualization, the process in which the endometrium undergoes changes to prepare for implantation, which will lead to the attachment of the embryo. The endometrium houses stromal cells that will differentiate to produce an optimal environment for the embryo to attach (decidualization). OPN is a vital protein for stromal cell proliferation and differentiation as well as it binds to the receptor αvβ3 to assist with adhesion. OPN along with decidualization ultimately encourages the successful implantation of the early embryo. A OPN gene knock-out results in attachment instability at the maternal-fetal interface.[91][92]	https://www.wikidoc.org/index.php/Osteopontin
425627991cea21a3ec6ea2d6619f8a49b02d1fd1	wikidoc	Sex steroid	Sex steroid # Overview Sex steroids, also known as gonadal steroids, are steroid hormones which interact with vertebrate androgen or estrogen receptors. The term sex hormone nearly always is synonymous with sex steroid. # Production Natural sex steroids are made by the gonads (ovaries or testes), by adrenal glands, or by conversion from other sex steroids in other tissues such as liver or fat. # Functions Sex steroids play important roles in inducing the body changes known as primary sex characteristics and secondary sex characteristics. The development of both primary and secondary sexual characteristics is controlled by sex hormones after the initial fetal stage where the presence or absence of the Y-chromosome and/or the SRY gene determine development. # Synthetic sex steroids There are also many synthetic sex steroids. Synthetic androgens are often referred to as anabolic steroids. Synthetic estrogens and progestins are used in methods of hormonal contraception. Diethylstilbestrol (DES) is a synthetic estrogen. # Types In many contexts, the two main classes of sex steroids are androgens and estrogens, of which the most important human examples are testosterone and estradiol respectively. Other contexts will include progestagen as a third class of sex steroids, distinct from androgens and estrogens. Progesterone is the most important and only naturally occurring human progestagen. Sex steroids include: - androgens: testosterone androstenedione dihydrotestosterone dehydroepiandrosterone anabolic steroids - testosterone - androstenedione - dihydrotestosterone - dehydroepiandrosterone - anabolic steroids - estrogens: estradiol diethylstilbestrol - estradiol - diethylstilbestrol - progestagens: progesterone progestins - progesterone - progestins	Sex steroid Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Sex steroids, also known as gonadal steroids, are steroid hormones which interact with vertebrate androgen or estrogen receptors. The term sex hormone nearly always is synonymous with sex steroid. # Production Natural sex steroids are made by the gonads (ovaries or testes), by adrenal glands, or by conversion from other sex steroids in other tissues such as liver or fat. # Functions Sex steroids play important roles in inducing the body changes known as primary sex characteristics and secondary sex characteristics. The development of both primary and secondary sexual characteristics is controlled by sex hormones after the initial fetal stage where the presence or absence of the Y-chromosome and/or the SRY gene determine development. # Synthetic sex steroids There are also many synthetic sex steroids. Synthetic androgens are often referred to as anabolic steroids. Synthetic estrogens and progestins are used in methods of hormonal contraception. Diethylstilbestrol (DES) is a synthetic estrogen. # Types In many contexts, the two main classes of sex steroids are androgens and estrogens, of which the most important human examples are testosterone and estradiol respectively. Other contexts will include progestagen as a third class of sex steroids, distinct from androgens and estrogens. Progesterone is the most important and only naturally occurring human progestagen. Sex steroids include: - androgens: testosterone androstenedione dihydrotestosterone dehydroepiandrosterone anabolic steroids - testosterone - androstenedione - dihydrotestosterone - dehydroepiandrosterone - anabolic steroids - estrogens: estradiol diethylstilbestrol - estradiol - diethylstilbestrol - progestagens: progesterone progestins - progesterone - progestins	https://www.wikidoc.org/index.php/Ovarian_steroids
ec0dae5b9608e3a3193c44a387fdec0dd501ada7	wikidoc	Oviposition	Oviposition Oviposition is the process of laying eggs by oviparous animals. The turtle is a great example. The turtle often lays eggs in strange places. Some arthropods, for example, lay their eggs with an organ called the ovipositor. Reptiles or birds or monetremata also lay eggs. A major issue for human health is the prevention of oviposition by malaria-bearing anopheles mosquitos. Suggested methods include using floating plants to cover the surface of bodies of stagnant water.	Oviposition Oviposition is the process of laying eggs by oviparous animals. The turtle is a great example. The turtle often lays eggs in strange places. Some arthropods, for example, lay their eggs with an organ called the ovipositor. Reptiles or birds or monetremata also lay eggs. A major issue for human health is the prevention of oviposition by malaria-bearing anopheles mosquitos. Suggested methods include using floating plants to cover the surface of bodies of stagnant water.[1] Template:Reproductive physiology Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Oviposition
354f7636d87087f0cc4c9d0804a497c101266170	wikidoc	Oxamniquine	Oxamniquine # Overview Oxamniquine is "an anthelmintic with schistosomicidal activity against Schistosoma mansoni, but not against other Schistosoma spp. Oxamniquine is a potent single-dose agent for treatment of Schistosoma mansoni infection in man and it causes worms to shift from the mesenteric veins to the liver where the male worms are retained; the female worms return to the mesentery, but can no longer release eggs. # Category Anthelmintic # US Brand Names VANSIL® (DISCONTINUED) # Mechanism of Action Oxamniquine is a semisynthetic tetrahydroquinoline and possibly acts by DNA binding resulting in contraction and paralysis of the worms and eventual detachment from terminalvenules in the mesentry and death. It is also hypothesized that its biochemical mechanisms are related to an anticholinergic effect which increases the parasite’s motility, as well as to synthesis inhibition of nucleic acids. Oxamniquine acts mainly on male worms but also induces small changes on a small proportion of females. Like praziquantel, it promotes more severe damage of the dorsal tegument than of the ventral surface. The drug causes the male worms to shift from the mesenteric circulation to the liver where the cellular host response causes its final elimination. The changes caused in the females are reversible and are due primarily to the discontinued male stimulation rather than the direct effect of oxamniquine. # Historical Perspective Oxamniquine was first described by Kaye and Woolhouse in 1972 as a metabolite of the compound UK 3883 (2-isopropylaminomethyl-6-methyl-7-nitro-1,2,3,4-tetrahydroquinoline). Initially it was prepared by microbiological hydroxilation in the presence of the fungus Aspergillus sclerotiorum. In 1979, Pfizer at Sandwich was presented with the Queen’s Award for Technological Achievement in recognition of the outstanding contribution made to tropical medicine by MANSIL™ (oxamniquine). # Pharmacokinetics Peak plasma concentrations are achieved 1 to 3 hours after a dose and the plasma half-life is 1 to 2.5 hours. It is extensively metabolised to inactive metabolites, principally the 6-carboxy derivative, which are excreted in the urine. About 70% of a dose of oxamniquine is excreted as the 6-carboxy metabolite within 12 hours of a dose; traces of the 2-carboxy metabolite have also been detected in the urine. # Uses For treatment of schistosomiasis. According to one systematic review, it is equally effective as praziquantel (for treating S. mansoni infections). # Contraindications and Precautions Pregnancy # Side Effects It is generally well tolerated following oral doses. Dizziness with or without drowsiness occurs in at least a third of patients, beginning up to 3 hours after a dose and usually lasting for up to 6 hours. Headache and gastrointestinal effects such as nausea, vomiting, and diarrhea are also common. Allergic-type reactions including urticaria, pruritic skin rashes, and fever may occur. Liver enzyme values have been raised transiently in some patients. Epileptiform convulsions have been reported, especially in patients with a history of convulsive disorders. Hallucinations and excitement have occurred rarely. A reddish discoloration of urine, probably due to a metabolite of oxamniquine, has been reported. # Dosage Oral, 15 mg per kg of body weight two times a day for one day. # How Supplied - Vansil (Pfizer): 250 mg capsules; syrup 250 mg/5 ml - Mansil: 250 mg Tablets	Oxamniquine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Oxamniquine is "an anthelmintic with schistosomicidal activity against Schistosoma mansoni, but not against other Schistosoma spp. Oxamniquine is a potent single-dose agent for treatment of Schistosoma mansoni infection in man and it causes worms to shift from the mesenteric veins to the liver where the male worms are retained; the female worms return to the mesentery, but can no longer release eggs. # Category Anthelmintic # US Brand Names VANSIL® (DISCONTINUED) # Mechanism of Action Oxamniquine is a semisynthetic tetrahydroquinoline and possibly acts by DNA binding resulting in contraction and paralysis of the worms and eventual detachment from terminalvenules in the mesentry and death. It is also hypothesized that its biochemical mechanisms are related to an anticholinergic effect which increases the parasite’s motility, as well as to synthesis inhibition of nucleic acids. Oxamniquine acts mainly on male worms but also induces small changes on a small proportion of females. Like praziquantel, it promotes more severe damage of the dorsal tegument than of the ventral surface. The drug causes the male worms to shift from the mesenteric circulation to the liver where the cellular host response causes its final elimination. The changes caused in the females are reversible and are due primarily to the discontinued male stimulation rather than the direct effect of oxamniquine. # Historical Perspective Oxamniquine was first described by Kaye and Woolhouse in 1972 as a metabolite of the compound UK 3883 (2-isopropylaminomethyl-6-methyl-7-nitro-1,2,3,4-tetrahydroquinoline). Initially it was prepared by microbiological hydroxilation in the presence of the fungus Aspergillus sclerotiorum. In 1979, Pfizer at Sandwich was presented with the Queen’s Award for Technological Achievement in recognition of the outstanding contribution made to tropical medicine by MANSIL™ (oxamniquine). # Pharmacokinetics Peak plasma concentrations are achieved 1 to 3 hours after a dose and the plasma half-life is 1 to 2.5 hours. It is extensively metabolised to inactive metabolites, principally the 6-carboxy derivative, which are excreted in the urine. About 70% of a dose of oxamniquine is excreted as the 6-carboxy metabolite within 12 hours of a dose; traces of the 2-carboxy metabolite have also been detected in the urine. # Uses For treatment of schistosomiasis. According to one systematic review, it is equally effective as praziquantel (for treating S. mansoni infections). # Contraindications and Precautions Pregnancy # Side Effects It is generally well tolerated following oral doses. Dizziness with or without drowsiness occurs in at least a third of patients, beginning up to 3 hours after a dose and usually lasting for up to 6 hours. Headache and gastrointestinal effects such as nausea, vomiting, and diarrhea are also common. Allergic-type reactions including urticaria, pruritic skin rashes, and fever may occur. Liver enzyme values have been raised transiently in some patients. Epileptiform convulsions have been reported, especially in patients with a history of convulsive disorders. Hallucinations and excitement have occurred rarely. A reddish discoloration of urine, probably due to a metabolite of oxamniquine, has been reported. # Dosage Oral, 15 mg per kg of body weight two times a day for one day. # How Supplied - Vansil (Pfizer): 250 mg capsules; syrup 250 mg/5 ml - Mansil: 250 mg Tablets	https://www.wikidoc.org/index.php/Oxamniquine
60019214ead9904b5a5f8db88a20902c13bdce22	wikidoc	Oxeye daisy	Oxeye daisy The oxeye daisy (Leucanthemum vulgare, syn. Chrysanthemum leucanthemum) also known as the marguerite is a widespread flowering plant native to Europe and the temperate regions of Asia. It is one of a number of plants to be called by the common name daisy. It is also sometimes called moon daisy or dog daisy. It is a perennial prostrate herb with small flower head (not larger than 5 cm) that consists of about 20 white ray flowers and numerous yellow disc flowers, growing on the end of the stem. The stem is mostly unbranched and sprouts laterally from a creeping rootstock. The leaves are darkgreen on both sides. The basal and middle leaves are petiolate, obovate to spoon-shaped, and serrate to dentate. The upper leaves are shorter, sessile and borne along the stem. It produces an abundant number of flat seeds without pappus. It spreads also vegetatively by rooting underground stems. The oxeye daisy is a typical meadow flower, growing in a variety of plant communities such as dry fields, meadows, but also under scrubs, open-canopy forests and waste places. It thrives in a wide range of conditions and prefers heavy and damp soils. It was introduced in parts of North America, Australia and New Zealand, where it is now a common weed displacing native plant species in some areas. It is difficult to control or eradicate, since a new plant can regenerate from rhizome fragments. However, in North Carolina it is planted on roadsides by the highway department. See also: Yellow oxeye daisy # Uses The un-opened buds can be marinated and used in a similar way to capers # He loves me, he loves me not The game "He loves me, he loves me not" (effeuiller la marguerite (in French)) is associated with this flower.	Oxeye daisy The oxeye daisy (Leucanthemum vulgare, syn. Chrysanthemum leucanthemum) also known as the marguerite is a widespread flowering plant native to Europe and the temperate regions of Asia. It is one of a number of plants to be called by the common name daisy. It is also sometimes called moon daisy or dog daisy. It is a perennial prostrate herb with small flower head (not larger than 5 cm) that consists of about 20 white ray flowers and numerous yellow disc flowers, growing on the end of the stem. The stem is mostly unbranched and sprouts laterally from a creeping rootstock. The leaves are darkgreen on both sides. The basal and middle leaves are petiolate, obovate to spoon-shaped, and serrate to dentate. The upper leaves are shorter, sessile and borne along the stem. It produces an abundant number of flat seeds without pappus. It spreads also vegetatively by rooting underground stems. The oxeye daisy is a typical meadow flower, growing in a variety of plant communities such as dry fields, meadows, but also under scrubs, open-canopy forests and waste places. It thrives in a wide range of conditions and prefers heavy and damp soils. It was introduced in parts of North America, Australia and New Zealand, where it is now a common weed displacing native plant species in some areas. It is difficult to control or eradicate, since a new plant can regenerate from rhizome fragments. However, in North Carolina it is planted on roadsides by the highway department.[1] See also: Yellow oxeye daisy # Uses The un-opened buds can be marinated and used in a similar way to capers [2] # He loves me, he loves me not The game "He loves me, he loves me not" (effeuiller la marguerite (in French)) is associated with this flower. # External links - Ox-eye daisy, Leucanthemum vulgare diagnostic photographs and information # Gallery - Leucanthemum vulgare Leucanthemum vulgare - Ox-eye daisy Leucanthemum vulgare Ox-eye daisy Leucanthemum vulgare - Leucanthemum vulgare Leucanthemum vulgare - Ox-eye daisies in Germany Ox-eye daisies in Germany - Close-up of an ox-eye daisy with a spittlebug Close-up of an ox-eye daisy with a spittlebug # Reference - ↑ "Wildflowers Find Favor With Highway Gardeners" article by Felicity Barringer in the New York Times August 29, 2007 - ↑ Ox-eye Daisy Capers at Forbes wild foods. Retrieved December 12, 2006. 2. Blanchan, Neltje (2005). Wild Flowers Worth Knowing. Project Gutenberg Literary Archive Foundation. Check date values in: \|year= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} cs:Kopretina bílá de:Margerite it:Leucanthemum vulgare lt:Paprastoji baltagalvė nl:Gewone margriet fi:Päivänkakkara sv:Prästkrage Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Oxeye_daisy
f22fd0191fada07888941e7f7247e496d19278ee	wikidoc	Oxiconazole	Oxiconazole # 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 Oxiconazole is a azole and antifungal that is FDA approved for the treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to trichophyton rubrum, trichophyton mentagrophytes, or epidermophyton floccosum and tinea (pityriasis) versicolor due to Malassezia furfur. Common adverse reactions include pruritus, burning, irritation, allergic contact dermatitis, folliculitis, erythema, papules, rash, stinging, and nodules. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - OXISTAT® Cream and Lotion are indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, or Epidermophyton floccosum. OXISTAT® Cream is indicated for the topical treatment of tinea (pityriasis) versicolor due to Malassezia furfur. ### Dosing Information - OXISTAT® Cream or Lotion should be applied to affected and immediately surrounding areas once to twice daily in patients with tinea pedis, tinea corporis, or tinea cruris. OXISTAT® Cream should be applied once daily in the treatment of tinea (pityriasis) versicolor. Tinea corporis, tinea cruris, and tinea (pityriasis) versicolor should be treated for 2 weeks and tinea pedis for 1 month to reduce the possibility of recurrence. If a patient shows no clinical improvement after the treatment period, the diagnosis should be reviewed. - Note: Tinea (pityriasis) versicolor may give rise to hyperpigmented or hypopigmented patches on the trunk that may extend to the neck, arms, and upper thighs. Treatment of the infection may not immediately result in restoration of pigment to the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental sun exposure. Although tinea (pityriasis) versicolor is not contagious, it may recur because the organism that causes the disease is part of the normal skin flora. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oxiconazole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxiconazole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - OXISTAT® Cream may be used in pediatric patients for tinea corporis, tinea cruris, tinea pedis, and tinea (pityriasis) versicolor; however, these indications for which OXISTAT® Cream has been shown to be effective rarely occur in children below the age of 12. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oxiconazole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxiconazole in pediatric patients. # Contraindications - OXISTAT® Cream and Lotion are contraindicated in individuals who have shown hypersensitivity to any of their components. # Warnings - OXISTAT® (oxiconazole nitrate) Cream, 1% and OXISTAT® (oxiconazole nitrate) Lotion, 1% are not for ophthalmic or intravaginal use. ### PRECAUTIONS - OXISTAT® Cream and Lotion are for external dermal use only. Avoid introduction of OXISTAT® Cream or Lotion into the eyes or vagina. If a reaction suggesting sensitivity or chemical irritation should occur with the use of OXISTAT® Cream or Lotion, treatment should be discontinued and appropriate therapy instituted. If signs of epidermal irritation should occur, the drug should be discontinued. # Adverse Reactions ## Clinical Trials Experience - During clinical trials, of 955 patients treated with oxiconazole nitrate cream, 1%, 41 (4.3%) reported adverse reactions thought to be related to drug therapy. These reactions included pruritus (1.6%); burning (1.4%); irritation and allergic contact dermatitis (0.4% each); folliculitis (0.3%); erythema (0.2%); and papules, fissure, maceration, rash, stinging, and nodules (0.1% each). - In a controlled, multicenter clinical trial of 269 patients treated with oxiconazole nitrate lotion, 1%, 7 (2.6%) reported adverse reactions thought to be related to drug therapy. These reactions included burning and stinging (0.7% each) and pruritus, scaling, tingling, pain, and dyshidrotic eczema (0.4% each). ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Oxiconazole in the drug label. # Drug Interactions There is limited information regarding Drug Interactions of Oxiconazole in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rabbits, rats, and mice at oral doses up to 100, 150, and 200 mg/kg/day (57, 40, and 27 times the human dose based on mg/m2), respectively, and revealed no evidence of harm to the fetus due to oxiconazole nitrate. 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 Oxiconazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Oxiconazole during labor and delivery. ### Nursing Mothers - Because oxiconazole is excreted in human milk, caution should be exercised when the drug is administered to a nursing woman. ### Pediatric Use - OXISTAT® Cream may be used in pediatric patients for tinea corporis, tinea cruris, tinea pedis, and tinea (pityriasis) versicolor; however, these indications for which OXISTAT® Cream has been shown to be effective rarely occur in children below the age of 12. ### Geriatic Use - A limited number of patients at or above 60 years of age (n ~ 396) have been treated with OXISTAT® Cream in US and non-US clinical trials, and a limited number (n = 43) have been treated with OXISTAT® Lotion in US clinical trials. The number of patients is too small to permit separate analysis of efficacy and safety. No adverse events were reported with OXISTAT® Lotion in geriatric patients, and the adverse reactions reported with OXISTAT® Cream in this population were similar to those reported by younger patients. Based on available data, no adjustment of dosage of OXISTAT® Cream and Lotion in geriatric patients is warranted. ### Gender There is no FDA guidance on the use of Oxiconazole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Oxiconazole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Oxiconazole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Oxiconazole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Oxiconazole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Oxiconazole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Oxiconazole in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Oxiconazole in the drug label. # Overdosage - When 5% oxiconazole cream (5 times the concentration of the marketed product) was applied at a rate of 1 g/kg to approximately 10% of body surface area of a group of 40 male and female rats for 35 days, 3 deaths and severe dermal inflammation were reported. No overdoses in humans have been reported with use of oxiconazole nitrate cream or lotion. # Pharmacology There is limited information regarding Oxiconazole Pharmacology in the drug label. ## Mechanism of Action - Oxiconazole nitrate is an imidazole derivative whose antifungal activity is derived primarily from the inhibition of ergosterol biosynthesis, which is critical for cellular membrane integrity. It has in vitro activity against a wide range of pathogenic fungi. ## Structure - OXISTAT® (oxiconazole nitrate) Cream, 1% and OXISTAT® (oxiconazole nitrate) Lotion, 1% formulations contain the antifungal active compound oxiconazole nitrate. Both formulations are for topical dermatologic use only. - Chemically, oxiconazole nitrate is 2',4'-dichloro-2-imidazol-1-ylacetophenone (Z)-0-(2,4-dichlorobenzyl)oxime, mononitrate. The compound has the molecular formula C18H13ON3CI4·HNO3, a molecular weight of 492.15, and the following structural formula: ## Pharmacodynamics ### Microbiology: - Oxiconazole nitrate is an imidazole derivative whose antifungal activity is derived primarily from the inhibition of ergosterol biosynthesis, which is critical for cellular membrane integrity. It has in vitro activity against a wide range of pathogenic fungi. - Oxiconazole has been shown to be active against most strains of the following organisms both in vitro and in clinical infections at indicated body sites. - Epidermophyton floccosum - Trichophyton mentagrophytes - Trichophyton rubrum - Malassezia furfur - The following in vitro data are available; however, their clinical significance is unknown. Oxiconazole exhibits satisfactory in vitro minimum inhibitory concentrations (MICs) against most strains of the following organisms; however, the safety and efficacy of oxiconazole in treating clinical infections due to these organisms have not been established in adequate and well-controlled clinical trials: - Candida albicans - Microsporum audouini - Microsporum canis - Microsporum gypseum - Trichophyton tonsurans - Trichophyton violaceum ## Pharmacokinetics - The penetration of oxiconazole nitrate into different layers of the skin was assessed using an in vitro permeation technique with human skin. Five hours after application of 2.5 mg/cm2 of oxiconazole nitrate cream onto human skin, the concentration of oxiconazole nitrate was demonstrated to be 16.2 μmol in the epidermis, 3.64 μmol in the upper corium, and 1.29 μmol in the deeper corium. Systemic absorption of oxiconazole nitrate is low. Using radiolabeled drug, less than 0.3% of the applied dose of oxiconazole nitrate was recovered in the urine of volunteer subjects up to 5 days after application of the cream formulation. - Neither in vitro nor in vivo studies have been conducted to establish relative activity between the lotion and cream formulations. ## Nonclinical Toxicology - Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no evidence of mutagenic effect was found in 2 mutation assays (Ames test and Chinese hamster V79 in vitro cell mutation assay) or in 2 cytogenetic assays (human peripheral blood lymphocyte in vitro chromosome aberration assay and in vivo micronucleus assay in mice). - Reproductive studies revealed no impairment of fertility in rats at oral doses of 3 mg/kg/day in females (1 time the human dose based on mg/m2) and 15 mg/kg/day in males (4 times the human dose based on mg/m2). However, at doses above this level, the following effects were observed: a reduction in the fertility parameters of males and females, a reduction in the number of sperm in vaginal smears, extended estrous cycle, and a decrease in mating frequency. # Clinical Studies - The following definitions were applied to the clinical and microbiological outcomes in patients enrolled in the clinical trials that form the basis for the approvals of OXISTAT® Lotion and OXISTAT® Cream. - Mycological Cure: No evidence (culture and KOH preparation) of the baseline (original) pathogen in a specimen from the affected area taken at the 2-week post-treatment visit (for tinea versicolor, mycological cure was limited to KOH only). - Treatment Success: Both a global evaluation of 90% clinical improvement and a microbiologic eradication (see above) at the 2-week post-treatment visit. Tinea Pedis: THERE ARE NO HEAD-TO-HEAD COMPARISON TRIALS OF THE OXISTAT® CREAM AND LOTION FORMULATIONS IN THE TREATMENT OF TINEA PEDIS. - Lotion Formulation: The clinical trial for the lotion formulation line extension involved 332 evaluable patients with clinically and microbiologically established tinea pedis. Of these evaluable patients, 64% were diagnosed with hyperkeratotic plantar tinea pedis and 28% with interdigital tinea pedis. Seventy-seven percent (77%) had disease secondary to infection with Trichophyton rubrum, 18% had disease secondary to infection with Trichophyton mentagrophytes, and 4% had disease secondary to infection with Epidermophyton floccosum. - The results of this clinical trial at the 2-week post-treatment follow-up visit are shown in the following table: t In this study, the improvement and cure rates of the b.i.d.- and q.d.-treated groups did not differ significantly (95% confidence interval) from each other but were statistically (95% confidence interval) superior to the vehicle-treated group. Cream Formulation: The two pivotal trials for the cream formulation involved 281 evaluable patients (total from both trials) with clinically and microbiologically established tinea pedis. The combined results of these 2 clinical trials at the 2-week post-treatment follow-up visit are shown in the following table: t - All the improvement and cure rates of the b.i.d.- and q.d.- treated groups did not differ significantly (95% confidence interval) from each other but were statistically (95% confidence interval) superior to the vehicle-treated group. - In addition, pediatric data (95 children ages 10 and under) available with the cream formulation indicate that it is safe and effective for use in children when used as directed. Adverse events were reported in 2 children; 1 child was reported to have reddening of the skin and 1 child was reported to have eczema-like skin alterations. - Tinea (pityriasis) Versicolor: Two pivotal clinical trials of OXISTAT® Cream in tinea (pityriasis) versicolor involved 219 evaluable patients in the q day OXISTAT® and vehicle arms of the trial with clinical and mycological evidence of tinea (pityriasis) versicolor. Patients were treated for 2 weeks with OXISTAT® Cream once daily, or with cream vehicle. The combined results of these clinical trials at the 2-week post-treatment follow-up visit are shown in the following table. These results are based on 207 patients (110 in the OXISTAT® group and 97 in the vehicle group) with efficacy evaluations at this visit. t - Only once a day was shown in both studies to be statistically superior to vehicle for all efficacy parameters at 2 weeks and follow-up. # How Supplied OXISTAT® (oxiconazole nitrate) Cream, 1% is supplied in: 30-g tubes (NDC 10337-358-30), 60-g tubes (NDC 10337-358-60), and 90-g tubes (NDC 10337-358-90). Store between 15° and 30° C (59° and 86° F). OXISTAT® (oxiconazole nitrate) Lotion, 1% is supplied in: 30-mL bottle (NDC 10337-359-30) 60-mL bottle (NDC 10337-359-60). Store between 15° and 30° C (59° and 86° F). Shake well before using. PharmaDerm® A division of Fougera Pharmaceuticals Inc. Melville, NY 11747 USA www.pharmaderm.com I8358F/IF8358F R01/12 ## Storage - Store between 15° and 30° C (59° and 86° F). # Images ## Drug Images ## Package and Label Display Panel PharmaDerm® NDC 10337-358-30 Oxistat® Cream, 1%* (oxiconazole nitrate cream) - Potency expressed as oxiconazole. For Topical Dermatologic Use ONLY. Not for Ophthalmic or Intravaginal Use. Rx only 30 g f PharmaDerm® NDC 10337-358-30 Oxistat® Cream, 1%* (oxiconazole nitrate cream) - Potency expressed as oxiconazole. For Topical Dermatologic Use ONLY. Not for Ophthalmic or Intravaginal Use. Rx only 30 g # Patient Counseling Information - The patient should be instructed to: - Use OXISTAT® as directed by the physician. The hands should be washed after applying the medication to the affected area(s). Avoid contact with the eyes, nose, mouth, and other mucous membranes. OXISTAT® is for external use only. - Use the medication for the full treatment time recommended by the physician, even though symptoms may have improved. Notify the physician if there is no improvement after 2 to 4 weeks, or sooner if the condition worsens (see below). - Inform the physician if the area of application shows signs of increased irritation, itching, burning, blistering, swelling, or oozing. - Avoid the use of occlusive dressings unless otherwise directed by the physician. - Do not use this medication for any disorder other than that for which it was prescribed. # Precautions with Alcohol - Alcohol-Oxiconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - OXISTAT® # Look-Alike Drug Names There is limited information regarding Oxiconazole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Oxiconazole 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 Oxiconazole is a azole and antifungal that is FDA approved for the treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to trichophyton rubrum, trichophyton mentagrophytes, or epidermophyton floccosum and tinea (pityriasis) versicolor due to Malassezia furfur. Common adverse reactions include pruritus, burning, irritation, allergic contact dermatitis, folliculitis, erythema, papules, rash, stinging, and nodules. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - OXISTAT® Cream and Lotion are indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, or Epidermophyton floccosum. OXISTAT® Cream is indicated for the topical treatment of tinea (pityriasis) versicolor due to Malassezia furfur. ### Dosing Information - OXISTAT® Cream or Lotion should be applied to affected and immediately surrounding areas once to twice daily in patients with tinea pedis, tinea corporis, or tinea cruris. OXISTAT® Cream should be applied once daily in the treatment of tinea (pityriasis) versicolor. Tinea corporis, tinea cruris, and tinea (pityriasis) versicolor should be treated for 2 weeks and tinea pedis for 1 month to reduce the possibility of recurrence. If a patient shows no clinical improvement after the treatment period, the diagnosis should be reviewed. - Note: Tinea (pityriasis) versicolor may give rise to hyperpigmented or hypopigmented patches on the trunk that may extend to the neck, arms, and upper thighs. Treatment of the infection may not immediately result in restoration of pigment to the affected sites. Normalization of pigment following successful therapy is variable and may take months, depending on individual skin type and incidental sun exposure. Although tinea (pityriasis) versicolor is not contagious, it may recur because the organism that causes the disease is part of the normal skin flora. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oxiconazole in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxiconazole in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - OXISTAT® Cream may be used in pediatric patients for tinea corporis, tinea cruris, tinea pedis, and tinea (pityriasis) versicolor; however, these indications for which OXISTAT® Cream has been shown to be effective rarely occur in children below the age of 12. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Oxiconazole in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxiconazole in pediatric patients. # Contraindications - OXISTAT® Cream and Lotion are contraindicated in individuals who have shown hypersensitivity to any of their components. # Warnings - OXISTAT® (oxiconazole nitrate) Cream, 1% and OXISTAT® (oxiconazole nitrate) Lotion, 1% are not for ophthalmic or intravaginal use. ### PRECAUTIONS - OXISTAT® Cream and Lotion are for external dermal use only. Avoid introduction of OXISTAT® Cream or Lotion into the eyes or vagina. If a reaction suggesting sensitivity or chemical irritation should occur with the use of OXISTAT® Cream or Lotion, treatment should be discontinued and appropriate therapy instituted. If signs of epidermal irritation should occur, the drug should be discontinued. # Adverse Reactions ## Clinical Trials Experience - During clinical trials, of 955 patients treated with oxiconazole nitrate cream, 1%, 41 (4.3%) reported adverse reactions thought to be related to drug therapy. These reactions included pruritus (1.6%); burning (1.4%); irritation and allergic contact dermatitis (0.4% each); folliculitis (0.3%); erythema (0.2%); and papules, fissure, maceration, rash, stinging, and nodules (0.1% each). - In a controlled, multicenter clinical trial of 269 patients treated with oxiconazole nitrate lotion, 1%, 7 (2.6%) reported adverse reactions thought to be related to drug therapy. These reactions included burning and stinging (0.7% each) and pruritus, scaling, tingling, pain, and dyshidrotic eczema (0.4% each). ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Oxiconazole in the drug label. # Drug Interactions There is limited information regarding Drug Interactions of Oxiconazole in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies have been performed in rabbits, rats, and mice at oral doses up to 100, 150, and 200 mg/kg/day (57, 40, and 27 times the human dose based on mg/m2), respectively, and revealed no evidence of harm to the fetus due to oxiconazole nitrate. 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 Oxiconazole in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Oxiconazole during labor and delivery. ### Nursing Mothers - Because oxiconazole is excreted in human milk, caution should be exercised when the drug is administered to a nursing woman. ### Pediatric Use - OXISTAT® Cream may be used in pediatric patients for tinea corporis, tinea cruris, tinea pedis, and tinea (pityriasis) versicolor; however, these indications for which OXISTAT® Cream has been shown to be effective rarely occur in children below the age of 12. ### Geriatic Use - A limited number of patients at or above 60 years of age (n ~ 396) have been treated with OXISTAT® Cream in US and non-US clinical trials, and a limited number (n = 43) have been treated with OXISTAT® Lotion in US clinical trials. The number of patients is too small to permit separate analysis of efficacy and safety. No adverse events were reported with OXISTAT® Lotion in geriatric patients, and the adverse reactions reported with OXISTAT® Cream in this population were similar to those reported by younger patients. Based on available data, no adjustment of dosage of OXISTAT® Cream and Lotion in geriatric patients is warranted. ### Gender There is no FDA guidance on the use of Oxiconazole with respect to specific gender populations. ### Race There is no FDA guidance on the use of Oxiconazole with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Oxiconazole in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Oxiconazole in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Oxiconazole in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Oxiconazole in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Oxiconazole in the drug label. - Description # IV Compatibility There is limited information regarding IV Compatibility of Oxiconazole in the drug label. # Overdosage - When 5% oxiconazole cream (5 times the concentration of the marketed product) was applied at a rate of 1 g/kg to approximately 10% of body surface area of a group of 40 male and female rats for 35 days, 3 deaths and severe dermal inflammation were reported. No overdoses in humans have been reported with use of oxiconazole nitrate cream or lotion. # Pharmacology There is limited information regarding Oxiconazole Pharmacology in the drug label. ## Mechanism of Action - Oxiconazole nitrate is an imidazole derivative whose antifungal activity is derived primarily from the inhibition of ergosterol biosynthesis, which is critical for cellular membrane integrity. It has in vitro activity against a wide range of pathogenic fungi. ## Structure - OXISTAT® (oxiconazole nitrate) Cream, 1% and OXISTAT® (oxiconazole nitrate) Lotion, 1% formulations contain the antifungal active compound oxiconazole nitrate. Both formulations are for topical dermatologic use only. - Chemically, oxiconazole nitrate is 2',4'-dichloro-2-imidazol-1-ylacetophenone (Z)-0-(2,4-dichlorobenzyl)oxime, mononitrate. The compound has the molecular formula C18H13ON3CI4·HNO3, a molecular weight of 492.15, and the following structural formula: ## Pharmacodynamics ### Microbiology: - Oxiconazole nitrate is an imidazole derivative whose antifungal activity is derived primarily from the inhibition of ergosterol biosynthesis, which is critical for cellular membrane integrity. It has in vitro activity against a wide range of pathogenic fungi. - Oxiconazole has been shown to be active against most strains of the following organisms both in vitro and in clinical infections at indicated body sites. - Epidermophyton floccosum - Trichophyton mentagrophytes - Trichophyton rubrum - Malassezia furfur - The following in vitro data are available; however, their clinical significance is unknown. Oxiconazole exhibits satisfactory in vitro minimum inhibitory concentrations (MICs) against most strains of the following organisms; however, the safety and efficacy of oxiconazole in treating clinical infections due to these organisms have not been established in adequate and well-controlled clinical trials: - Candida albicans - Microsporum audouini - Microsporum canis - Microsporum gypseum - Trichophyton tonsurans - Trichophyton violaceum ## Pharmacokinetics - The penetration of oxiconazole nitrate into different layers of the skin was assessed using an in vitro permeation technique with human skin. Five hours after application of 2.5 mg/cm2 of oxiconazole nitrate cream onto human skin, the concentration of oxiconazole nitrate was demonstrated to be 16.2 μmol in the epidermis, 3.64 μmol in the upper corium, and 1.29 μmol in the deeper corium. Systemic absorption of oxiconazole nitrate is low. Using radiolabeled drug, less than 0.3% of the applied dose of oxiconazole nitrate was recovered in the urine of volunteer subjects up to 5 days after application of the cream formulation. - Neither in vitro nor in vivo studies have been conducted to establish relative activity between the lotion and cream formulations. ## Nonclinical Toxicology - Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no evidence of mutagenic effect was found in 2 mutation assays (Ames test and Chinese hamster V79 in vitro cell mutation assay) or in 2 cytogenetic assays (human peripheral blood lymphocyte in vitro chromosome aberration assay and in vivo micronucleus assay in mice). - Reproductive studies revealed no impairment of fertility in rats at oral doses of 3 mg/kg/day in females (1 time the human dose based on mg/m2) and 15 mg/kg/day in males (4 times the human dose based on mg/m2). However, at doses above this level, the following effects were observed: a reduction in the fertility parameters of males and females, a reduction in the number of sperm in vaginal smears, extended estrous cycle, and a decrease in mating frequency. # Clinical Studies - The following definitions were applied to the clinical and microbiological outcomes in patients enrolled in the clinical trials that form the basis for the approvals of OXISTAT® Lotion and OXISTAT® Cream. - Mycological Cure: No evidence (culture and KOH preparation) of the baseline (original) pathogen in a specimen from the affected area taken at the 2-week post-treatment visit (for tinea [pityriasis] versicolor, mycological cure was limited to KOH only). - Treatment Success: Both a global evaluation of 90% clinical improvement and a microbiologic eradication (see above) at the 2-week post-treatment visit. Tinea Pedis: THERE ARE NO HEAD-TO-HEAD COMPARISON TRIALS OF THE OXISTAT® CREAM AND LOTION FORMULATIONS IN THE TREATMENT OF TINEA PEDIS. - Lotion Formulation: The clinical trial for the lotion formulation line extension involved 332 evaluable patients with clinically and microbiologically established tinea pedis. Of these evaluable patients, 64% were diagnosed with hyperkeratotic plantar tinea pedis and 28% with interdigital tinea pedis. Seventy-seven percent (77%) had disease secondary to infection with Trichophyton rubrum, 18% had disease secondary to infection with Trichophyton mentagrophytes, and 4% had disease secondary to infection with Epidermophyton floccosum. - The results of this clinical trial at the 2-week post-treatment follow-up visit are shown in the following table: t In this study, the improvement and cure rates of the b.i.d.- and q.d.-treated groups did not differ significantly (95% confidence interval) from each other but were statistically (95% confidence interval) superior to the vehicle-treated group. Cream Formulation: The two pivotal trials for the cream formulation involved 281 evaluable patients (total from both trials) with clinically and microbiologically established tinea pedis. The combined results of these 2 clinical trials at the 2-week post-treatment follow-up visit are shown in the following table: t - All the improvement and cure rates of the b.i.d.- and q.d.- treated groups did not differ significantly (95% confidence interval) from each other but were statistically (95% confidence interval) superior to the vehicle-treated group. - In addition, pediatric data (95 children ages 10 and under) available with the cream formulation indicate that it is safe and effective for use in children when used as directed. Adverse events were reported in 2 children; 1 child was reported to have reddening of the skin and 1 child was reported to have eczema-like skin alterations. - Tinea (pityriasis) Versicolor: Two pivotal clinical trials of OXISTAT® Cream in tinea (pityriasis) versicolor involved 219 evaluable patients in the q day OXISTAT® and vehicle arms of the trial with clinical and mycological evidence of tinea (pityriasis) versicolor. Patients were treated for 2 weeks with OXISTAT® Cream once daily, or with cream vehicle. The combined results of these clinical trials at the 2-week post-treatment follow-up visit are shown in the following table. These results are based on 207 patients (110 in the OXISTAT® group and 97 in the vehicle group) with efficacy evaluations at this visit. t - Only once a day was shown in both studies to be statistically superior to vehicle for all efficacy parameters at 2 weeks and follow-up. # How Supplied OXISTAT® (oxiconazole nitrate) Cream, 1% is supplied in: 30-g tubes (NDC 10337-358-30), 60-g tubes (NDC 10337-358-60), and 90-g tubes (NDC 10337-358-90). Store between 15° and 30° C (59° and 86° F). OXISTAT® (oxiconazole nitrate) Lotion, 1% is supplied in: 30-mL bottle (NDC 10337-359-30) 60-mL bottle (NDC 10337-359-60). Store between 15° and 30° C (59° and 86° F). Shake well before using. PharmaDerm® A division of Fougera Pharmaceuticals Inc. Melville, NY 11747 USA www.pharmaderm.com I8358F/IF8358F R01/12 - 178 ## Storage - Store between 15° and 30° C (59° and 86° F). # Images ## Drug Images ## Package and Label Display Panel PharmaDerm® NDC 10337-358-30 Oxistat® Cream, 1%* (oxiconazole nitrate cream) - Potency expressed as oxiconazole. For Topical Dermatologic Use ONLY. Not for Ophthalmic or Intravaginal Use. Rx only 30 g f PharmaDerm® NDC 10337-358-30 Oxistat® Cream, 1%* (oxiconazole nitrate cream) - Potency expressed as oxiconazole. For Topical Dermatologic Use ONLY. Not for Ophthalmic or Intravaginal Use. Rx only 30 g # Patient Counseling Information - The patient should be instructed to: - Use OXISTAT® as directed by the physician. The hands should be washed after applying the medication to the affected area(s). Avoid contact with the eyes, nose, mouth, and other mucous membranes. OXISTAT® is for external use only. - Use the medication for the full treatment time recommended by the physician, even though symptoms may have improved. Notify the physician if there is no improvement after 2 to 4 weeks, or sooner if the condition worsens (see below). - Inform the physician if the area of application shows signs of increased irritation, itching, burning, blistering, swelling, or oozing. - Avoid the use of occlusive dressings unless otherwise directed by the physician. - Do not use this medication for any disorder other than that for which it was prescribed. # Precautions with Alcohol - Alcohol-Oxiconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - OXISTAT® # Look-Alike Drug Names There is limited information regarding Oxiconazole Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Oxiconazole
6734252f3f8a47e6c00838bbbcd7f5981fad653e	wikidoc	Oxygenation	Oxygenation # Overview Oxygenation refers to the amount of oxygen in a medium. In blood it may be taken to be synonymous with saturation, which describes the degree to which the oxygen-carrying capacity of haemoglobin is utilised, normally 98-100%. Oxygenation also refers to the process of adding oxygen to a medium such as water or body tissue. Claims have been made that oxygenation of human tissue prevent diseases, including cancer, however some regard these claims as unverifiable. Oxygenation of various fluorocarbon liquids has been used successfully in liquid breathing systems, allowing air-breathing animals, including humans, to breathe via liquids for short periods of time. # Monitoring ## Respiration and oxygenation An example in a healthy person: A higher ratio indicates better gas exchange: - Normal is 500 - ARDS is < 200 Comparative studies suggest this measure correlates better with pulmonary shunts than does the A-a gradient. ### Oxygenation index -r A lower oxygenation index indicates better gas exchange. The oxygenation index, which includes the mean airway pressure, may better correlate with intrapulmonary shunting than the PF ratio ### Alveolar-arterial oxygen (A-a) gradient (alveolar-arterial oxygen difference - AVO2D) - Normal is < 10 mm Hg The A-a gradient is harder to calculate, but accounts for changes in respiration as measured by the partial pressure of carbon dioxide. However, this calculation relies on the respiratory quotient being constant in the prediction of alveolar CO2 When compared to the PF ratio, the A-a gradient is found to correlate less well with pulmonary shunting. Among outpatients with possible pulmonary embolism, the A-a gradient may be a better test. An online calculator for the A-a gradient is at . ### ROX The respiratory rate‑oxygenation (ROX) index by dividing the oximetry-derived oxygen saturation by the respiratory rate. - The ROX predicts respiratory failure from COVID-19 when ≤1.4 ("with a sensitivity of 85%, a specificity of 86%, and an AUC of 0.86"). ## Tissue perfusion In patients with septic shock, maintaining the central venous oxygen saturation (ScvO2) > 70% is a health care quality assurance measure for the Institute for Healthcare Improvement. This is measured from the superior vena cava. This is hard to predict by physical examination. In patients with septic shock, maintaining the mixed venous oxygen saturation (ScvO2) > 65% is a health care quality assurance measure for the Institute for Healthcare Improvement that is an alternative to the central venous oxygen saturation. This is measured from a pulmonary artery catheter. This is hard to predict by physical examination. The mixed venous pressure may be lower than the central venous pressure due to mixing with blood from the splanchnic circulation or carotid sinuses that has lower oxygen content. Tissue oxygen saturation (StO2) at the thenar eminence may be an alternative, non-invasive measurement. Maintaining lactate clearance about 10% may be an easier alternative than invasive measurements of oxygenation according to a randomized controlled trial by EMShockNet. Capnography, which is "continuous recording of the carbon dioxide content of expired air," may detect respiratory depression before hypoxemia occurs. Proposed criteria for respiratory depression are: - End tidal CO2 (ETCO2) level 50 mm Hg - ETCO2 change from baseline of 10% - Loss of waveform for 15 seconds # See Also - Oxygenate - ↑ Jump up to: 1.0 1.1 Covelli HD, Nessan VJ, Tuttle WK (1983). "Oxygen derived variables in acute respiratory failure". Crit. Care Med. 11 (8): 646–9. PMID 6409506.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} - ↑ Jump up to: 2.0 2.1 2.2 El-Khatib MF, Jamaleddine GW (2004). "A new oxygenation index for reflecting intrapulmonary shunting in patients undergoing open-heart surgery". Chest. 125 (2): 592–6. PMID 14769743. - ↑ Jump up to: 3.0 3.1 Cane RD, Shapiro BA, Templin R, Walther K (1988). "Unreliability of oxygen tension-based indices in reflecting intrapulmonary shunting in critically ill patients". Crit. Care Med. 16 (12): 1243–5. PMID 3191742.CS1 maint: Multiple names: authors list (link) - ↑ Marini JJ, Ravenscraft SA (1992). "Mean airway pressure: physiologic determinants and clinical importance--Part 1: Physiologic determinants and measurements". Crit Care Med. 20 (10): 1461–72. PMID 1395670. - ↑ Marini JJ, Ravenscraft SA (1992). "Mean airway pressure: physiologic determinants and clinical importance--Part 2: Clinical implications". Crit Care Med. 20 (11): 1604–16. PMID 1424706. - ↑ McFarlane MJ, Imperiale TF (1994). "Use of the alveolar-arterial oxygen gradient in the diagnosis of pulmonary embolism". Am. J. Med. 96 (1): 57–62. PMID 8304364. - ↑ Mukhtar A, Rady A, Hasanin A, Lotfy A, El Adawy A, Hussein A; et al. (2021). "Admission SpO2 and ROX index predict outcome in patients with COVID-19". Am J Emerg Med. 50: 106–110. doi:10.1016/j.ajem.2021.07.049. PMC 8313790 Check \|pmc= value (help). PMID 34332217 Check \|pmid= value (help).CS1 maint: Multiple names: authors list (link) - ↑ Maintain Adequate Central Venous Oxygen Saturation Institute for Healthcare Improvement - ↑ Jump up to: 9.0 9.1 Grissom CK, Morris AH, Lanken PN, Ancukiewicz M, Orme JF, Schoenfeld DA; et al. (2009). "Association of physical examination with pulmonary artery catheter parameters in acute lung injury". Crit Care Med. 37 (10): 2720–6. PMID 19885995.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Maintain Adequate Central Venous Oxygen Saturation Institute for Healthcare Improvement - ↑ Kopterides P, Mavrou I, Kostadima E (2005). "Central or mixed venous oxygen saturation?". Chest. 128 (2): 1073–4, author reply 1074-5. doi:10.1378/chest.128.2.1073. PMID 16100219.CS1 maint: Multiple names: authors list (link) - ↑ Podbregar M, Mozina H (2007). "Skeletal muscle oxygen saturation does not estimate mixed venous oxygen saturation in patients with severe left heart failure and additional severe sepsis or septic shock". Crit Care. 11 (1): R6. doi:10.1186/cc5153. PMC 2147710. PMID 17227587.CS1 maint: PMC format (link) - ↑ Leone M, Blidi S, Antonini F, Meyssignac B, Bordon S, Garcin F; et al. (2009). "Oxygen tissue saturation is lower in nonsurvivors than in survivors after early resuscitation of septic shock". Anesthesiology. 111 (2): 366–71. doi:10.1097/ALN.0b013e3181aae72d. PMID 19602965.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; et al. (2010). "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial". JAMA. 303 (8): 739–46. doi:10.1001/jama.2010.158. PMID 20179283.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Anonymous (2023), Capnography (English). Medical Subject Headings. U.S. National Library of Medicine. - ↑ Jump up to: 16.0 16.1 Deitch K, Miner J, Chudnofsky CR, Dominici P, Latta D (2010). "Does end tidal CO2 monitoring during emergency department procedural sedation and analgesia with propofol decrease the incidence of hypoxic events? A randomized, controlled trial". Ann Emerg Med. 55 (3): 258–64. doi:10.1016/j.annemergmed.2009.07.030. PMID 19783324.CS1 maint: Multiple names: authors list (link)	Oxygenation Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Oxygenation refers to the amount of oxygen in a medium. In blood it may be taken to be synonymous with saturation, which describes the degree to which the oxygen-carrying capacity of haemoglobin is utilised, normally 98-100%. Oxygenation also refers to the process of adding oxygen to a medium such as water or body tissue. Claims have been made that oxygenation of human tissue prevent diseases, including cancer, however some regard these claims as unverifiable. Oxygenation of various fluorocarbon liquids has been used successfully in liquid breathing systems, allowing air-breathing animals, including humans, to breathe via liquids for short periods of time. # Monitoring ## Respiration and oxygenation An example in a healthy person: A higher ratio indicates better gas exchange: - Normal is 500 - ARDS is < 200 Comparative studies suggest this measure correlates better with pulmonary shunts than does the A-a gradient.[1][2][3] ### Oxygenation index or A lower oxygenation index indicates better gas exchange. The oxygenation index, which includes the mean airway pressure[4][5], may better correlate with intrapulmonary shunting than the PF ratio[2] ### Alveolar-arterial oxygen (A-a) gradient (alveolar-arterial oxygen difference - AVO2D) - Normal is < 10 mm Hg The A-a gradient is harder to calculate, but accounts for changes in respiration as measured by the partial pressure of carbon dioxide. However, this calculation relies on the respiratory quotient being constant in the prediction of alveolar CO2 When compared to the PF ratio, the A-a gradient is found to correlate less well with pulmonary shunting.[1][2][3] Among outpatients with possible pulmonary embolism, the A-a gradient may be a better test.[6] An online calculator for the A-a gradient is at http://www.mdcalc.com/aagrad. ### ROX The respiratory rate‑oxygenation (ROX) index by dividing the oximetry-derived oxygen saturation by the respiratory rate. - The ROX predicts respiratory failure from COVID-19 when ≤1.4 ("with a sensitivity of 85%, a specificity of 86%, and an AUC of 0.86")[7]. ## Tissue perfusion In patients with septic shock, maintaining the central venous oxygen saturation (ScvO2) > 70% is a health care quality assurance measure for the Institute for Healthcare Improvement.[8] This is measured from the superior vena cava. This is hard to predict by physical examination.[9] In patients with septic shock, maintaining the mixed venous oxygen saturation (ScvO2) > 65% is a health care quality assurance measure for the Institute for Healthcare Improvement that is an alternative to the central venous oxygen saturation.[10] This is measured from a pulmonary artery catheter. This is hard to predict by physical examination.[9] The mixed venous pressure may be lower than the central venous pressure due to mixing with blood from the splanchnic circulation or carotid sinuses that has lower oxygen content.[11] Tissue oxygen saturation (StO2) at the thenar eminence may be an alternative, non-invasive measurement.[12][13] Maintaining lactate clearance about 10% may be an easier alternative than invasive measurements of oxygenation according to a randomized controlled trial by EMShockNet.[14] Capnography, which is "continuous recording of the carbon dioxide content of expired air,"[15] may detect respiratory depression before hypoxemia occurs.[16] Proposed criteria for respiratory depression are:[16] - End tidal CO2 (ETCO2) level 50 mm Hg - ETCO2 change from baseline of 10% - Loss of waveform for 15 seconds # See Also - Oxygenate Template:WikiDoc Sources - ↑ Jump up to: 1.0 1.1 Covelli HD, Nessan VJ, Tuttle WK (1983). "Oxygen derived variables in acute respiratory failure". Crit. Care Med. 11 (8): 646–9. PMID 6409506.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} - ↑ Jump up to: 2.0 2.1 2.2 El-Khatib MF, Jamaleddine GW (2004). "A new oxygenation index for reflecting intrapulmonary shunting in patients undergoing open-heart surgery". Chest. 125 (2): 592–6. PMID 14769743. - ↑ Jump up to: 3.0 3.1 Cane RD, Shapiro BA, Templin R, Walther K (1988). "Unreliability of oxygen tension-based indices in reflecting intrapulmonary shunting in critically ill patients". Crit. Care Med. 16 (12): 1243–5. PMID 3191742.CS1 maint: Multiple names: authors list (link) - ↑ Marini JJ, Ravenscraft SA (1992). "Mean airway pressure: physiologic determinants and clinical importance--Part 1: Physiologic determinants and measurements". Crit Care Med. 20 (10): 1461–72. PMID 1395670. - ↑ Marini JJ, Ravenscraft SA (1992). "Mean airway pressure: physiologic determinants and clinical importance--Part 2: Clinical implications". Crit Care Med. 20 (11): 1604–16. PMID 1424706. - ↑ McFarlane MJ, Imperiale TF (1994). "Use of the alveolar-arterial oxygen gradient in the diagnosis of pulmonary embolism". Am. J. Med. 96 (1): 57–62. PMID 8304364. - ↑ Mukhtar A, Rady A, Hasanin A, Lotfy A, El Adawy A, Hussein A; et al. (2021). "Admission SpO2 and ROX index predict outcome in patients with COVID-19". Am J Emerg Med. 50: 106–110. doi:10.1016/j.ajem.2021.07.049. PMC 8313790 Check \|pmc= value (help). PMID 34332217 Check \|pmid= value (help).CS1 maint: Multiple names: authors list (link) - ↑ Maintain Adequate Central Venous Oxygen Saturation Institute for Healthcare Improvement - ↑ Jump up to: 9.0 9.1 Grissom CK, Morris AH, Lanken PN, Ancukiewicz M, Orme JF, Schoenfeld DA; et al. (2009). "Association of physical examination with pulmonary artery catheter parameters in acute lung injury". Crit Care Med. 37 (10): 2720–6. PMID 19885995.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Maintain Adequate Central Venous Oxygen Saturation Institute for Healthcare Improvement - ↑ Kopterides P, Mavrou I, Kostadima E (2005). "Central or mixed venous oxygen saturation?". Chest. 128 (2): 1073–4, author reply 1074-5. doi:10.1378/chest.128.2.1073. PMID 16100219.CS1 maint: Multiple names: authors list (link) - ↑ Podbregar M, Mozina H (2007). "Skeletal muscle oxygen saturation does not estimate mixed venous oxygen saturation in patients with severe left heart failure and additional severe sepsis or septic shock". Crit Care. 11 (1): R6. doi:10.1186/cc5153. PMC 2147710. PMID 17227587.CS1 maint: PMC format (link) - ↑ Leone M, Blidi S, Antonini F, Meyssignac B, Bordon S, Garcin F; et al. (2009). "Oxygen tissue saturation is lower in nonsurvivors than in survivors after early resuscitation of septic shock". Anesthesiology. 111 (2): 366–71. doi:10.1097/ALN.0b013e3181aae72d. PMID 19602965.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; et al. (2010). "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial". JAMA. 303 (8): 739–46. doi:10.1001/jama.2010.158. PMID 20179283.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) - ↑ Anonymous (2023), Capnography (English). Medical Subject Headings. U.S. National Library of Medicine. - ↑ Jump up to: 16.0 16.1 Deitch K, Miner J, Chudnofsky CR, Dominici P, Latta D (2010). "Does end tidal CO2 monitoring during emergency department procedural sedation and analgesia with propofol decrease the incidence of hypoxic events? A randomized, controlled trial". Ann Emerg Med. 55 (3): 258–64. doi:10.1016/j.annemergmed.2009.07.030. PMID 19783324.CS1 maint: Multiple names: authors list (link)	https://www.wikidoc.org/index.php/Oxygenation
dba735be340cd451d4457a3eb3fd0de28e32b459	wikidoc	PR interval	PR interval # Overview The PR interval starts at the beginning of the atrial excitation (beginning of the P wave and ends at the beginning of the ventricular excitation (beginning of the QRS complex. It is termed the PQ interval if a Q wave is present. The PR interval measures the time required for an electrical impulse to travel from the atrial myocardium adjacent to the sinoatrial (SA) node to the ventricular myocardium adjacent to the fibers of the Purkinje network. The duration of the PR interval is normally from 0.10 to 0.21 s. A major portion of the PR interval reflects the slow conduction of an impulse through the AV node, which is controlled by the balance between the sympathetic and parasympathetic divisions of the autonomic nervous system. Therefore, the PR interval varies with the heart rate, being shorter at faster rates when the sympathetic component predominates, and vice versa. The PR interval tends to increase with age; - In childhood: 0.10 - 0.20 sec - In adolescence: 0.12 - 0.16 sec - In adulthood: 0.14 - 0.21 sec # Changes in PR interval A prolonged PQ interval is a sign of delayed conduction through the atrium and AV node. Pathophysiologically, this can be due to 1st, 2nd or 3rd degree AV block, increased vagal tone , or it can be pharmacologically induced. A short PR interval can be seen in the WPW syndrome in which a faster connection exists between the atria and the ventricles. - Shortens up to a rate of 140 to 150 beats per minute through a withdrawal of parasympathetic tone. - PR may increase with increasing rate in the presence of digoxin or if the conducting system is diseased. - If the atria are artificially paced the PR increases as the paced rate increases. - Children have shorter PR intervals (0.11 at 1 year). 80% of the PR prolongations ranged from 0.21 to 0.24. In a second study 59 of 19.000 (0.31%) airmen had a PR of 0.24 or more. - In healthy middle aged men, a prolongation of the PR in the presence of a normal QRS does not affect prognosis and is not related to ischemic heart disease. - Prolongation can be a normal variant: 67.000 healthy airmen studied and 0.52% found to have a prolonged PR. - PR prolongation often signifies a delay in the AV node but may reflect intra atrial or His Purkinje disease. # Shortened PR Interval A short PR interval is defined as a PR interval of less than 0.12 seconds. Although a short PR interval may be a normal variant, it is also associated with the presence of an accessory bypass tract (e.g. WPW syndrome and LGL syndrome), and close proximity of the atrial impulse to the AV node such as occurs in a premature atrial beat. In isorhythmic A-V dissociation, the atrial impulse does not conduct to the ventricle, but the atrium and the ventricle may separately beat at similar rates and the PR interval may vary from beat to beat. # Prolonged PR Interval PR prolongation can be a normal variant or can caused by several etiologies which include beta blocker therapy, AV block due to coronary artery disease or rheumatic heart disease, hyperthyroidism. # Depressed PR Interval PR segment depression can be caused by acute pericarditis or atrial infarction.	PR interval Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] # Overview The PR interval starts at the beginning of the atrial excitation (beginning of the P wave and ends at the beginning of the ventricular excitation (beginning of the QRS complex. It is termed the PQ interval if a Q wave is present. The PR interval measures the time required for an electrical impulse to travel from the atrial myocardium adjacent to the sinoatrial (SA) node to the ventricular myocardium adjacent to the fibers of the Purkinje network. The duration of the PR interval is normally from 0.10 to 0.21 s. A major portion of the PR interval reflects the slow conduction of an impulse through the AV node, which is controlled by the balance between the sympathetic and parasympathetic divisions of the autonomic nervous system. Therefore, the PR interval varies with the heart rate, being shorter at faster rates when the sympathetic component predominates, and vice versa. The PR interval tends to increase with age;[1] [2] - In childhood: 0.10 - 0.20 sec - In adolescence: 0.12 - 0.16 sec - In adulthood: 0.14 - 0.21 sec # Changes in PR interval A prolonged PQ interval is a sign of delayed conduction through the atrium and AV node. Pathophysiologically, this can be due to 1st, 2nd or 3rd degree AV block, increased vagal tone [Bezold-Jarisch reflex; described as an eponym for a triad of responses (apnea, bradycardia, and hypotension) following intravenous injection of veratrum alkaloids in experimental animals], or it can be pharmacologically induced.[3] [4] A short PR interval can be seen in the WPW syndrome in which a faster connection exists between the atria and the ventricles. - Shortens up to a rate of 140 to 150 beats per minute through a withdrawal of parasympathetic tone.[5] [6] - PR may increase with increasing rate in the presence of digoxin or if the conducting system is diseased. - If the atria are artificially paced the PR increases as the paced rate increases.[7] - Children have shorter PR intervals (0.11 at 1 year). 80% of the PR prolongations ranged from 0.21 to 0.24.[8] In a second study 59 of 19.000 (0.31%) airmen had a PR of 0.24 or more.[9] - In healthy middle aged men, a prolongation of the PR in the presence of a normal QRS does not affect prognosis and is not related to ischemic heart disease.[10] - Prolongation can be a normal variant: 67.000 healthy airmen studied and 0.52% found to have a prolonged PR. - PR prolongation often signifies a delay in the AV node but may reflect intra atrial or His Purkinje disease. # Shortened PR Interval A short PR interval is defined as a PR interval of less than 0.12 seconds. Although a short PR interval may be a normal variant, it is also associated with the presence of an accessory bypass tract (e.g. WPW syndrome and LGL syndrome), and close proximity of the atrial impulse to the AV node such as occurs in a premature atrial beat. In isorhythmic A-V dissociation, the atrial impulse does not conduct to the ventricle, but the atrium and the ventricle may separately beat at similar rates and the PR interval may vary from beat to beat. Click here to read more about short PR interval, its pathophysiology and causes. # Prolonged PR Interval PR prolongation can be a normal variant or can caused by several etiologies which include beta blocker therapy, AV block due to coronary artery disease or rheumatic heart disease, hyperthyroidism. Click here to learn more about PR prolongation and its causes. # Depressed PR Interval PR segment depression can be caused by acute pericarditis or atrial infarction.	https://www.wikidoc.org/index.php/P-R_interval
c2ef95a20c4e7146fb9dfa1f7f3b07eb3bc5386a	wikidoc	TP53 (gene)	TP53 (gene) # Overview TP53 is a tumor suppressor gene that is named after, and provides instructions for making, a protein called tumor protein 53 (TP53). Through the effect of the protein that it produces, TP53 is a tumor suppressor gene, which means that it regulates the cycle of cell division by keeping cells from growing and dividing too fast or in an uncontrolled way. The p53 tumor protein is located in the nucleus of cells throughout the body and can bind directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the cell will undergo programmed cell death (apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, the p53 tumor protein prevents the cell from dividing and signals it to undergo apoptosis. This process prevents cells with mutated or damaged DNA from dividing, which helps prevent the development of tumors. Because the p53 tumor protein is essential for regulating cell division, it has been nicknamed the "guardian of the genome." The TP53 gene is located on the short (p) arm of chromosome 17 at position 13.1, from base pair 7,512,463 to base pair 7,531,641. # Related conditions Bladder cancer: Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the TP53 gene have been found in some cases of bladder cancer. Most of these mutations replace one amino acid (a building block of proteins) with another amino acid in the p53 tumor protein. The altered protein cannot bind to DNA correctly, which prevents the protein from effectively regulating cell growth and division. As a result, DNA damage accumulates in cells and they divide in an uncontrolled way, leading to a cancerous tumor. Mutations in the TP53 gene may also help predict whether bladder cancer will progress and spread to nearby tissues and whether the disease will recur after treatment. Li-Fraumeni syndrome: More than 55 different inherited mutations in the TP53 gene have been found in individuals with Li-Fraumeni syndrome. Many of these changes involve the substitution of one amino acid for another amino acid in the part of p53 tumor protein that binds to DNA. Other types of mutations include deletions of small amounts of DNA within the gene. Mutations in the TP53 gene lead to a version of the p53 tumor protein that cannot regulate cell growth and division. The altered protein is unable to signal cells with mutated or damaged DNA to undergo apoptosis. As a result, such cells continue to divide and can form tumors. Other cancers: Somatic mutations in the TP53 gene are the most common genetic changes found in human cancer, occurring in about half of all cancers. For example, TP53 gene mutations have been identified in several types of brain tumor, a type of bone cancer called osteosarcoma, a cancer of muscle tissue called rhabdomyosarcoma, and adrenocortical carcinoma (a cancer of the outer layer of the adrenal glands, which are small glands located on top of each kidney). Most TP53 gene mutations substitute one amino acid for another in the p53 tumor protein, which leads to the production of an altered version of the protein that cannot effectively bind to DNA. This altered protein can build up in nuclei of cells, preventing the cells from undergoing apoptosis in response to DNA damage. Instead, these damaged cells continue to grow and divide in an unregulated way, which can lead to cancerous tumors.	TP53 (gene) Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview TP53 is a tumor suppressor gene that is named after, and provides instructions for making, a protein called tumor protein 53 (TP53). Through the effect of the protein that it produces, TP53 is a tumor suppressor gene, which means that it regulates the cycle of cell division by keeping cells from growing and dividing too fast or in an uncontrolled way. The p53 tumor protein is located in the nucleus of cells throughout the body and can bind directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the cell will undergo programmed cell death (apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, the p53 tumor protein prevents the cell from dividing and signals it to undergo apoptosis. This process prevents cells with mutated or damaged DNA from dividing, which helps prevent the development of tumors. Because the p53 tumor protein is essential for regulating cell division, it has been nicknamed the "guardian of the genome." The TP53 gene is located on the short (p) arm of chromosome 17 at position 13.1, from base pair 7,512,463 to base pair 7,531,641. # Related conditions Bladder cancer: Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the TP53 gene have been found in some cases of bladder cancer. Most of these mutations replace one amino acid (a building block of proteins) with another amino acid in the p53 tumor protein. The altered protein cannot bind to DNA correctly, which prevents the protein from effectively regulating cell growth and division. As a result, DNA damage accumulates in cells and they divide in an uncontrolled way, leading to a cancerous tumor. Mutations in the TP53 gene may also help predict whether bladder cancer will progress and spread to nearby tissues and whether the disease will recur after treatment. Li-Fraumeni syndrome: More than 55 different inherited mutations in the TP53 gene have been found in individuals with Li-Fraumeni syndrome. Many of these changes involve the substitution of one amino acid for another amino acid in the part of p53 tumor protein that binds to DNA. Other types of mutations include deletions of small amounts of DNA within the gene. Mutations in the TP53 gene lead to a version of the p53 tumor protein that cannot regulate cell growth and division. The altered protein is unable to signal cells with mutated or damaged DNA to undergo apoptosis. As a result, such cells continue to divide and can form tumors. Other cancers: Somatic mutations in the TP53 gene are the most common genetic changes found in human cancer, occurring in about half of all cancers. For example, TP53 gene mutations have been identified in several types of brain tumor, a type of bone cancer called osteosarcoma, a cancer of muscle tissue called rhabdomyosarcoma, and adrenocortical carcinoma (a cancer of the outer layer of the adrenal glands, which are small glands located on top of each kidney). Most TP53 gene mutations substitute one amino acid for another in the p53 tumor protein, which leads to the production of an altered version of the protein that cannot effectively bind to DNA. This altered protein can build up in nuclei of cells, preventing the cells from undergoing apoptosis in response to DNA damage. Instead, these damaged cells continue to grow and divide in an unregulated way, which can lead to cancerous tumors.	https://www.wikidoc.org/index.php/P53_gene
00b5476ee08c7b4c9cd45f0264d2d2ff4f9e2d29	wikidoc	PIGN (gene)	PIGN (gene) Phosphatidylinositol glycan anchor biosynthesis, class N is a protein that in humans is encoded by the PIGN gene. # Function This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. # Clinical aspect Mutations in PIGN cause Congenital Diaphragmatic Hernia .	PIGN (gene) Phosphatidylinositol glycan anchor biosynthesis, class N is a protein that in humans is encoded by the PIGN gene.[1] # Function This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. # Clinical aspect Mutations in PIGN cause Congenital Diaphragmatic Hernia .[2]	https://www.wikidoc.org/index.php/PIGN_(gene)
f5f3d57d2687f98a2435c345b296b25fde34bb24	wikidoc	PIM2 (gene)	PIM2 (gene) Serine/threonine-protein kinase Pim-2 is an enzyme that in humans is encoded by the PIM2 . PIM2 or Proviral Integrations of Moloney virus 2 is serine/threonine kinase that has roles in cell growth, proliferation, apoptosis, and regulation of signal transduction cascades. # Structure Thus far, most of the structural information pertaining to the PIM kinase family has been limited to PIM1. As a result, most of inhibitor development efforts has also been towards PIM1. PIM2 shares 55% sequence identity with PIM1, and the structure of PIM2 is quite closely related to PIM1. Like PIM1, PIM2 shows a bi-lobal kinase architecture with a constitutively active closed conformation. The main chain of both molecules is identical with the exception of two flexible regions in the N-terminal lobe. The most significant structural difference between PIM1 and PIM2 is the absence of the terminal αJ helix in PIM2. The last 23 residues of PIM2 are quite different from PIM1, as PIM2 contains 6 proline residues in this region and is not believed to form the same tertiary structures. As a result, the absence of the interactions present in this region may increase flexibility in PIM2 within the N-terminal kinase lobe and contribute to the disordered regions of the PIM2 structure. # Function PIM2 is expressed with high levels in the brain and lymphoid cells. PIM1-3 compound knockout mice that survived the perinatal period showed a large reduction in body size. This suggests that the PIM enzymes are important for body growth. Experiments have implicated that PIM1 and PIM2 are necessary for cytokine-dependent proliferation and survival of lymphocytes. Experiments with transgenic mice with induced lymphomas revealed elevated levels of PIM2 as a frequent but late event in tumorigenesis. Experiments done on nuclear factor κB (NFκB) nuclear translocation in human perineural invasion (PNI) revealed that an up-regulation of NFκB and its downstream target, PIM2, were components of an antiapoptosis signaling cascade, which is associated with cancer cells in PNI. This cascade may regulate the inhibition of apoptosis.The study also showed that elevated levels of PIM2 have been associated with PNI. The PIM2 kinase has therefore emerged as a key drug target to restore apoptosis in drug resistant human cancers. # Mechanism In reported crystal structures, PIM1 and PIM2 assume an active conformation. Typically, kinases’ active state is characterized by the presence of the conserved lysine, a closed lobe conformation, and a well-structured activation segment. The activation segment often necessitates phosphorylation in order for there to be catalytic activity. Once phosphorylated, the active segment folds onto the lower lobe and reorganizes the peptide-binding site, which consequently leads to enzymatic activation. However, PIM kinases are catalytically active without phosphorylation. The crystal structures show that the unphosphorylated activation segment forms many polar interactions with the lower kinase lobe, which stabilizes the active conformation. While PIM kinase do autophosphorylate, the functional consequences are not known. # Inhibitors - Inhibitor acts as ATP mimetic in ATP binding pocket Inhibitor acts as ATP mimetic in ATP binding pocket - Staurosporine and Ruthenium Compound 12 Staurosporine and Ruthenium Compound 12 - General Structure of Organoruthenium inhibitor General Structure of Organoruthenium inhibitor PIM2 (along with PIM1) has a unique binding pocket for ATP with a hinged region, making it an attractive target for potent small-molecule PIM kinase inhibitors. Many inhibitors are often more selective for PIM1 and PIM3 over PIM2. In other words, PIM2 is usually inhibited with much lower potency. Thus far, structural models are unable to explain this phenomenon. However, it could be related to the differences in the dynamic properties of the different PIM isoforms. In a series of organoruthenium compounds based on a Staurosporine scaffold compound 12 gave almost complete inhibition at a concentration of 10 nM. However, it was marginally less effective against PIM1. The SAR suggests that the addition of potential hydrogen bonding groups at the R1 and R2 positions dramatically increases potency against both kinases. Similar substitution of the R3 position was less effective and halogen substitution was even more disruptive. # Clinical significance In a study with 48 patients who had non-Hodgkin's lymphoma (NHL) and lymphocytic leukemia, hPim-2 expression was analyzed using in-situ hybridization, quantitative RT-PCR and FACS analysis. The studies showed higher levels of expression in NHL over normal lymphocytes as well as in chronic lymphocytic leukemia over normal B-Cells. Elevated PIM2 levels have also been found in primary blasts from acute myeloid leukemia patients. PIM2 may be an important kinase in the phosphorylation of 4E-BP1. Constitutive phosphorylation of 4E-BP1 is commonly found in cancers and contributes to the sustrained translation of malignancy related transcripts, among which are c-Myc and Cyclin D. Knockdown of PIM2 by iRNA strongly reduced the accumulation of oncogenic proteins. As a result, PIM2 may be an attractive target for acute myeloid leukemia.	PIM2 (gene) Serine/threonine-protein kinase Pim-2 is an enzyme that in humans is encoded by the PIM2 .[1][2] PIM2 or Proviral Integrations of Moloney virus 2 is serine/threonine kinase that has roles in cell growth, proliferation, apoptosis, and regulation of signal transduction cascades.[3] # Structure Thus far, most of the structural information pertaining to the PIM kinase family has been limited to PIM1. As a result, most of inhibitor development efforts has also been towards PIM1. PIM2 shares 55% sequence identity with PIM1, and the structure of PIM2 is quite closely related to PIM1.[4] Like PIM1, PIM2 shows a bi-lobal kinase architecture with a constitutively active closed conformation. The main chain of both molecules is identical with the exception of two flexible regions in the N-terminal lobe. The most significant structural difference between PIM1 and PIM2 is the absence of the terminal αJ helix in PIM2. The last 23 residues of PIM2 are quite different from PIM1, as PIM2 contains 6 proline residues in this region and is not believed to form the same tertiary structures. As a result, the absence of the interactions present in this region may increase flexibility in PIM2 within the N-terminal kinase lobe and contribute to the disordered regions of the PIM2 structure.[5] # Function PIM2 is expressed with high levels in the brain and lymphoid cells. PIM1-3 compound knockout mice that survived the perinatal period showed a large reduction in body size. This suggests that the PIM enzymes are important for body growth.[6] Experiments have implicated that PIM1 and PIM2 are necessary for cytokine-dependent proliferation and survival of lymphocytes.[7] Experiments with transgenic mice with induced lymphomas revealed elevated levels of PIM2 as a frequent but late event in tumorigenesis.[8] Experiments done on nuclear factor κB (NFκB) nuclear translocation in human perineural invasion (PNI) revealed that an up-regulation of NFκB and its downstream target, PIM2, were components of an antiapoptosis signaling cascade, which is associated with cancer cells in PNI. This cascade may regulate the inhibition of apoptosis.The study also showed that elevated levels of PIM2 have been associated with PNI.[9] The PIM2 kinase has therefore emerged as a key drug target to restore apoptosis in drug resistant human cancers.[10] # Mechanism In reported crystal structures, PIM1 and PIM2 assume an active conformation. Typically, kinases’ active state is characterized by the presence of the conserved lysine, a closed lobe conformation, and a well-structured activation segment. The activation segment often necessitates phosphorylation in order for there to be catalytic activity. Once phosphorylated, the active segment folds onto the lower lobe and reorganizes the peptide-binding site, which consequently leads to enzymatic activation. However, PIM kinases are catalytically active without phosphorylation. The crystal structures show that the unphosphorylated activation segment forms many polar interactions with the lower kinase lobe, which stabilizes the active conformation. While PIM kinase do autophosphorylate, the functional consequences are not known.[11] # Inhibitors - Inhibitor acts as ATP mimetic in ATP binding pocket Inhibitor acts as ATP mimetic in ATP binding pocket - Staurosporine and Ruthenium Compound 12 Staurosporine and Ruthenium Compound 12 - General Structure of Organoruthenium inhibitor General Structure of Organoruthenium inhibitor PIM2 (along with PIM1) has a unique binding pocket for ATP with a hinged region, making it an attractive target for potent small-molecule PIM kinase inhibitors.[12] Many inhibitors are often more selective for PIM1 and PIM3 over PIM2. In other words, PIM2 is usually inhibited with much lower potency. Thus far, structural models are unable to explain this phenomenon. However, it could be related to the differences in the dynamic properties of the different PIM isoforms. In a series of organoruthenium compounds [13] based on a Staurosporine scaffold[14] compound 12 gave almost complete inhibition at a concentration of 10 nM. However, it was marginally less effective against PIM1. The SAR suggests that the addition of potential hydrogen bonding groups at the R1 and R2 positions dramatically increases potency against both kinases. Similar substitution of the R3 position was less effective and halogen substitution was even more disruptive. # Clinical significance In a study with 48 patients who had non-Hodgkin's lymphoma (NHL) and lymphocytic leukemia, hPim-2 expression was analyzed using in-situ hybridization, quantitative RT-PCR and FACS analysis. The studies showed higher levels of expression in NHL over normal lymphocytes as well as in chronic lymphocytic leukemia over normal B-Cells.[15] Elevated PIM2 levels have also been found in primary blasts from acute myeloid leukemia patients. PIM2 may be an important kinase in the phosphorylation of 4E-BP1. Constitutive phosphorylation of 4E-BP1 is commonly found in cancers and contributes to the sustrained translation of malignancy related transcripts, among which are c-Myc and Cyclin D. Knockdown of PIM2 by iRNA strongly reduced the accumulation of oncogenic proteins.[16] As a result, PIM2 may be an attractive target for acute myeloid leukemia.	https://www.wikidoc.org/index.php/PIM2_(gene)
a0d44a83dfac93e29449c02dbcfd99b9d1f244ee	wikidoc	PLATO count	PLATO count # PLATO reading Log Please use the spreadsheet to record the number of PLATO films you have read To record the number of films you have read, please click on the CHECK OUT link to open the log and save to your computer. PLATO CHECK OUT To save your new version of the file, please click on the CHECK IN link and choose the "upload a new version of this file" option PLATO CHECK IN	PLATO count ## PLATO reading Log Please use the spreadsheet to record the number of PLATO films you have read To record the number of films you have read, please click on the CHECK OUT link to open the log and save to your computer. PLATO CHECK OUT To save your new version of the file, please click on the CHECK IN link and choose the "upload a new version of this file" option PLATO CHECK IN	https://www.wikidoc.org/index.php/PLATO_count
290d0f204df341b4d3ede0b3c2fc5f80c2af5562	wikidoc	POP1 (gene)	POP1 (gene) Ribonucleases P/MRP protein subunit POP1 is a protein that in humans is encoded by the POP1 gene. # Function POP1 is a protein subunit of two different small nucleolar ribonucleoprotein complexes: the endoribonuclease for mitochondrial RNA processing complex and the ribonuclease P complex. This protein is a ribonuclease that localizes to the nucleus and functions in pre-RNA processing. # Clinical significance POP1 is also an autoantigen in patients suffering from connective tissue diseases. Mutations in the POP1 gene result in severe anauxetic dysplasia. # Interactions POP1 (gene) has been shown to interact with POP4.	POP1 (gene) Ribonucleases P/MRP protein subunit POP1 is a protein that in humans is encoded by the POP1 gene.[1][2] # Function POP1 is a protein subunit of two different small nucleolar ribonucleoprotein complexes: the endoribonuclease for mitochondrial RNA processing complex and the ribonuclease P complex. This protein is a ribonuclease that localizes to the nucleus and functions in pre-RNA processing.[3] # Clinical significance POP1 is also an autoantigen in patients suffering from connective tissue diseases. Mutations in the POP1 gene result in severe anauxetic dysplasia.[4] # Interactions POP1 (gene) has been shown to interact with POP4.[5]	https://www.wikidoc.org/index.php/POP1_(gene)
e52ccc4d08f8ef4dcd3fa771ddd1c8b0b4dfe172	wikidoc	PPIE (gene)	PPIE (gene) Peptidylprolyl isomerase E (cyclophilin E), also known as PPIE, is an enzyme which in humans is encoded by the PPIE gene on chromosome 1. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPIE participates in many biological processes, including mitochondrial metabolism, apoptosis, and inflammation, as well as related diseases and conditions, such as ischemic reperfusion injury, AIDS, influenza, and cancer. # Structure Like other cyclophilins, PPIE forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel. In particular, PPIE contains two RNA-binding domains at the N-terminal and a 165-bases long PPIase domain at the C-terminal. The PPIase domain is homologous to PPIA and can be bound and inhibited by CsA. # Function The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved. The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn). As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell. In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types. In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation. PPIE in particular also exhibits RNA-binding activity. # Clinical significance Due to the close homology in the PPIase domain between PPIE and PPIA, PPIE may also be involved in the replication process of HIV. Moreover, PPIE helps to prevent infections by influenza A virus. As a cyclophilin, PPIE also binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation. In cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury. Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated. # Interactions PPIE (gene) has been shown to interact with CsA and MLL.	PPIE (gene) Peptidylprolyl isomerase E (cyclophilin E), also known as PPIE, is an enzyme which in humans is encoded by the PPIE gene on chromosome 1. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins.[1] In addition, PPIE participates in many biological processes, including mitochondrial metabolism, apoptosis, and inflammation, as well as related diseases and conditions, such as ischemic reperfusion injury, AIDS, influenza, and cancer.[2][3][4] # Structure Like other cyclophilins, PPIE forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel. In particular, PPIE contains two RNA-binding domains at the N-terminal and a 165-bases long PPIase domain at the C-terminal. The PPIase domain is homologous to PPIA and can be bound and inhibited by CsA.[4] # Function The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins.[1] Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.[2][5] The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn).[2][4] As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within in the cell or secreted by the cell.[3] In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types.[3][4] In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation.[2][3][4] PPIE in particular also exhibits RNA-binding activity.[1] # Clinical significance Due to the close homology in the PPIase domain between PPIE and PPIA, PPIE may also be involved in the replication process of HIV.[4] Moreover, PPIE helps to prevent infections by influenza A virus.[6] As a cyclophilin, PPIE also binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation.[3] In cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury. Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated.[3] # Interactions PPIE (gene) has been shown to interact with CsA and MLL.[3][7]	https://www.wikidoc.org/index.php/PPIE_(gene)
13b5a1e24e57eecf72e004df57a621e9f73f482c	wikidoc	PSCA (gene)	PSCA (gene) Prostate stem cell antigen is a protein that in humans is encoded by the PSCA gene. This gene encodes a glycosylphosphatidylinositol-anchored cell membrane glycoprotein. In addition to being highly expressed in the prostate it is also expressed in the bladder, placenta, colon, kidney, and stomach. This gene has a nonsynonymous nucleotide polymorphism at its start codon. # Clinical significance This gene is up-regulated in a large proportion of prostate cancers and is also detected in cancers of the bladder and pancreas.	PSCA (gene) Prostate stem cell antigen is a protein that in humans is encoded by the PSCA gene.[1][2] This gene encodes a glycosylphosphatidylinositol-anchored cell membrane glycoprotein. In addition to being highly expressed in the prostate it is also expressed in the bladder, placenta, colon, kidney, and stomach. This gene has a nonsynonymous nucleotide polymorphism at its start codon.[2] # Clinical significance This gene is up-regulated in a large proportion of prostate cancers and is also detected in cancers of the bladder and pancreas.[2]	https://www.wikidoc.org/index.php/PSCA_(gene)
94b2e4c3bf414c5deb0ab00c4521989c25b1bd11	wikidoc	PSG1 (gene)	PSG1 (gene) Pregnancy specific beta-1-glycoprotein 1 (PSBG-1) also known as CD66f (Cluster of Differentiation 66f), is a protein that in humans is encoded by the PSG1 gene and is a member of the carcinoembryonic antigen (CEA) gene family.. Pregnancy-specific glycoproteins (PSGs) are a complex consisting of carbohydrate and protein, which is present in the mammalian body specifically during pregnancy. This glycoprotein is the most abundant protein found in the maternal bloodstream during the later stages of pregnancy and it is of vital importance in fetal development. The PSG functions primarily as an immunomodulator to protect the growing fetus. # Structure PSG is a member of the immunoglobulin (Ig) superfamily and contains four immunoglobulin domains. The complete isolation of certain glycoproteins, later classified as pregnancy-specific, within human blood serum occurred in the early 1980s, when experimental techniques like molecular cloning became common practice. The serum was being collected during the first trimester of pregnancy to test for other vital molecules that are present during pregnancy and it was in those samples that they were able to isolate the PSGs specifically and characterize their structure. PSGs have been studied extensively in multiple mammalian species; mammals including rodents, monkeys, elk, moose, cows, sheep, and humans. Mice are the primary subject in significant portion of PSG studies. Specific structure can vary between species regarding different sugars within the carbohydrate and amino acids within the protein; all species that contain a glycoprotein will have a core protein covalently bound to a carbohydrate. This covalently bound complex structure greatly contributes to the stability of the PSG; mammalian PSGs have demonstrated continual activity when subjected to an environment from 20-60 °C and within a pH of 5.0-11.0. The protein portion of the PSG varies depending on the gene coding for it. Several of the genes and proteins have been characterized by common experimental methods such as polymerase chain reaction, gel electrophoresis, ELISA, and restriction enzymes. The different genes produce PSGs with varying masses that contain different exposed amino acids residues; the residues that are exposed determine the type of binding site that can be used to bind PSG. While receptors for other PSG family members have been identified, the precise receptor for PSG1 remains unknown. Cell surface receptors for PSGs are found on many cells throughout the body including dendrites and epithelial cells. These receptors are present both during development and in the adult. These receptors are also similar between species. Studies comparing mice and human PSGs discovered that some human PSGs when inserted into mice demonstrated partial levels of activity, because receptors present on the mice cells were able to interact with the human PSG. PSGs require the presence of a proteoglycan (PG) on the surface of the cell in order to bind. The PSG actually will specifically bind to the glycosaminoglycan (GAG) portion of the PG, which protrudes from the membrane of the cell. Their binding of PSG can be affected by heparin, which is a competitive inhibitor that binds to the GAG portion of a PG. # Formation Pregnancy-specific beta-1-glycoprotein is a major product of the syncytiotrophoblast in the placenta, reaching concentrations of 100 to 290 mg/L at term in the serum of pregnant women. PSGs are synthesized through a gene’s coding for a specific protein. These genes belong to a specific gene family; they are a subgroup of the carcinoembryonic antigen (CEA) family of genes. CEAs are immunoglobulins. Within humans there are total of 11 PSG genes located on the 19th chromosome; there are 17 genes within mice on the 7th chromosome. These genes code for PSGs that are of varying lengths of amino acids. In order to characterize these separate types of PSGs, samples of the human placenta can be extracted and analyzed or they can be collected from blood. Though PSGs are abundant in the bloodstream a larger concentration is also found in the placenta, because PSGs are synthesized in the syncytiotrophoblast cells located in the placenta. Rodents also produce PSGs within their placenta but these cells are called spongiotrophoblasts. The presence of the PSGs can be recognized as early as 14 days after the initial fertilization of the egg. Throughout the course of the pregnancy the levels of PCGs within the bloodstream will continue to slowly and steadily rise. # Function PSGs are extremely vital to development and health of a fetus. Specifically they are important in inducing, enhancing or inhibiting an immune response. PSGs regulate lymphocytes and without the presence of the PSGs the fetus would be susceptible to various types of immune attacks from the maternal bloodstream. This includes immune responses to things such as inflammation, infection, and trauma which may occur during pregnancy. In addition PSG presence within the maternal bloodstream can induce the secretion of growth factors affecting fetal growth. Low levels of PSGs in the maternal bloodstream are associated with higher occurrences of abortion, fetal retardation, low birth weight and hypoxia. # Inhibitors Antibodies can form within the body that are specific to PSGs. These antibodies, when present, will cause symptoms similar as when PSG levels are low. Rodents and monkeys that were injected with a serum composed of the antibodies demonstrated an elevated abortion rate if pregnant and an increase of infertility if not pregnant. The receptors of some PSGs in mice have been discovered to be receptors for certain types of viruses. The mouse hepatitis virus (MHV) has been known to bind to a receptor for PSGs that is located within the brain. External factors can also have an effect on the presence and function of PSGs. Specifically smoking during the first trimester of pregnancy can have adverse effects of the fetus. A pregnant female who has smoked is likely to have a significantly lower blood concentration of PSGs, specifically in the second and third trimester. The later effect on concentration correlates with restriction of fetal growth. A significant difference between the concentrations during the first trimester has not been conclusively proven. # Applications A lack of PSGs can have such a detrimental effect on the success of a pregnancy that it is a standard practice to test and measure the levels of PSGs within the maternal bloodstream during the first trimester. A low concentration level of PSGs can be an indication of Down syndrome. Though high levels of PSGs are ideal during fetal development; their concentration throughout the rest of life, excluding the times in which a female is pregnant, is ideally low. A low concentration in adults is wanted to ensure normal and effective responses from the immune system. Adults that have a high level of PSG within their system are significantly more likely to suffer from tumors, because the immune system is repressed from fighting of abnormal cell growth.	PSG1 (gene) Pregnancy specific beta-1-glycoprotein 1 (PSBG-1) also known as CD66f (Cluster of Differentiation 66f), is a protein that in humans is encoded by the PSG1 gene and is a member of the carcinoembryonic antigen (CEA) gene family..[1] Pregnancy-specific glycoproteins (PSGs) are a complex consisting of carbohydrate and protein, which is present in the mammalian body specifically during pregnancy. This glycoprotein is the most abundant protein found in the maternal bloodstream during the later stages of pregnancy[2] and it is of vital importance in fetal development.[3] The PSG functions primarily as an immunomodulator to protect the growing fetus.[4] # Structure PSG is a member of the immunoglobulin (Ig) superfamily and contains four immunoglobulin domains.[5][6] The complete isolation of certain glycoproteins, later classified as pregnancy-specific, within human blood serum occurred in the early 1980s, when experimental techniques like molecular cloning became common practice.[7] The serum was being collected during the first trimester of pregnancy to test for other vital molecules that are present during pregnancy and it was in those samples that they were able to isolate the PSGs specifically and characterize their structure. PSGs have been studied extensively in multiple mammalian species; mammals including rodents, monkeys, elk, moose, cows, sheep, and humans.[8] Mice are the primary subject in significant portion of PSG studies. Specific structure can vary between species regarding different sugars within the carbohydrate and amino acids within the protein; all species that contain a glycoprotein will have a core protein covalently bound to a carbohydrate. This covalently bound complex structure greatly contributes to the stability of the PSG; mammalian PSGs have demonstrated continual activity when subjected to an environment from 20-60 °C and within a pH of 5.0-11.0. The protein portion of the PSG varies depending on the gene coding for it. Several of the genes and proteins have been characterized by common experimental methods such as polymerase chain reaction, gel electrophoresis, ELISA, and restriction enzymes.[9] The different genes produce PSGs with varying masses that contain different exposed amino acids residues; the residues that are exposed determine the type of binding site that can be used to bind PSG. While receptors for other PSG family members have been identified, the precise receptor for PSG1 remains unknown.[4] Cell surface receptors for PSGs are found on many cells throughout the body including dendrites and epithelial cells. These receptors are present both during development and in the adult. These receptors are also similar between species. Studies comparing mice and human PSGs discovered that some human PSGs when inserted into mice demonstrated partial levels of activity, because receptors present on the mice cells were able to interact with the human PSG. PSGs require the presence of a proteoglycan (PG) on the surface of the cell in order to bind.[4] The PSG actually will specifically bind to the glycosaminoglycan (GAG) portion of the PG, which protrudes from the membrane of the cell. Their binding of PSG can be affected by heparin, which is a competitive inhibitor that binds to the GAG portion of a PG. # Formation Pregnancy-specific beta-1-glycoprotein is a major product of the syncytiotrophoblast in the placenta, reaching concentrations of 100 to 290 mg/L at term in the serum of pregnant women.[1][10] PSGs are synthesized through a gene’s coding for a specific protein. These genes belong to a specific gene family; they are a subgroup of the carcinoembryonic antigen (CEA) family of genes.[2] CEAs are immunoglobulins. Within humans there are total of 11 PSG genes located on the 19th chromosome; there are 17 genes within mice on the 7th chromosome.[2][3] These genes code for PSGs that are of varying lengths of amino acids. In order to characterize these separate types of PSGs, samples of the human placenta can be extracted and analyzed or they can be collected from blood. Though PSGs are abundant in the bloodstream a larger concentration is also found in the placenta, because PSGs are synthesized in the syncytiotrophoblast cells located in the placenta.[2] Rodents also produce PSGs within their placenta but these cells are called spongiotrophoblasts.[2][3] The presence of the PSGs can be recognized as early as 14 days after the initial fertilization of the egg.[4] Throughout the course of the pregnancy the levels of PCGs within the bloodstream will continue to slowly and steadily rise.[5] # Function PSGs are extremely vital to development and health of a fetus. Specifically they are important in inducing, enhancing or inhibiting an immune response. PSGs regulate lymphocytes and without the presence of the PSGs the fetus would be susceptible to various types of immune attacks from the maternal bloodstream.[11] This includes immune responses to things such as inflammation, infection, and trauma which may occur during pregnancy. In addition PSG presence within the maternal bloodstream can induce the secretion of growth factors affecting fetal growth. Low levels of PSGs in the maternal bloodstream are associated with higher occurrences of abortion, fetal retardation, low birth weight and hypoxia. # Inhibitors Antibodies can form within the body that are specific to PSGs. These antibodies, when present, will cause symptoms similar as when PSG levels are low. Rodents and monkeys that were injected with a serum composed of the antibodies demonstrated an elevated abortion rate if pregnant and an increase of infertility if not pregnant.[3] The receptors of some PSGs in mice have been discovered to be receptors for certain types of viruses. The mouse hepatitis virus (MHV) has been known to bind to a receptor for PSGs that is located within the brain.[12] External factors can also have an effect on the presence and function of PSGs. Specifically smoking during the first trimester of pregnancy can have adverse effects of the fetus.[13] A pregnant female who has smoked is likely to have a significantly lower blood concentration of PSGs, specifically in the second and third trimester. The later effect on concentration correlates with restriction of fetal growth. A significant difference between the concentrations during the first trimester has not been conclusively proven. # Applications A lack of PSGs can have such a detrimental effect on the success of a pregnancy that it is a standard practice to test and measure the levels of PSGs within the maternal bloodstream during the first trimester.[13] A low concentration level of PSGs can be an indication of Down syndrome. Though high levels of PSGs are ideal during fetal development; their concentration throughout the rest of life, excluding the times in which a female is pregnant, is ideally low. A low concentration in adults is wanted to ensure normal and effective responses from the immune system. Adults that have a high level of PSG within their system are significantly more likely to suffer from tumors, because the immune system is repressed from fighting of abnormal cell growth.[7]	https://www.wikidoc.org/index.php/PSG1_(gene)
1f21fd34942e93dd9528c53d7fcd421116ec4d42	wikidoc	PTEN (gene)	PTEN (gene) Phosphatase and tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers. Genes corresponding to PTEN (orthologs) have been identified in most mammals for which complete genome data are available. PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly. It is a target of many cancer drugs. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin-like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating Akt/PKB signaling pathway. # Function The PTEN protein is widely expressed throughout the body. PTEN protein acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3). PTEN specifically catalyses the dephosphorylation of the 3` phosphate of the inositol ring in PIP3, resulting in the biphosphate product PIP2 (PtdIns(4,5)P2). This dephosphorylation is important because it results in inhibition of the AKT signaling pathway, which plays an important role in regulating cellular behaviors such as cell growth, surivival, and migration. PTEN also has weak protein phosphatase activity, but this activity is also crucial for its role as a tumor suppressor. PTEN's protein phosphatase activity may be involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly. There have been numerous reported protein substrates for PTEN, including IRS1 and Dishevelled. PTEN is one of the targets for drug candidates such as the oncomiR, MIRN21. # Structure The structure of the core of PTEN (solved by X-ray crystallography, see figure to the upper right) reveals that it consists primarily of a phosphatase domain, and a C2 domain: the phosphatase domain contains the active site, which carries out the enzymatic function of the protein, while the C2 domain binds the phospholipid membrane. Thus PTEN binds the membrane through both its phosphatase and C2 domains, bringing the active site to the membrane-bound PIP3 to dephosphorylate it. The two domains of PTEN, a protein tyrosine phosphatase domain and a C2 domain, are inherited together as a single unit and thus constitute a superdomain, not only in PTEN but also in various other proteins in fungi, plants and animals, for example, tensin proteins and auxilin. The active site of PTEN consists of three loops, the TI Loop, the P Loop, and the WPD Loop, all named following the PTPB1 nomenclature. Together they form an unusually deep and wide pocket which allows PTEN to accommodate the bulky phosphatidylinositol 3,4,5-trisphosphate substrate. The dephosphorylation reaction mechanism of PTEN is thought to proceed through a phosphoenzyme intermediate, with the formation of a phosphodiester bond on the active site cysteine, C124. Not present in the crystal structure of PTEN is a short 10-amino-acid unstructured region N-terminal of the phosphatase domain (from residues 6 to 15), known variously as the PIP2 Binding Domain (PBD) or PIP2 Binding Motif (PBM) This region increases PTEN's affinity for the plasma membrane by binding to Phosphatidylinositol 4,5-bisphosphate, or possibly any anionic lipid. Also not present in the crystal structure is the intrinsically disordered C-terminal region (CTR) (spanning residues 353-403). The CTR is constitutively phosphorylated at various positions that effect various aspects of PTEN, including its ability to bind to lipid membranes, and also act as either a protein or lipid phosphatase. Additionally, PTEN can also be expressed as PTEN-L (known as PTEN-Long, or PTEN-α), a leucine initiator alternative start site variant, which adds an additional 173 amino acids to the N-terminus of PTEN. The exact role of this 173-amino acid extension is not yet known, either causing PTEN to be secreted from the cell, or to interact with the mitochondria. The N-terminal extension has been predicted to be largely disordered, although there is evidence that there is some structure in the last twenty amino acids of the extension (most proximal to the start methionine of PTEN). # Clinical significance ## Cancer PTEN is one of the most commonly lost tumor suppressors in human cancer; in fact, up to 70% of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis. During tumor development, mutations and deletions of PTEN occur that inactivate its enzymatic activity leading to increased cell proliferation and reduced cell death. Frequent genetic inactivation of PTEN occurs in glioblastoma, endometrial cancer, and prostate cancer; and reduced expression is found in many other tumor types such as lung and breast cancer. Furthermore, PTEN mutation also causes a variety of inherited predispositions to cancer. ## Non-cancerous neoplasia Researchers have identified more than 70 mutations in the PTEN gene in people with Cowden syndrome. These mutations can be changes in a small number of base pairs or, in some cases, deletions of a large number of base pairs. Most of these mutations cause the PTEN gene to make a protein that does not function properly or does not work at all. The defective protein is unable to stop cell division or signal abnormal cells to die, which can lead to tumor growth, particularly in the breast, thyroid, or uterus. Mutations in the PTEN gene cause several other disorders that, like Cowden syndrome, are characterized by the development of non-cancerous tumors called hamartomas. These disorders include Bannayan-Riley-Ruvalcaba syndrome and Proteus-like syndrome. Together, the disorders caused by PTEN mutations are called PTEN hamartoma tumor syndromes, or PHTS. Mutations responsible for these syndromes cause the resulting protein to be non-functional or absent. The defective protein allows the cell to divide in an uncontrolled way and prevents damaged cells from dying, which can lead to the growth of tumors. ## Brain function and autism Defects of the PTEN gene have been cited to be a potential cause of autism spectrum disorders. When defective, PTEN protein interacts with the protein of a second gene known as Tp53 to dampen energy production in neurons. This severe stress leads to a spike in harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus, brain regions critical for social behavior and cognition. When PTEN protein is insufficient, its interaction with p53 triggers deficiencies and defects in other proteins that also have been found in patients with learning disabilities including autism. Patients with defective PTEN can develop cerebellar mass lesions called dysplastic gangliocytomas or Lhermitte–Duclos disease. ## Cell regeneration PTEN's strong link to cell growth inhibition is being studied as a possible therapeutic target in tissues that do not traditionally regenerate in mature animals, such as central neurons. PTEN deletion mutants have recently been shown to allow nerve regeneration in mice. # As a drug target ## PTEN inhibitors Bisperoxovanadium compounds, have a neuroprotective effect after CNS injury. PTEN inhibited by Sarcopoterium. ## PTEN agonists e.g. rapamycin, sirolimus and temsirolimus. # Cell lines Cell lines with known PTEN mutations include: - prostate: LNCaP, PC-3 - kidney: 786-O - glioblastoma: U87MG - breast : MB-MDA-468, BT549 - bladder: J82, UMUC-3 # Interactions PTEN (gene) has been shown to interact with: - CSNK2A2, - CSNK2A1, - MAGI3 - MVP, - NEDD4, - NR3C4, - P53, and - PTK2.	PTEN (gene) Phosphatase and tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene.[2] Mutations of this gene are a step in the development of many cancers. Genes corresponding to PTEN (orthologs)[3] have been identified in most mammals for which complete genome data are available. PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly.[4] It is a target of many cancer drugs. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin-like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating Akt/PKB signaling pathway.[5] # Function The PTEN protein is widely expressed throughout the body. PTEN protein acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3). PTEN specifically catalyses the dephosphorylation of the 3` phosphate of the inositol ring in PIP3, resulting in the biphosphate product PIP2 (PtdIns(4,5)P2). This dephosphorylation is important because it results in inhibition of the AKT signaling pathway, which plays an important role in regulating cellular behaviors such as cell growth, surivival, and migration. PTEN also has weak protein phosphatase activity, but this activity is also crucial for its role as a tumor suppressor. PTEN's protein phosphatase activity may be involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly.[4] There have been numerous reported protein substrates for PTEN, including IRS1[6] and Dishevelled.[7] PTEN is one of the targets for drug candidates such as the oncomiR, MIRN21. # Structure The structure of the core of PTEN (solved by X-ray crystallography, see figure to the upper right[1]) reveals that it consists primarily of a phosphatase domain, and a C2 domain: the phosphatase domain contains the active site, which carries out the enzymatic function of the protein, while the C2 domain binds the phospholipid membrane. Thus PTEN binds the membrane through both its phosphatase and C2 domains, bringing the active site to the membrane-bound PIP3 to dephosphorylate it. The two domains of PTEN, a protein tyrosine phosphatase domain and a C2 domain, are inherited together as a single unit and thus constitute a superdomain, not only in PTEN but also in various other proteins in fungi, plants and animals, for example, tensin proteins and auxilin.[8] The active site of PTEN consists of three loops, the TI Loop, the P Loop, and the WPD Loop, all named following the PTPB1 nomenclature.[1] Together they form an unusually deep and wide pocket which allows PTEN to accommodate the bulky phosphatidylinositol 3,4,5-trisphosphate substrate. The dephosphorylation reaction mechanism of PTEN is thought to proceed through a phosphoenzyme intermediate, with the formation of a phosphodiester bond on the active site cysteine, C124. Not present in the crystal structure of PTEN is a short 10-amino-acid unstructured region N-terminal of the phosphatase domain (from residues 6 to 15), known variously as the PIP2 Binding Domain (PBD) or PIP2 Binding Motif (PBM)[9][10][11] This region increases PTEN's affinity for the plasma membrane by binding to Phosphatidylinositol 4,5-bisphosphate, or possibly any anionic lipid. Also not present in the crystal structure is the intrinsically disordered C-terminal region (CTR) (spanning residues 353-403). The CTR is constitutively phosphorylated at various positions that effect various aspects of PTEN, including its ability to bind to lipid membranes, and also act as either a protein or lipid phosphatase.[12][13] Additionally, PTEN can also be expressed as PTEN-L[14] (known as PTEN-Long, or PTEN-α[15]), a leucine initiator alternative start site variant, which adds an additional 173 amino acids to the N-terminus of PTEN. The exact role of this 173-amino acid extension is not yet known, either causing PTEN to be secreted from the cell, or to interact with the mitochondria. The N-terminal extension has been predicted to be largely disordered,[16] although there is evidence that there is some structure in the last twenty amino acids of the extension (most proximal to the start methionine of PTEN).[13] # Clinical significance ## Cancer PTEN is one of the most commonly lost tumor suppressors in human cancer; in fact, up to 70% of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis.[17] During tumor development, mutations and deletions of PTEN occur that inactivate its enzymatic activity leading to increased cell proliferation and reduced cell death. Frequent genetic inactivation of PTEN occurs in glioblastoma, endometrial cancer, and prostate cancer; and reduced expression is found in many other tumor types such as lung and breast cancer. Furthermore, PTEN mutation also causes a variety of inherited predispositions to cancer. ## Non-cancerous neoplasia Researchers have identified more than 70 mutations in the PTEN gene in people with Cowden syndrome.[citation needed] These mutations can be changes in a small number of base pairs or, in some cases, deletions of a large number of base pairs.[citation needed] Most of these mutations cause the PTEN gene to make a protein that does not function properly or does not work at all. The defective protein is unable to stop cell division or signal abnormal cells to die, which can lead to tumor growth, particularly in the breast, thyroid, or uterus.[18] Mutations in the PTEN gene cause several other disorders that, like Cowden syndrome, are characterized by the development of non-cancerous tumors called hamartomas. These disorders include Bannayan-Riley-Ruvalcaba syndrome and Proteus-like syndrome. Together, the disorders caused by PTEN mutations are called PTEN hamartoma tumor syndromes, or PHTS. Mutations responsible for these syndromes cause the resulting protein to be non-functional or absent. The defective protein allows the cell to divide in an uncontrolled way and prevents damaged cells from dying, which can lead to the growth of tumors.[18] ## Brain function and autism Defects of the PTEN gene have been cited to be a potential cause of autism spectrum disorders.[19] When defective, PTEN protein interacts with the protein of a second gene known as Tp53 to dampen energy production in neurons. This severe stress leads to a spike in harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus, brain regions critical for social behavior and cognition. When PTEN protein is insufficient, its interaction with p53 triggers deficiencies and defects in other proteins that also have been found in patients with learning disabilities including autism.[19] Patients with defective PTEN can develop cerebellar mass lesions called dysplastic gangliocytomas or Lhermitte–Duclos disease.[18] ## Cell regeneration PTEN's strong link to cell growth inhibition is being studied as a possible therapeutic target in tissues that do not traditionally regenerate in mature animals, such as central neurons. PTEN deletion mutants have recently[20] been shown to allow nerve regeneration in mice.[21] # As a drug target ## PTEN inhibitors Bisperoxovanadium compounds, have a neuroprotective effect after CNS injury.[22] PTEN inhibited by Sarcopoterium.[23] ## PTEN agonists e.g. rapamycin, sirolimus and temsirolimus.[24] # Cell lines Cell lines with known PTEN mutations include: - prostate: LNCaP, PC-3 - kidney: 786-O - glioblastoma: U87MG[25] - breast : MB-MDA-468, BT549[25] - bladder: J82, UMUC-3 # Interactions PTEN (gene) has been shown to interact with: - CSNK2A2,[26] - CSNK2A1,[26] - MAGI3[27] - MVP,[28] - NEDD4,[29] - NR3C4,[30] - P53,[31] and - PTK2.[32][33]	https://www.wikidoc.org/index.php/PTEN
920340c2663be6b5bf39e512aeb2b12789e09d6a	wikidoc	Paco (drug)	Paco (drug) Paco (Spanish, Pasta de Cocaina) is a smokable, cheap, and highly addictive street drug. It is a chemical byproduct left over when Andean coca leaves are turned into a paste and then formulated into cocaine bound for US and European markets. Formerly considered lab trash, the substance became popular in the impoverished Argentinian neighborhoods after the country's 2001 financial collapse. Because the drug is smoked rather than sniffed, the physiological impacts are addictive and can cause lasting physical damage. Buenos Aires' provincial government says that intense paco consumption can cause "cerebral death" in as little as six months. In Argentina, paco usually goes for about 30 cents (USD) a dose, enough for a powerful two-minute high. Kelly Hearn wrote: - Users describe being hooked by the first use, of needing more, sacrificing everything and eventually ending up as bone-thin, wraith-like addicts who sell clothes and household appliances, turn to crime, all to keep up the flow of “dosis,” or packets that cost around 30 cents and provide a high that lasts only a few minutes. - Leonardo Gorbacz, a national lawmaker who was involved in the study headed by Elisa Carrió, said Argentine government officials estimate 400,000 doses of paco are consumed each day in Argentina.	Paco (drug) Paco (Spanish, Pasta de Cocaina) is a smokable, cheap, and highly addictive street drug. It is a chemical byproduct left over when Andean coca leaves are turned into a paste and then formulated into cocaine bound for US and European markets. Formerly considered lab trash, the substance became popular in the impoverished Argentinian neighborhoods after the country's 2001 financial collapse. [1] Because the drug is smoked rather than sniffed, the physiological impacts are addictive and can cause lasting physical damage. Buenos Aires' provincial government says that intense paco consumption can cause "cerebral death" in as little as six months. In Argentina, paco usually goes for about 30 cents (USD) a dose, enough for a powerful two-minute high. [2] Kelly Hearn wrote: - Users describe being hooked by the first use, of needing more, sacrificing everything and eventually ending up as bone-thin, wraith-like addicts who sell clothes and household appliances, turn to crime, all to keep up the flow of “dosis,” or packets that cost around 30 cents and provide a high that lasts only a few minutes. - Leonardo Gorbacz, a national lawmaker who was involved in the study headed by Elisa Carrió, said Argentine government officials estimate 400,000 doses of paco are consumed each day in Argentina.[3]	https://www.wikidoc.org/index.php/Paco_(drug)
283ae0c8eab4a916e60378df3d2e0cff41ee353b	wikidoc	Soft palate	Soft palate # Overview The soft palate (or velum, or muscular palate) is the soft tissue constituting the back of the roof of the mouth. The soft palate is distinguished from the hard palate at the front of the mouth in that it does not contain bone. # Function It is movable, consisting of muscle fibers sheathed in mucous membrane, and is responsible for closing off the nasal passages during the act of swallowing. The soft palate's motion during breathing is responsible for the sound of snoring. Touching the soft palate evokes a strong gag response in most people. The soft palate also functions during speech to separate the oral cavity (mouth) from the nose, in order to produce the oral speech sounds. If this separation is incomplete, air escapes through the nose during speech and the speech is perceived as hypernasal. # Muscles of soft palate # Additional images - Soft palate without tonsils (after tonsillectomy) - Mouth (oral cavity) - Mouth - Sagittal section of nose mouth, pharynx, and larynx. - The mouth cavity. The cheeks have been slit transversely and the tongue pulled forward.	Soft palate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Template:Infobox Anatomy The soft palate (or velum, or muscular palate) is the soft tissue constituting the back of the roof of the mouth. The soft palate is distinguished from the hard palate at the front of the mouth in that it does not contain bone. # Function It is movable, consisting of muscle fibers sheathed in mucous membrane, and is responsible for closing off the nasal passages during the act of swallowing. The soft palate's motion during breathing is responsible for the sound of snoring. Touching the soft palate evokes a strong gag response in most people. The soft palate also functions during speech to separate the oral cavity (mouth) from the nose, in order to produce the oral speech sounds. If this separation is incomplete, air escapes through the nose during speech and the speech is perceived as hypernasal. # Muscles of soft palate # Additional images - Soft palate without tonsils (after tonsillectomy) - Mouth (oral cavity) - Mouth - Sagittal section of nose mouth, pharynx, and larynx. - The mouth cavity. The cheeks have been slit transversely and the tongue pulled forward.	https://www.wikidoc.org/index.php/Palatine_velum
7fc5aee10c81148cb5314e5f7a0b9a899de72697	wikidoc	Palivizumab	Palivizumab # 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 Palivizumab is a monoclonal antibody that is FDA approved for the treatment of prevention of serious lower respiratory tract disease caused by RSV in children at high risk of RSV disease. Common adverse reactions include fever and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding FDA-Labeled Use of Palivizumab in adult patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Palivizumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Palivizumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Synagis is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk of RSV disease. - The following points should be considered when prescribing Synagis: - Safety and efficacy were established in children with bronchopulmonary dysplasia (BPD), infants with a history of premature birth (less than or equal to 35 weeks gestational age), and children with hemodynamically significant congenital heart disease (CHD). - The safety and efficacy of Synagis have not been established for treatment of RSV disease. - The recommended dose of Synagis is 15 mg per kg of body weight given monthly by intramuscular injection. The first dose of Synagis should be administered prior to commencement of the RSV season and the remaining doses should be administered monthly throughout the RSV season. Children who develop an RSV infection should continue to receive monthly doses throughout the RSV season. In the northern hemisphere, the RSV season typically commences in November and lasts through April, but it may begin earlier or persist later in certain communities. - Synagis serum levels are decreased after cardio-pulmonary bypass. Children undergoing cardio-pulmonary bypass should receive an additional dose of Synagis as soon as possible after the cardio-pulmonary bypass procedure (even if sooner than a month from the previous dose). Thereafter, doses should be administered monthly as scheduled. - The efficacy of Synagis at doses less than 15 mg per kg, or of dosing less frequently than monthly throughout the RSV season, has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Palivizumab in pediatric patients. ### Non–Guideline-Supported Use - Prophylactic palivizumab administration to pediatric patients with cystic fibrosis. # Contraindications - Synagis is contraindicated in children who have had a previous significant hypersensitivity reaction to Synagis. # Warnings ### Precautions - Hypersensitivity Reactions - Cases of anaphylaxis and anaphylactic shock, including fatal cases, have been reported following initial exposure or re-exposure to Synagis. Other acute hypersensitivity reactions, which may be severe, have also been reported on initial exposure or re-exposure to Synagis. Signs and symptoms may include urticaria, pruritus, angioedema, dyspnea, respiratory failure, cyanosis, hypotonia, hypotension, and unresponsiveness. The relationship between these reactions and the development of antibodies to Synagis is unknown. If a significant hypersensitivity reaction occurs with Synagis, its use should be permanently discontinued. If anaphylaxis or other significant hypersensitivity reaction occurs, administer appropriate medications (e.g., epinephrine) and provide supportive care as required. If a mild hypersensitivity reaction occurs, clinical judgment should be used regarding cautious readministration of Synagis. - Coagulation Disorders - Synagis is for intramuscular use only. As with any intramuscular injection, Synagis should be given with caution to children with thrombocytopenia or any coagulation disorder. - RSV Diagnostic Test Interference - Palivizumab may interfere with immunological-based RSV diagnostic tests such as some antigen detection-based assays. In addition, palivizumab inhibits virus replication in cell culture, and therefore may also interfere with viral culture assays. Palivizumab does not interfere with reverse transcriptase-polymerase chain reaction based assays. Assay interference could lead to false-negative RSV diagnostic test results. Therefore, diagnostic test results, when obtained, should be used in conjunction with clinical findings to guide medical decisions. - Treatment of RSV Disease - The safety and efficacy of Synagis have not been established for treatment of RSV disease. - Proper Administration - The single-dose vial of Synagis does not contain a preservative. Administration of Synagis should occur immediately after dose withdrawal from the vial. The vial should not be re-entered. Discard any unused portion. # 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 data described below reflect exposure to Synagis (n=1639) compared with placebo (n=1143) in children 3 days to 24.1 months of age at high risk of RSV-related hospitalization in two clinical trials. Trial 1 was conducted during a single RSV season and studied a total of 1502 children less than or equal to 24 months of age with BPD or infants with premature birth (less than or equal to 35 weeks gestation) who were less than or equal to 6 months of age at study entry. Trial 2 was conducted over four consecutive seasons among a total of 1287 children less than or equal to 24 months of age with hemodynamically significant congenital heart disease. - In Trials 1 and 2 combined, fever and rash were each reported more frequently among Synagis than placebo recipients, 27% versus 25%, and 12% versus 10%, respectively. Adverse reactions observed in the 153-patient crossover study comparing the liquid and lyophilized formulations were comparable for the two formulations, and were similar to those observed with Synagis in Trials 1 and 2. - Immunogenicity - In Trial 1, the incidence of anti-palivizumab antibody following the fourth injection was 1.1% in the placebo group and 0.7% in the Synagis group. In children receiving Synagis for a second season, one of the fifty-six children had transient, low titer reactivity. This reactivity was not associated with adverse events or alteration in serum concentrations. Immunogenicity was not assessed in Trial 2. - A trial of high-risk preterm children less than or equal to 24 months of age was conducted to evaluate the immunogenicity of the lyophilized formulation of Synagis (used in Trials 1 and 2 above) and the liquid formulation of Synagis. Three hundred seventy-nine children contributed to the 4 to 6 months post-final dose analysis. The rate of anti-palivizumab antibodies at this time point was low in both formulation groups (anti-palivizumab antibodies were not detected in any subject in the liquid formulation group and were detected in one subject in the lyophilized group (0.5%), with an overall rate of 0.3% for both treatment groups combined). - These data reflect the percentage of children whose test results were considered positive for antibodies to palivizumab in an enzyme-linked immunosorbent assay (ELISA) and are highly dependent on the sensitivity and specificity of the assay. - The ELISA has substantial limitations in detecting anti-palivizumab antibodies in the presence of palivizumab. Immunogenicity samples tested with the ELISA assay likely contained palivizumab at levels that may interfere with the detection of anti-palivizumab antibodies. - An electrochemical luminescence (ECL) based immunogenicity assay, with a higher tolerance for palivizumab presence compared to the ELISA, was used to evaluate the presence of anti-palivizumab antibodies in subject samples from two additional clinical trials. The rates of anti-palivizumab antibody positive results in these trials were 1.1% and 1.5%. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of Synagis. 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. - Blood and Lymphatic System Disorders: severe thrombocytopenia (platelet count less than 50,000 per microliter) - General Disorders and Administration Site Conditions: injection site reactions - Limited information from post-marketing reports suggests that, within a single RSV season, adverse events after a sixth or greater dose of Synagis are similar in character and frequency to those after the initial five doses. # Drug Interactions - No formal drug-drug interaction studies were conducted. In Trial 1, the proportions of children in the placebo and Synagis groups who received routine childhood vaccines, influenza vaccine, bronchodilators, or corticosteroids were similar and no incremental increase in adverse reactions was observed among children receiving these agents. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Synagis is not indicated for adult usage. It is not known whether Synagis can cause fetal harm or could affect reproductive capacity when administered to a pregnant woman. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Palivizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Palivizumab during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Palivizumab with respect to nursing mothers. ### Pediatric Use - The safety and effectiveness of Synagis in children greater than 24 months of age at the start of dosing have not been established. ### Geriatic Use There is no FDA guidance on the use of Palivizumab with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Palivizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Palivizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Palivizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Palivizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Palivizumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Palivizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intramuscular ### Monitoring There is limited information regarding Monitoring of Palivizumab in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Palivizumab in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Overdoses with doses up to 85 mg per kg have been reported in clinical studies and post-marketing experience with Synagis, and in some cases, adverse reactions were reported. ### Management - In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. ## Chronic Overdose There is limited information regarding Chronic Overdose of Palivizumab in the drug label. # Pharmacology ## Mechanism of Action - Palivizumab, a recombinant humanized monoclonal antibody which provides passive immunity against RSV, acts by binding the RSV envelope fusion protein (RSV F) on the surface of the virus and blocking a critical step in the membrane fusion process. Palivizumab also prevents cell-to-cell fusion of RSV-infected cells. ## Structure - Palivizumab is a humanized monoclonal antibody (IgG1к) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of RSV. Palivizumab is a composite of human (95%) and murine (5%) antibody sequences. The human heavy chain sequence was derived from the constant domains of human IgG1 and the variable framework regions of the VH genes Cor and Cess. The human light chain sequence was derived from the constant domain of Cк and the variable framework regions of the VL gene K104 with Jк -4. The murine sequences were derived from a murine monoclonal antibody, Mab 1129, in a process that involved the grafting of the murine complementarity determining regions into the human antibody frameworks. Palivizumab is composed of two heavy chains and two light chains and has a molecular weight of approximately 148,000 Daltons. - Synagis is supplied as a sterile, preservative-free liquid solution at 100 mg per mL to be administered by intramuscular injection. Thimerosal or other mercury-containing salts are not used in the production of Synagis. The solution has a pH of 6.0 and should appear clear or slightly opalescent. - Each 100 mg single-dose vial of Synagis liquid solution contains 100 mg of palivizumab and also contains chloride (0.5 mg), glycine (0.1 mg), and histidine (3.9 mg), in a volume of 1 mL. - Each 50 mg single-dose vial of Synagis liquid solution contains 50 mg of palivizumab and also contains chloride (0.2 mg), glycine (0.06 mg), and histidine (1.9 mg), in a volume of 0.5 mL. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Palivizumab in the drug label. ## Pharmacokinetics - In children less than or equal to 24 months of age without congenital heart disease (CHD), the mean half-life of palivizumab was 20 days and monthly intramuscular doses of 15 mg per kg achieved mean ± SD 30 day trough serum drug concentrations of 37 ± 21 mcg per mL after the first injection, 57 ± 41 mcg per mL after the second injection, 68 ± 51 mcg per mL after the third injection, and 72 ± 50 mcg per mL after the fourth injection. Trough concentrations following the first and fourth Synagis dose were similar in children with CHD and in non-cardiac patients. In children given Synagis for a second season, the mean ± SD serum concentrations following the first and fourth injections were 61 ± 17 mcg per mL and 86 ± 31 mcg per mL, respectively. - In 139 children less than or equal to 24 months of age with hemodynamically significant CHD who received Synagis and underwent cardio-pulmonary bypass for open-heart surgery, the mean ± SD serum palivizumab concentration was 98 ± 52 mcg per mL before bypass and declined to 41 ± 33 mcg per mL after bypass, a reduction of 58%. The clinical significance of this reduction is unknown. - Specific studies were not conducted to evaluate the effects of demographic parameters on palivizumab systemic exposure. However, no effects of gender, age, body weight, or race on palivizumab serum trough concentrations were observed in a clinical study with 639 children with CHD (less than or equal to 24 months of age) receiving five monthly intramuscular injections of 15 mg per kg of Synagis. - The pharmacokinetics and safety of Synagis liquid solution and Synagis lyophilized formulation administered via intramuscular injection at 15 mg per kg were studied in a cross-over trial of 153 infants less than or equal to 6 months of age with a history of prematurity. The results of this trial indicated that the trough serum concentrations of palivizumab were comparable between the liquid solution and the lyophilized formulation, which was the formulation used in the clinical studies. - A population pharmacokinetic analysis was performed across 22 studies in 1800 patients (1684 pediatric and 116 adult patients) to characterize palivizumab pharmacokinetics and inter-subject variability in serum concentrations. Palivizumab pharmacokinetics was described by a two-compartment linear model with an elimination half-life of 24.5 days in pediatric patients. Clearance of palivizumab in a typical pediatric patient (body weight 4.5 kg) less than or equal to 24 months of age without CHD was estimated to be 11 mL per day with a bioavailability of 70% following intramuscular administration. The inter-patient variability in drug clearance was 48.7% (CV%). Covariate analysis did not identify any factors that could account for the inter-patient variability in order to predict serum concentrations a priori in an individual patient. - Mechanism of Action - Palivizumab, a recombinant humanized monoclonal antibody which provides passive immunity against - RSV, acts by binding the RSV envelope fusion protein (RSV F) on the surface of the virus and blocking a critical step in the membrane fusion process. Palivizumab also prevents cell-to-cell fusion of RSV-infected cells. - Antiviral Activity - The antiviral activity of palivizumab was assessed in a microneutralization assay in which increasing concentrations of antibody were incubated with RSV prior to addition of the human epithelial cells HEp-2. After incubation for 4-5 days, RSV antigen was measured in an ELISA assay. The neutralization titer (50% effective concentration ) is expressed as the antibody concentration required to reduce detection of RSV antigen by 50% compared with untreated virus-infected cells. Palivizumab exhibited median EC50 values of 0.65 mcg per mL (mean 0.75 ± 0.53 mcg per mL; n=69, range 0.07-2.89 mcg per mL) and 0.28 mcg per mL (mean 0.35 ± 0.23 mcg per mL; n=35, range 0.03-0.88 mcg per mL) against clinical RSV A and RSV B isolates, respectively. The majority of clinical RSV isolates tested (n=96) were collected from subjects across the United States (CA, CO, CT, IL, MA, NC, NY, PA, RI, TN, TX, VA), with the remainder from Japan (n=1), Australia (n=5) and Israel (n=2). These isolates encoded the most common RSV F sequence polymorphisms found among clinical isolates worldwide. - Palivizumab serum concentrations of greater than or equal to 40 mcg per mL have been shown to reduce pulmonary RSV replication in the cotton rat model of RSV infection by 100-fold. - Resistance - Palivizumab binds a highly conserved region on the extracellular domain of mature RSV F, referred to as antigenic site II or site A, which encompasses amino acids 262 to 275. All RSV mutants that exhibit resistance to palivizumab have been shown to contain amino acid changes in this region on the F protein. - F protein sequence variations within antigenic site A: Amino acid substitutions in antigenic site A selected either in cell culture, in animal models, or in human subjects that resulted in palivizumab resistance were N262D, N268I, K272E/M/N/Q/T, and S275F/L. RSV variants expressing the K272N substitution in F protein showed a 5164 ± 1731-fold decrease in susceptibility (i.e., fold increase in EC50 value) when compared to the wild-type RSV, while variants containing the N262D, S275F/L, or K272E/M/Q/T substitutions showed a greater than 25,000-fold decrease in susceptibility to palivizumab. The N268I substitution conferred partial resistance to palivizumab; however, fold changes in susceptibility were not quantified for this mutant. Studies carried out to investigate the mechanism of virus escape from palivizumab showed a correlation between antibody binding and virus neutralization. RSV with substitutions in antigenic site A that were resistant to neutralization by palivizumab did not bind to palivizumab. - At least one of the palivizumab resistance-associated substitutions, N262D, K272E/Q, or S275F/L was identified in 8 of 126 clinical RSV (59 RSV A and 67 RSV B) isolates from subjects who failed immunoprophylaxis, resulting in a combined resistance-associated mutation frequency of 6.3%. A review of clinical findings revealed no association between antigenic A site sequence changes and RSV disease severity among children receiving palivizumab immunoprophylaxis who develop RSV lower respiratory tract disease. - Analysis of 254 clinical RSV isolates (145 RSV A and 109 RSV B) collected from immunoprophylaxis-naïve subjects revealed palivizumab resistance-associated substitutions in 2 (1 with N262D and 1 with S275F), resulting in a resistance-associated mutation frequency of 0.79%. - F protein sequence variations outside antigenic site A: In addition to the sequence variations in antigenic site A known to confer palivizumab resistance, F protein substitutions T100A, G139S, N165D/V406I; T326A, V450A in RSV A, and T74I, A147V, I206L, S285G, V450I, T455I in RSV B were identified in viruses isolated from failures of immunoprophylaxis. These substitutions were not identified in RSV F sequences derived from 254 clinical isolates from immunoprophylaxis-naïve subjects and thus are considered treatment-associated and non-polymorphic. Recombinant RSV B encoding the S285G substitution exhibited palivizumab sensitivity (EC50 value = 0.39 ± 0.02 mcg per mL) similar to recombinant wild-type RSV B (EC50 value = 0.17 ± 0.02 mcg per mL). - Palivizumab susceptibility of RSV encoding common F protein sequence polymorphisms located proximal to antigenic site A was evaluated. Recombinant RSV A encoding N276S (EC50 value = 0.72 ± 0.07 mcg per mL), and recombinant RSV B with S276N (EC50 value = 0.42 ± 0.04 mcg per mL), exhibited sensitivities comparable to the corresponding recombinant wild-type RSV A (EC50 value = 0.63 ± 0.22 mcg per mL) and RSV B (EC50 value = 0.23 ± 0.07 mcg per mL). Likewise, RSV B clinical isolates containing the polymorphic variation V278A were at least as sensitive to neutralization by palivizumab (EC50 range 0.08-0.45 mcg per mL) as laboratory strains of wild-type RSV B (EC50 value = 0.54 ± 0.08 mcg per mL). No known polymorphic or non-polymorphic sequence variations outside the antigenic site A on RSV F have been demonstrated to render RSV resistant to neutralization by palivizumab. - Interference of RSV Diagnostic Assays by Palivizumab - Interference with immunologically-based RSV diagnostic assays by palivizumab has been observed in laboratory studies. Rapid chromatographic/enzyme immunoassays (CIA/EIA), immunofluorescence assays (IFA), and direct immunofluorescence assays (DFA) using monoclonal antibodies targeting RSV F protein may be inhibited. Therefore, caution should be used in interpreting negative immunological assay results when clinical observations are consistent with RSV infection. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay, which is not inhibited by palivizumab, may prove useful for laboratory confirmation of RSV infection. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Palivizumab in the drug label. # Clinical Studies - The safety and efficacy of Synagis were assessed in two randomized, double-blind, placebo-controlled trials of prophylaxis against RSV infection in children at high risk of an RSV-related hospitalization. Trial 1 was conducted during a single RSV season and studied a total of 1502 children less than or equal to 24 months of age with BPD or infants with premature birth (less than or equal to 35 weeks gestation) who were less than or equal to 6 months of age at study entry. Trial 2 was conducted over four consecutive seasons among a total of 1287 children less than or equal to 24 months of age with hemodynamically significant congenital heart disease. In both trials participants received 15 mg per kg Synagis or an equivalent volume of placebo via intramuscular injection monthly for five injections and were followed for 150 days from randomization. In Trial 1, 99% of all subjects completed the study and 93% completed all five injections. In Trial 2, 96% of all subjects completed the study and 92% completed all five injections. The incidence of RSV hospitalization is shown in Table 1. The results were shown to be statistically significant using Fisher’s exact test. - In Trial 1, the reduction of RSV hospitalization was observed both in children with BPD (34/266 placebo versus 39/496 Synagis) and in premature infants without BPD (19/234 placebo versus 9/506 Synagis). In Trial 2, reductions were observed in acyanotic (36/305 placebo versus 15/300 Synagis) and cyanotic children (27/343 placebo versus 19/339 Synagis). - The clinical studies do not suggest that RSV infection was less severe among children hospitalized with RSV infection who received Synagis for RSV prophylaxis compared to those who received placebo. # How Supplied - Synagis is supplied in single-dose vials as a preservative-free, sterile liquid solution at 100 mg per mL for intramuscular injection. - 50 mg vial NDC 60574-4114-1 - The 50 mg vial contains 50 mg Synagis in 0.5 mL. - 100 mg vial NDC 60574-4113-1 - The 100 mg vial contains 100 mg Synagis in 1 mL. - The rubber stopper used for sealing vials of Synagis is not made with natural rubber latex. - Storage - Upon receipt and until use, Synagis should be stored between 2°C and 8°C (36°F and 46°F) in its original container. DO NOT freeze. DO NOT use beyond the expiration date. ## Storage There is limited information regarding Palivizumab Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Read this Patient Information before your child starts receiving SYNAGIS and before each injection. The information may have changed. This leaflet does not take the place of talking with your child’s healthcare provider about your child’s condition or treatment. - SYNAGIS is a prescription medication that is used to help prevent a serious lung disease caused by Respiratory Syncytial Virus (RSV). Your child is prescribed SYNAGIS because he or she is at high risk for severe lung disease from RSV. - SYNAGIS contains man-made, disease-fighting proteins called antibodies. These antibodies help prevent RSV disease. Children at high risk for severe RSV disease often do not have enough of their own antibodies. SYNAGIS is used in certain groups of children to help prevent severe RSV disease by increasing protective RSV antibodies. - SYNAGIS is not used to treat the symptoms of RSV disease once a child already has it. It is only used to prevent RSV disease. - SYNAGIS is not for adults or for children older than 24 months of age at the start of dosing. - Your child should not receive SYNAGIS if they have ever had a severe allergic reaction to it. Signs and symptoms of a severe allergic reaction could include: - severe rash, hives, or itching skin - swelling of the lips, tongue, or face - closing of the throat, difficulty swallowing - difficult, rapid, or irregular breathing - bluish color of skin, lips, or under fingernails - muscle weakness or floppiness - a drop in blood pressure - unresponsiveness - Tell your child’s healthcare provider about: - any reactions you believe your child has ever had to SYNAGIS. - any bleeding or bruising problems. SYNAGIS is given by injection. If your child has a problem with bleeding or bruises easily, an injection could cause a problem. - any other medical problems. - Tell your child’s healthcare provider about all the medicines your child takes, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your child’s healthcare provider if your child takes a blood thinner medicine. - SYNAGIS is given as a monthly injection, usually in the thigh (leg) muscle, by your child’s healthcare provider. Your child’s healthcare provider will prescribe the amount of SYNAGIS that is right for your child (based on their weight). - Your child’s healthcare provider will give you detailed instructions on when SYNAGIS will be given. - “RSV season” is a term used to describe the time of year when RSV infections most commonly occur (usually fall through spring in most parts of the country). During this time, when RSV is most active, your child will need to receive SYNAGIS shots. Your child’s healthcare provider can tell you when the RSV season starts in your area. - Your child should receive their first SYNAGIS shot before the RSV season starts to help protect them before RSV becomes active. If the season has already started, your child should receive their first SYNAGIS shot as soon as possible to help protect them when exposure to the virus is more likely. - SYNAGIS is needed every 28-30 days during the RSV season. Each dose of SYNAGIS helps protect your child from severe RSV disease for about a month. Keep all appointments with your child’s healthcare provider. - If your child misses an injection, talk to your healthcare provider and schedule another injection as soon as possible. - Your child may still get severe RSV disease after receiving SYNAGIS; talk to your child’s healthcare provider about what symptoms to look for. If your child has an RSV infection, they should continue to get their scheduled SYNAGIS injections to help prevent severe disease from new RSV infections. - If your child has certain types of heart disease and has corrective surgery, your healthcare provider may need to give your child an additional SYNAGIS injection soon after surgery. - Synagis may cause serious side effects including: - Severe allergic reactions (may occur after any dose of SYNAGIS). Such reactions may be life-threatening or cause death. - See “Who should not take SYNAGIS?” for a list of signs and symptoms. - Unusual bruising or groups of tiny red spots on the skin. - Call your child’s healthcare provider or get medical help right away if your child has any of the serious side effects listed above after any dose of SYNAGIS. - Common side effects of SYNAGIS include: - fever - rash - Other possible side effects include skin reactions around the area where the shot was given (like redness, swelling, warmth, or discomfort). - These are not all the possible side effects of SYNAGIS. Tell your child’s healthcare provider about any side effect that bothers your child or that does not go away. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - You may also report side effects to MedImmune at 1-877-633-4411. - Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. - This leaflet summarizes important information about SYNAGIS. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SYNAGIS that is written for health professionals. - For more information, go to www.synagis.com or call 1-877-633-4411. - Active Ingredient: palivizumab - Inactive Ingredients: chloride, glycine, and histidine - Respiratory Syncytial Virus (RSV) is a common virus that is easily spread from person to person. RSV infects nearly all children by their second birthday. In most children, RSV infection is usually no worse than a bad cold. For some children, RSV infection can cause serious lung disease (like pneumonia and bronchiolitis) or breathing problems, and affected children may need to be admitted to the hospital or need emergency care. - Children who are more likely to get severe RSV disease (high-risk children) include babies born prematurely (35 weeks or less) or babies born with certain heart or lung problems. - This Patient Information has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol - Alcohol-Palivizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Synagis® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Palivizumab 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 Palivizumab is a monoclonal antibody that is FDA approved for the treatment of prevention of serious lower respiratory tract disease caused by RSV in children at high risk of RSV disease. Common adverse reactions include fever and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) There is limited information regarding FDA-Labeled Use of Palivizumab in adult patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Palivizumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Palivizumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Synagis is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk of RSV disease. - The following points should be considered when prescribing Synagis: - Safety and efficacy were established in children with bronchopulmonary dysplasia (BPD), infants with a history of premature birth (less than or equal to 35 weeks gestational age), and children with hemodynamically significant congenital heart disease (CHD). - The safety and efficacy of Synagis have not been established for treatment of RSV disease. - The recommended dose of Synagis is 15 mg per kg of body weight given monthly by intramuscular injection. The first dose of Synagis should be administered prior to commencement of the RSV season and the remaining doses should be administered monthly throughout the RSV season. Children who develop an RSV infection should continue to receive monthly doses throughout the RSV season. In the northern hemisphere, the RSV season typically commences in November and lasts through April, but it may begin earlier or persist later in certain communities. - Synagis serum levels are decreased after cardio-pulmonary bypass. Children undergoing cardio-pulmonary bypass should receive an additional dose of Synagis as soon as possible after the cardio-pulmonary bypass procedure (even if sooner than a month from the previous dose). Thereafter, doses should be administered monthly as scheduled. - The efficacy of Synagis at doses less than 15 mg per kg, or of dosing less frequently than monthly throughout the RSV season, has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Palivizumab in pediatric patients. ### Non–Guideline-Supported Use - Prophylactic palivizumab administration to pediatric patients with cystic fibrosis.[1] # Contraindications - Synagis is contraindicated in children who have had a previous significant hypersensitivity reaction to Synagis. # Warnings ### Precautions - Hypersensitivity Reactions - Cases of anaphylaxis and anaphylactic shock, including fatal cases, have been reported following initial exposure or re-exposure to Synagis. Other acute hypersensitivity reactions, which may be severe, have also been reported on initial exposure or re-exposure to Synagis. Signs and symptoms may include urticaria, pruritus, angioedema, dyspnea, respiratory failure, cyanosis, hypotonia, hypotension, and unresponsiveness. The relationship between these reactions and the development of antibodies to Synagis is unknown. If a significant hypersensitivity reaction occurs with Synagis, its use should be permanently discontinued. If anaphylaxis or other significant hypersensitivity reaction occurs, administer appropriate medications (e.g., epinephrine) and provide supportive care as required. If a mild hypersensitivity reaction occurs, clinical judgment should be used regarding cautious readministration of Synagis. - Coagulation Disorders - Synagis is for intramuscular use only. As with any intramuscular injection, Synagis should be given with caution to children with thrombocytopenia or any coagulation disorder. - RSV Diagnostic Test Interference - Palivizumab may interfere with immunological-based RSV diagnostic tests such as some antigen detection-based assays. In addition, palivizumab inhibits virus replication in cell culture, and therefore may also interfere with viral culture assays. Palivizumab does not interfere with reverse transcriptase-polymerase chain reaction based assays. Assay interference could lead to false-negative RSV diagnostic test results. Therefore, diagnostic test results, when obtained, should be used in conjunction with clinical findings to guide medical decisions. - Treatment of RSV Disease - The safety and efficacy of Synagis have not been established for treatment of RSV disease. - Proper Administration - The single-dose vial of Synagis does not contain a preservative. Administration of Synagis should occur immediately after dose withdrawal from the vial. The vial should not be re-entered. Discard any unused portion. # 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 data described below reflect exposure to Synagis (n=1639) compared with placebo (n=1143) in children 3 days to 24.1 months of age at high risk of RSV-related hospitalization in two clinical trials. Trial 1 was conducted during a single RSV season and studied a total of 1502 children less than or equal to 24 months of age with BPD or infants with premature birth (less than or equal to 35 weeks gestation) who were less than or equal to 6 months of age at study entry. Trial 2 was conducted over four consecutive seasons among a total of 1287 children less than or equal to 24 months of age with hemodynamically significant congenital heart disease. - In Trials 1 and 2 combined, fever and rash were each reported more frequently among Synagis than placebo recipients, 27% versus 25%, and 12% versus 10%, respectively. Adverse reactions observed in the 153-patient crossover study comparing the liquid and lyophilized formulations were comparable for the two formulations, and were similar to those observed with Synagis in Trials 1 and 2. - Immunogenicity - In Trial 1, the incidence of anti-palivizumab antibody following the fourth injection was 1.1% in the placebo group and 0.7% in the Synagis group. In children receiving Synagis for a second season, one of the fifty-six children had transient, low titer reactivity. This reactivity was not associated with adverse events or alteration in serum concentrations. Immunogenicity was not assessed in Trial 2. - A trial of high-risk preterm children less than or equal to 24 months of age was conducted to evaluate the immunogenicity of the lyophilized formulation of Synagis (used in Trials 1 and 2 above) and the liquid formulation of Synagis. Three hundred seventy-nine children contributed to the 4 to 6 months post-final dose analysis. The rate of anti-palivizumab antibodies at this time point was low in both formulation groups (anti-palivizumab antibodies were not detected in any subject in the liquid formulation group and were detected in one subject in the lyophilized group (0.5%), with an overall rate of 0.3% for both treatment groups combined). - These data reflect the percentage of children whose test results were considered positive for antibodies to palivizumab in an enzyme-linked immunosorbent assay (ELISA) and are highly dependent on the sensitivity and specificity of the assay. - The ELISA has substantial limitations in detecting anti-palivizumab antibodies in the presence of palivizumab. Immunogenicity samples tested with the ELISA assay likely contained palivizumab at levels that may interfere with the detection of anti-palivizumab antibodies. - An electrochemical luminescence (ECL) based immunogenicity assay, with a higher tolerance for palivizumab presence compared to the ELISA, was used to evaluate the presence of anti-palivizumab antibodies in subject samples from two additional clinical trials. The rates of anti-palivizumab antibody positive results in these trials were 1.1% and 1.5%. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of Synagis. 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. - Blood and Lymphatic System Disorders: severe thrombocytopenia (platelet count less than 50,000 per microliter) - General Disorders and Administration Site Conditions: injection site reactions - Limited information from post-marketing reports suggests that, within a single RSV season, adverse events after a sixth or greater dose of Synagis are similar in character and frequency to those after the initial five doses. # Drug Interactions - No formal drug-drug interaction studies were conducted. In Trial 1, the proportions of children in the placebo and Synagis groups who received routine childhood vaccines, influenza vaccine, bronchodilators, or corticosteroids were similar and no incremental increase in adverse reactions was observed among children receiving these agents. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Synagis is not indicated for adult usage. It is not known whether Synagis can cause fetal harm or could affect reproductive capacity when administered to a pregnant woman. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Palivizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Palivizumab during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Palivizumab with respect to nursing mothers. ### Pediatric Use - The safety and effectiveness of Synagis in children greater than 24 months of age at the start of dosing have not been established. ### Geriatic Use There is no FDA guidance on the use of Palivizumab with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Palivizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Palivizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Palivizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Palivizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Palivizumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Palivizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intramuscular ### Monitoring There is limited information regarding Monitoring of Palivizumab in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Palivizumab in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - Overdoses with doses up to 85 mg per kg have been reported in clinical studies and post-marketing experience with Synagis, and in some cases, adverse reactions were reported. ### Management - In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. ## Chronic Overdose There is limited information regarding Chronic Overdose of Palivizumab in the drug label. # Pharmacology ## Mechanism of Action - Palivizumab, a recombinant humanized monoclonal antibody which provides passive immunity against RSV, acts by binding the RSV envelope fusion protein (RSV F) on the surface of the virus and blocking a critical step in the membrane fusion process. Palivizumab also prevents cell-to-cell fusion of RSV-infected cells. ## Structure - Palivizumab is a humanized monoclonal antibody (IgG1к) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of RSV. Palivizumab is a composite of human (95%) and murine (5%) antibody sequences. The human heavy chain sequence was derived from the constant domains of human IgG1 and the variable framework regions of the VH genes Cor and Cess. The human light chain sequence was derived from the constant domain of Cк and the variable framework regions of the VL gene K104 with Jк -4. The murine sequences were derived from a murine monoclonal antibody, Mab 1129, in a process that involved the grafting of the murine complementarity determining regions into the human antibody frameworks. Palivizumab is composed of two heavy chains and two light chains and has a molecular weight of approximately 148,000 Daltons. - Synagis is supplied as a sterile, preservative-free liquid solution at 100 mg per mL to be administered by intramuscular injection. Thimerosal or other mercury-containing salts are not used in the production of Synagis. The solution has a pH of 6.0 and should appear clear or slightly opalescent. - Each 100 mg single-dose vial of Synagis liquid solution contains 100 mg of palivizumab and also contains chloride (0.5 mg), glycine (0.1 mg), and histidine (3.9 mg), in a volume of 1 mL. - Each 50 mg single-dose vial of Synagis liquid solution contains 50 mg of palivizumab and also contains chloride (0.2 mg), glycine (0.06 mg), and histidine (1.9 mg), in a volume of 0.5 mL. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Palivizumab in the drug label. ## Pharmacokinetics - In children less than or equal to 24 months of age without congenital heart disease (CHD), the mean half-life of palivizumab was 20 days and monthly intramuscular doses of 15 mg per kg achieved mean ± SD 30 day trough serum drug concentrations of 37 ± 21 mcg per mL after the first injection, 57 ± 41 mcg per mL after the second injection, 68 ± 51 mcg per mL after the third injection, and 72 ± 50 mcg per mL after the fourth injection. Trough concentrations following the first and fourth Synagis dose were similar in children with CHD and in non-cardiac patients. In children given Synagis for a second season, the mean ± SD serum concentrations following the first and fourth injections were 61 ± 17 mcg per mL and 86 ± 31 mcg per mL, respectively. - In 139 children less than or equal to 24 months of age with hemodynamically significant CHD who received Synagis and underwent cardio-pulmonary bypass for open-heart surgery, the mean ± SD serum palivizumab concentration was 98 ± 52 mcg per mL before bypass and declined to 41 ± 33 mcg per mL after bypass, a reduction of 58%. The clinical significance of this reduction is unknown. - Specific studies were not conducted to evaluate the effects of demographic parameters on palivizumab systemic exposure. However, no effects of gender, age, body weight, or race on palivizumab serum trough concentrations were observed in a clinical study with 639 children with CHD (less than or equal to 24 months of age) receiving five monthly intramuscular injections of 15 mg per kg of Synagis. - The pharmacokinetics and safety of Synagis liquid solution and Synagis lyophilized formulation administered via intramuscular injection at 15 mg per kg were studied in a cross-over trial of 153 infants less than or equal to 6 months of age with a history of prematurity. The results of this trial indicated that the trough serum concentrations of palivizumab were comparable between the liquid solution and the lyophilized formulation, which was the formulation used in the clinical studies. - A population pharmacokinetic analysis was performed across 22 studies in 1800 patients (1684 pediatric and 116 adult patients) to characterize palivizumab pharmacokinetics and inter-subject variability in serum concentrations. Palivizumab pharmacokinetics was described by a two-compartment linear model with an elimination half-life of 24.5 days in pediatric patients. Clearance of palivizumab in a typical pediatric patient (body weight 4.5 kg) less than or equal to 24 months of age without CHD was estimated to be 11 mL per day with a bioavailability of 70% following intramuscular administration. The inter-patient variability in drug clearance was 48.7% (CV%). Covariate analysis did not identify any factors that could account for the inter-patient variability in order to predict serum concentrations a priori in an individual patient. - Mechanism of Action - Palivizumab, a recombinant humanized monoclonal antibody which provides passive immunity against - RSV, acts by binding the RSV envelope fusion protein (RSV F) on the surface of the virus and blocking a critical step in the membrane fusion process. Palivizumab also prevents cell-to-cell fusion of RSV-infected cells. - Antiviral Activity - The antiviral activity of palivizumab was assessed in a microneutralization assay in which increasing concentrations of antibody were incubated with RSV prior to addition of the human epithelial cells HEp-2. After incubation for 4-5 days, RSV antigen was measured in an ELISA assay. The neutralization titer (50% effective concentration [EC50]) is expressed as the antibody concentration required to reduce detection of RSV antigen by 50% compared with untreated virus-infected cells. Palivizumab exhibited median EC50 values of 0.65 mcg per mL (mean 0.75 ± 0.53 mcg per mL; n=69, range 0.07-2.89 mcg per mL) and 0.28 mcg per mL (mean 0.35 ± 0.23 mcg per mL; n=35, range 0.03-0.88 mcg per mL) against clinical RSV A and RSV B isolates, respectively. The majority of clinical RSV isolates tested (n=96) were collected from subjects across the United States (CA, CO, CT, IL, MA, NC, NY, PA, RI, TN, TX, VA), with the remainder from Japan (n=1), Australia (n=5) and Israel (n=2). These isolates encoded the most common RSV F sequence polymorphisms found among clinical isolates worldwide. - Palivizumab serum concentrations of greater than or equal to 40 mcg per mL have been shown to reduce pulmonary RSV replication in the cotton rat model of RSV infection by 100-fold. - Resistance - Palivizumab binds a highly conserved region on the extracellular domain of mature RSV F, referred to as antigenic site II or site A, which encompasses amino acids 262 to 275. All RSV mutants that exhibit resistance to palivizumab have been shown to contain amino acid changes in this region on the F protein. - F protein sequence variations within antigenic site A: Amino acid substitutions in antigenic site A selected either in cell culture, in animal models, or in human subjects that resulted in palivizumab resistance were N262D, N268I, K272E/M/N/Q/T, and S275F/L. RSV variants expressing the K272N substitution in F protein showed a 5164 ± 1731-fold decrease in susceptibility (i.e., fold increase in EC50 value) when compared to the wild-type RSV, while variants containing the N262D, S275F/L, or K272E/M/Q/T substitutions showed a greater than 25,000-fold decrease in susceptibility to palivizumab. The N268I substitution conferred partial resistance to palivizumab; however, fold changes in susceptibility were not quantified for this mutant. Studies carried out to investigate the mechanism of virus escape from palivizumab showed a correlation between antibody binding and virus neutralization. RSV with substitutions in antigenic site A that were resistant to neutralization by palivizumab did not bind to palivizumab. - At least one of the palivizumab resistance-associated substitutions, N262D, K272E/Q, or S275F/L was identified in 8 of 126 clinical RSV (59 RSV A and 67 RSV B) isolates from subjects who failed immunoprophylaxis, resulting in a combined resistance-associated mutation frequency of 6.3%. A review of clinical findings revealed no association between antigenic A site sequence changes and RSV disease severity among children receiving palivizumab immunoprophylaxis who develop RSV lower respiratory tract disease. - Analysis of 254 clinical RSV isolates (145 RSV A and 109 RSV B) collected from immunoprophylaxis-naïve subjects revealed palivizumab resistance-associated substitutions in 2 (1 with N262D and 1 with S275F), resulting in a resistance-associated mutation frequency of 0.79%. - F protein sequence variations outside antigenic site A: In addition to the sequence variations in antigenic site A known to confer palivizumab resistance, F protein substitutions T100A, G139S, N165D/V406I; T326A, V450A in RSV A, and T74I, A147V, I206L, S285G, V450I, T455I in RSV B were identified in viruses isolated from failures of immunoprophylaxis. These substitutions were not identified in RSV F sequences derived from 254 clinical isolates from immunoprophylaxis-naïve subjects and thus are considered treatment-associated and non-polymorphic. Recombinant RSV B encoding the S285G substitution exhibited palivizumab sensitivity (EC50 value = 0.39 ± 0.02 mcg per mL) similar to recombinant wild-type RSV B (EC50 value = 0.17 ± 0.02 mcg per mL). - Palivizumab susceptibility of RSV encoding common F protein sequence polymorphisms located proximal to antigenic site A was evaluated. Recombinant RSV A encoding N276S (EC50 value = 0.72 ± 0.07 mcg per mL), and recombinant RSV B with S276N (EC50 value = 0.42 ± 0.04 mcg per mL), exhibited sensitivities comparable to the corresponding recombinant wild-type RSV A (EC50 value = 0.63 ± 0.22 mcg per mL) and RSV B (EC50 value = 0.23 ± 0.07 mcg per mL). Likewise, RSV B clinical isolates containing the polymorphic variation V278A were at least as sensitive to neutralization by palivizumab (EC50 range 0.08-0.45 mcg per mL) as laboratory strains of wild-type RSV B (EC50 value = 0.54 ± 0.08 mcg per mL). No known polymorphic or non-polymorphic sequence variations outside the antigenic site A on RSV F have been demonstrated to render RSV resistant to neutralization by palivizumab. - Interference of RSV Diagnostic Assays by Palivizumab - Interference with immunologically-based RSV diagnostic assays by palivizumab has been observed in laboratory studies. Rapid chromatographic/enzyme immunoassays (CIA/EIA), immunofluorescence assays (IFA), and direct immunofluorescence assays (DFA) using monoclonal antibodies targeting RSV F protein may be inhibited. Therefore, caution should be used in interpreting negative immunological assay results when clinical observations are consistent with RSV infection. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay, which is not inhibited by palivizumab, may prove useful for laboratory confirmation of RSV infection. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Palivizumab in the drug label. # Clinical Studies - The safety and efficacy of Synagis were assessed in two randomized, double-blind, placebo-controlled trials of prophylaxis against RSV infection in children at high risk of an RSV-related hospitalization. Trial 1 was conducted during a single RSV season and studied a total of 1502 children less than or equal to 24 months of age with BPD or infants with premature birth (less than or equal to 35 weeks gestation) who were less than or equal to 6 months of age at study entry. Trial 2 was conducted over four consecutive seasons among a total of 1287 children less than or equal to 24 months of age with hemodynamically significant congenital heart disease. In both trials participants received 15 mg per kg Synagis or an equivalent volume of placebo via intramuscular injection monthly for five injections and were followed for 150 days from randomization. In Trial 1, 99% of all subjects completed the study and 93% completed all five injections. In Trial 2, 96% of all subjects completed the study and 92% completed all five injections. The incidence of RSV hospitalization is shown in Table 1. The results were shown to be statistically significant using Fisher’s exact test. - In Trial 1, the reduction of RSV hospitalization was observed both in children with BPD (34/266 [12.8%] placebo versus 39/496 [7.9%] Synagis) and in premature infants without BPD (19/234 [8.1%] placebo versus 9/506 [1.8%] Synagis). In Trial 2, reductions were observed in acyanotic (36/305 [11.8%] placebo versus 15/300 [5.0%] Synagis) and cyanotic children (27/343 [7.9%] placebo versus 19/339 [5.6%] Synagis). - The clinical studies do not suggest that RSV infection was less severe among children hospitalized with RSV infection who received Synagis for RSV prophylaxis compared to those who received placebo. # How Supplied - Synagis is supplied in single-dose vials as a preservative-free, sterile liquid solution at 100 mg per mL for intramuscular injection. - 50 mg vial NDC 60574-4114-1 - The 50 mg vial contains 50 mg Synagis in 0.5 mL. - 100 mg vial NDC 60574-4113-1 - The 100 mg vial contains 100 mg Synagis in 1 mL. - The rubber stopper used for sealing vials of Synagis is not made with natural rubber latex. - Storage - Upon receipt and until use, Synagis should be stored between 2°C and 8°C (36°F and 46°F) in its original container. DO NOT freeze. DO NOT use beyond the expiration date. ## Storage There is limited information regarding Palivizumab Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Read this Patient Information before your child starts receiving SYNAGIS and before each injection. The information may have changed. This leaflet does not take the place of talking with your child’s healthcare provider about your child’s condition or treatment. - SYNAGIS is a prescription medication that is used to help prevent a serious lung disease caused by Respiratory Syncytial Virus (RSV). Your child is prescribed SYNAGIS because he or she is at high risk for severe lung disease from RSV. - SYNAGIS contains man-made, disease-fighting proteins called antibodies. These antibodies help prevent RSV disease. Children at high risk for severe RSV disease often do not have enough of their own antibodies. SYNAGIS is used in certain groups of children to help prevent severe RSV disease by increasing protective RSV antibodies. - SYNAGIS is not used to treat the symptoms of RSV disease once a child already has it. It is only used to prevent RSV disease. - SYNAGIS is not for adults or for children older than 24 months of age at the start of dosing. - Your child should not receive SYNAGIS if they have ever had a severe allergic reaction to it. Signs and symptoms of a severe allergic reaction could include: - severe rash, hives, or itching skin - swelling of the lips, tongue, or face - closing of the throat, difficulty swallowing - difficult, rapid, or irregular breathing - bluish color of skin, lips, or under fingernails - muscle weakness or floppiness - a drop in blood pressure - unresponsiveness - Tell your child’s healthcare provider about: - any reactions you believe your child has ever had to SYNAGIS. - any bleeding or bruising problems. SYNAGIS is given by injection. If your child has a problem with bleeding or bruises easily, an injection could cause a problem. - any other medical problems. - Tell your child’s healthcare provider about all the medicines your child takes, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your child’s healthcare provider if your child takes a blood thinner medicine. - SYNAGIS is given as a monthly injection, usually in the thigh (leg) muscle, by your child’s healthcare provider. Your child’s healthcare provider will prescribe the amount of SYNAGIS that is right for your child (based on their weight). - Your child’s healthcare provider will give you detailed instructions on when SYNAGIS will be given. - “RSV season” is a term used to describe the time of year when RSV infections most commonly occur (usually fall through spring in most parts of the country). During this time, when RSV is most active, your child will need to receive SYNAGIS shots. Your child’s healthcare provider can tell you when the RSV season starts in your area. - Your child should receive their first SYNAGIS shot before the RSV season starts to help protect them before RSV becomes active. If the season has already started, your child should receive their first SYNAGIS shot as soon as possible to help protect them when exposure to the virus is more likely. - SYNAGIS is needed every 28-30 days during the RSV season. Each dose of SYNAGIS helps protect your child from severe RSV disease for about a month. Keep all appointments with your child’s healthcare provider. - If your child misses an injection, talk to your healthcare provider and schedule another injection as soon as possible. - Your child may still get severe RSV disease after receiving SYNAGIS; talk to your child’s healthcare provider about what symptoms to look for. If your child has an RSV infection, they should continue to get their scheduled SYNAGIS injections to help prevent severe disease from new RSV infections. - If your child has certain types of heart disease and has corrective surgery, your healthcare provider may need to give your child an additional SYNAGIS injection soon after surgery. - Synagis may cause serious side effects including: - Severe allergic reactions (may occur after any dose of SYNAGIS). Such reactions may be life-threatening or cause death. - See “Who should not take SYNAGIS?” for a list of signs and symptoms. - Unusual bruising or groups of tiny red spots on the skin. - Call your child’s healthcare provider or get medical help right away if your child has any of the serious side effects listed above after any dose of SYNAGIS. - Common side effects of SYNAGIS include: - fever - rash - Other possible side effects include skin reactions around the area where the shot was given (like redness, swelling, warmth, or discomfort). - These are not all the possible side effects of SYNAGIS. Tell your child’s healthcare provider about any side effect that bothers your child or that does not go away. - Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. - You may also report side effects to MedImmune at 1-877-633-4411. - Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. - This leaflet summarizes important information about SYNAGIS. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SYNAGIS that is written for health professionals. - For more information, go to www.synagis.com or call 1-877-633-4411. - Active Ingredient: palivizumab - Inactive Ingredients: chloride, glycine, and histidine - Respiratory Syncytial Virus (RSV) is a common virus that is easily spread from person to person. RSV infects nearly all children by their second birthday. In most children, RSV infection is usually no worse than a bad cold. For some children, RSV infection can cause serious lung disease (like pneumonia and bronchiolitis) or breathing problems, and affected children may need to be admitted to the hospital or need emergency care. - Children who are more likely to get severe RSV disease (high-risk children) include babies born prematurely (35 weeks or less) or babies born with certain heart or lung problems. - This Patient Information has been approved by the U.S. Food and Drug Administration. # Precautions with Alcohol - Alcohol-Palivizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Synagis®[2] # Look-Alike Drug Names - A® — B®[3] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Palivizumab
eb998f8166ce7518465f0025147592e2bafc886a	wikidoc	Pancuronium	Pancuronium # 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 Pancuronium is a skeletal muscle relaxant and neuromuscular blocking drugs that is FDA approved for the {{{indicationType}}} of general anesthesia; adjunct. There is a Black Box Warning for this drug as shown here. Common adverse reactions include musculoskeletal: prolonged neuromuscular block. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosage must be individualized - General anesthesia; adjunct: initial, 0.04 to 0.1 mg/kg IV (endotracheal intubation, 0.06 to 0.1 mg/kg IV); later incremental doses starting at 0.01 mg/kg may be used ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Induction of neuromuscular blockade - Percutaneous fetal procedure - Spasmodic torticollis ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pancuronium in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosage must be individualized - General anesthesia; adjunct: (all ages except neonates) initial, 0.04 to 0.1 mg/kg IV (endotracheal intubation, 0.06 to 0.1 mg/kg IV); later incremental doses starting at 0.01 mg/kg may be used - General anesthesia; adjunct: (neonates) administer a test dose of 0.02 mg/kg IV to measure responsiveness ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pancuronium in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pancuronium in pediatric patients. # Contraindications - Pancuronium Bromide Injection is contraindicated in patients known to be hypersensitive to the drug. # Warnings - Pancuronium bromide injection should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with its actions and the possible complications that might occur following its use. the drug should not be administered unless facilities for intubation, artificial respiration, oxygen therapy, and reversal agents are immediately available. the clinician must be prepared to assist or control respiration. - Severe anaphylactic reactions to neuromuscular blocking agents, including pancuronium bromide, have been reported. These reactions have in some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported in this class of drugs. - In patients who are known to have myasthenia gravis or the myasthenic (Eaton-Lambert) syndrome, small doses of pancuronium bromide may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants. - Benzyl alcohol has been reported to be associated with a fatal “gasping syndrome” in premature infants. - Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to those received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including pancuronium) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of pancuronium bromide for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse reaction to nondepolarizing blocking agents as a class consists of an extension of the drug’s pharmacological action beyond the time period needed. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiratory insufficiency or apnea. (See Precautions: Pediatric Use). - Inadequate reversal of the neuromuscular blockade is possible with pancuronium bromide as with all curariform drugs. These adverse experiences are managed by manual or mechanical ventilation until recovery is judged adequate. - Prolonged paralysis and/or skeletal muscle weakness have been reported after long-term use to support mechanical ventilation in the intensive care unit. - See discussion of circulatory effects in Clinical pharmacology. - Salivation is sometimes noted during very light anesthesia, especially if no anticholinergic premedication is used. - An occasional transient rash is noted accompanying the use of pancuronium bromide. - Although histamine release is not a characteristic action of pancuronium bromide, rare hypersensitivity reactions such as bronchospasm, flushing, redness, hypotension, tachycardia and other reactions possibly mediated by histamine release have been reported. - There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including pancuronium bromide. These reactions, in some cases, have been life threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see Warnings and Precautions). ## Postmarketing Experience There is limited information regarding Pancuronium Postmarketing Experience in the drug label. # Drug Interactions - Prior administration of succinylcholine may enhance the neuromuscular blocking effect of pancuronium and increase its duration of action. If succinylcholine is used before pancuronium bromide, the administration of pancuronium bromide should be delayed until the patient starts recovering from succinylcholine-induced neuromuscular blockade. - If a small dose of pancuronium bromide is given at least 3 minutes prior to the administration of succinylcholine, in order to reduce the incidence and intensity of succinylcholine-induced fasciculations, this dose may induce a degree of neuromuscular block sufficient to cause respiratory depression in some patients. - Other nondepolarizing neuromuscular blocking agents (vecuronium, atracurium, d-tubocurarine, metocurine, and gallamine) behave in a clinically similar fashion to pancuronium bromide. The combination of pancuronium bromide-metocurine and pancuronium bromide-d-tubocurarine are significantly more potent than the additive effects of each of the individual drugs given alone, however, the duration of blockade of these combinations is not prolonged. There are insufficient data to support concomitant use of pancuronium and the other three above mentioned muscle relaxants in the same patient. - Use of volatile inhalational anesthetics such as enflurane, isoflurane, and halothane with pancuronium bromide will enhance neuromuscular blockade. Potentiation is most prominent with use of enflurane and isoflurane. - With the above agents, the intubating dose of pancuronium bromide may be the same as with balanced anesthesia unless the inhalational anesthetic has been administered for a sufficient time at a sufficient dose to have reached clinical equilibrium. The relatively long duration of action of pancuronium should be taken into consideration when the drug is selected for intubation in these circumstances. - Clinical experience and animal experiments suggest that pancuronium should be given with caution to patients receiving chronic tricyclic antidepressant therapy who are anesthetized with halothane because severe ventricular arrhythmias may result from this combination. The severity of the arrhythmias appear in part related to the dose of pancuronium. - Parenteral/intraperitoneal administration of high doses of certain antibiotics may intensify or produce neuromuscular block on their own. The following antibiotics have been associated with various degrees of paralysis: aminoglycosides (such as neomycin, streptomycin, kanamycin, gentamicin, and dihydrostreptomycin); tetracyclines; bacitracin; polymyxin B; colistin; and sodium colistimethate. If these or other newly introduced antibiotics are used preoperatively or in conjunction with pancuronium bromide, unexpected prolongation of neuromuscular block should be considered a possibility. - Experience concerning injection of quinidine during recovery from use of other muscle relaxants suggests that recurrent paralysis may occur. This possibility must also be considered for pancuronium bromide. - Electrolyte imbalance and diseases which lead to electrolyte imbalance, such as adrenal cortical insufficiency, have been shown to alter neuromuscular blockade. Depending on the nature of the imbalance, either enhancement or inhibition may be expected. Magnesium salts, administered for the management of toxemia of pregnancy, may enhance the neuromuscular blockade. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been performed. It is not known whether pancuronium bromide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pancuronium bromide should be given to a pregnant woman only if the administering clinician decides that the benefits outweigh the risks. - Pancuronium bromide may be used in operative obstetrics (Caesarean Section), but reversal of pancuronium may be unsatisfactory in patients receiving magnesium sulfate for toxemia of pregnancy because magnesium salts enhance neuromuscular blockade. Dosage should usually be reduced, as indicated, in such cases. It is also recommended that the interval between use of pancuronium and delivery be reasonably short to avoid clinically significant placental transfer. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pancuronium in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Pancuronium during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Pancuronium in women who are nursing. ### Pediatric Use - Dose response studies in children indicate that, with the exception of neonates, dosage requirements are the same as for adults. Neonates are especially sensitive to nondepolarizing neuromuscular blocking agents, such as pancuronium bromide, during the first month of life. It is recommended that a test dose of 0.02 mg/kg be given first in this group to measure responsiveness. - The prolonged use of pancuronium bromide for the management of neonates undergoing mechanical ventilation has been associated in rare cases with severe skeletal muscle weakness that may first be noted during attempts to wean such patients from the ventilator; such patients usually receive other drugs such as antibiotics which may enhance neuromuscular blockade. Microscopic changes consistent with disuse atrophy have been noted at autopsy. Although a cause-and-effect relationship has not been established, the benefits-to-risk ratio must be considered when there is a need for neuromuscular blockade to facilitate long-term mechanical ventilation of neonates. - Rare cases of unexplained, clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included combined use of pancuronium, fentanyl and atropine. A direct cause-and-effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established ### Geriatic Use There is no FDA guidance on the use of Pancuronium in geriatric settings. ### Gender There is no FDA guidance on the use of Pancuronium with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pancuronium with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Pancuronium in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Pancuronium in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pancuronium in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pancuronium in patients who are immunocompromised. # Administration and Monitoring ### Administration - Pancuronium Bromide Injection is for intravenous use only. This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only. Since potent inhalational anesthetics or prior use of succinylcholine may enhance the intensity and duration of pancuronium bromide (see Precautions: Drug Interactions), the lower end of the recommended initial dosage range may suffice when pancuronium bromide is first used after intubation with succinylcholine and/or after maintenance doses of volatile liquid inhalational anesthetics are started. To obtain maximum clinical benefits of Pancuronium Bromide Injection and to minimize the possibility of overdosage, the monitoring of muscle twitch response to a peripheral nerve stimulator is advised. - In adults under balanced anesthesia the initial intravenous dosage range is 0.04 to 0.1 mg/kg. Later incremental doses starting at 0.01 mg/kg may be used. These increments slightly increase the magnitude of the blockade and significantly increase the duration of blockade because a significant number of myoneural junctions are still blocked when there is clinical need for more drug. - If Pancuronium Bromide Injection is used to provide skeletal muscle relaxation for endotracheal intubation, a bolus dose of 0.06 to 0.1 mg/kg is recommended. Conditions satisfactory for intubation are usually present within 2 to 3 minutes (see Precautions). - Dose response studies in children indicate that, with the exception of neonates, dosage requirements are the same as for adults. Neonates are especially sensitive to nondepolarizing neuromuscular blocking agents, such as Pancuronium Bromide Injection, during the first month of life. It is recommended that a test dose of 0.02 mg/kg be given first in this group to measure responsiveness. - The dosage to provide relaxation for intubation and operation is the same as for general surgical procedures. The dosage to provide relaxation, following usage of succinylcholine for intubation (see Precautions: Drug Interactions), is the same as for general surgical procedures. ### Monitoring There is limited information regarding Pancuronium Monitoring in the drug label. # IV Compatibility - Pancuronium Bromide Injection is compatible in solution with: - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - When mixed with the above solutions in glass or plastic containers, Pancuronium Bromide Injection will remain stable in solution for 48 hours with no alteration in potency or pH; no decomposition is observed and there is no absorption to either the glass or plastic container. # Overdosage - The possibility of iatrogenic overdosage can be minimized by carefully monitoring the muscle twitch response to peripheral nerve stimulation. - Excessive doses of pancuronium bromide can be expected to produce enhanced pharmacological effects. Residual neuromuscular blockade beyond the time period needed may occur with pancuronium bromide as with other neuromuscular blockers. This may be manifested by skeletal muscle weakness, decreased respiratory reserve, low tidal volume, or apnea. A peripheral nerve stimulator may be used to assess the degree of residual neuromuscular blockade and help to differentiate residual neuromuscular blockade from other causes of decreased respiratory reserve. - Pyridostigmine bromide, neostigmine, or edrophonium, in conjunction with atropine or glycopyrrolate, will usually antagonize the skeletal muscle relaxant action of pancuronium bromide. Satisfactory reversal can be judged by adequacy of skeletal muscle tone and by adequacy of respiration. A peripheral nerve stimulator may also be used to monitor restoration of twitch response. - Failure of prompt reversal (within 30 minutes) may occur in the presence of extreme debilitation, carcinomatosis, and with concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or cause respiratory depression of their own. Under such circumstances, the management is the same as that of prolonged neuromuscular blockade. Ventilation must be supported by artificial means until the patient has resumed control of his respiration. Prior to the use of reversal agents, reference should be made to the specific package insert of the reversal agent. # Pharmacology ## Mechanism of Action - Pancuronium bromide is a nondepolarizing neuromuscular blocking agent possessing all of the characteristic pharmacological actions of this class of drugs (curariform). It acts by competing for cholinergic receptors at the motor end-plate. The antagonism to acetylcholine is inhibited; and neuromuscular block is reversed by anticholinesterase agents such as pyridostigmine, neostigmine, and edrophonium. Pancuronium bromide is approximately 1/3 less potent than vecuronium and approximately 5 times as potent as d-tubocurarine: the duration of neuromuscular blockage produced by pancuronium bromide is longer than that of vecuronium at initially equipotent doses. ## Structure - Pancuronium Bromide is a nondepolarizing neuromuscular blocking agent chemically designated as the aminosteroid 2β, 16β - dipiperidino-5α-androstane-3α, 17-β diol diacetate dimethobromide, C35H60Br2N2O4. It is a fine white odorless powder which is soluble in water, alcohol and chloroform. - It has the following structural formula: - Pancuronium Bromide Injection is available in sterile, isotonic, nonpyrogenic solution for injection. Each mL contains pancuronium bromide 1 mg; sodium acetate, anhydrous 1.2 mg; benzyl alcohol 10 mg as preservative. Sodium chloride added to adjust tonicity. May contain acetic acid and/or sodium hydroxide for pH adjustment. pH is 4.0 (3.8 to 4.2). ## Pharmacodynamics The ED95 (dose required to produce 95% suppression of muscle twitch response) is approximately 0.05 mg/kg under balanced anesthesia and 0.03 mg/kg under halothane anesthesia. These doses produce effective skeletal muscle relaxation (as judged by time from maximum effect to 25% recovery of control twitch height) for approximately 22 minutes; the duration from injection to 90% recovery of control twitch height is approximately 65 minutes. The intubating dose of 0.1 mg/kg (balanced anesthesia) will effectively abolish twitch response within approximately 4 minutes; time from injection to 25% recovery from this dose is approximately 100 minutes. - Supplemental doses to maintain muscle relaxation slightly increase the magnitude of block and significantly increase the duration of block. The use of a peripheral nerve stimulator is of benefit in assessing the degree of neuromuscular blockade. - The most characteristic circulatory effects of pancuronium, studied under halothane anesthesia, are a moderate rise in heart rate, mean arterial pressure and cardiac output; systemic vascular resistance is not changed significantly, and central venous pressure may fall slightly. The heart rate rise is inversely related to the rate immediately before administration of pancuronium, is blocked by prior administration of atropine, and appears unrelated to the concentration of halothane or dose of pancuronium. - Data on histamine assays and available clinical experience indicate that hypersensitivity reactions such as bronchospasm, flushing, redness, hypotension, tachycardia, and other reactions commonly associated with histamine release are rare. (See Adverse reactions). ## Pharmacokinetics - The elimination half-life of pancuronium has been reported to range between 89-161 minutes. The volume of distribution ranges from 241-280 mL/kg; and plasma clearance is approximately 1.1−1.9 mL/minute/kg. Approximately 40% of the total dose of pancuronium has been recovered in urine as unchanged pancuronium and its metabolites while approximately 11% has been recovered in bile. As much as 25% of an injected dose may be recovered as 3-hydroxy metabolite, which is half as potent a blocking agent as pancuronium. Less than 5% of the injected dose is recovered as 17-hydroxy metabolite and 3,17-dihydroxy metabolite, which have been judged to be approximately 50 times less potent than pancuronium. Pancuronium exhibits strong binding to gamma globulin and moderate binding to albumin. Approximately 13% is unbound to plasma protein. In patients with cirrhosis the volume of distribution is increased by approximately 50%, the plasma clearance is decreased by approximately 22%, and the elimination half-life is doubled. Similar results were noted in patients with biliary obstruction, except that plasma clearance was less than half the normal rate. The initial total dose to achieve adequate relaxation may, thus, be high in patients with hepatic and/or biliary tract dysfunction, while the duration of action is greater than usual. - The elimination half-life is doubled, and the plasma clearance is reduced by approximately 60% in patients with renal failure. The volume of distribution is variable, and in some cases elevated. The rate of recovery of neuromuscular blockade, as determined by peripheral nerve stimulation is variable and sometimes very much slower than normal. ## Nonclinical Toxicology There is limited information regarding Pancuronium Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Pancuronium Clinical Studies in the drug label. # How Supplied - Pancuronium Bromide Injection is supplied as follows: ## Storage - Store in refrigerator 2° to 8°C (36° to 46°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Pancuronium Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Pancuronium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Pancuronium Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Pancuronium Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Pancuronium Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Pancuronium is a skeletal muscle relaxant and neuromuscular blocking drugs that is FDA approved for the {{{indicationType}}} of general anesthesia; adjunct. There is a Black Box Warning for this drug as shown here. Common adverse reactions include musculoskeletal: prolonged neuromuscular block. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosage must be individualized - General anesthesia; adjunct: initial, 0.04 to 0.1 mg/kg IV (endotracheal intubation, 0.06 to 0.1 mg/kg IV); later incremental doses starting at 0.01 mg/kg may be used ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Induction of neuromuscular blockade - Percutaneous fetal procedure - Spasmodic torticollis ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pancuronium in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosage must be individualized - General anesthesia; adjunct: (all ages except neonates) initial, 0.04 to 0.1 mg/kg IV (endotracheal intubation, 0.06 to 0.1 mg/kg IV); later incremental doses starting at 0.01 mg/kg may be used - General anesthesia; adjunct: (neonates) administer a test dose of 0.02 mg/kg IV to measure responsiveness ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pancuronium in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pancuronium in pediatric patients. # Contraindications - Pancuronium Bromide Injection is contraindicated in patients known to be hypersensitive to the drug. # Warnings - Pancuronium bromide injection should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with its actions and the possible complications that might occur following its use. the drug should not be administered unless facilities for intubation, artificial respiration, oxygen therapy, and reversal agents are immediately available. the clinician must be prepared to assist or control respiration. - Severe anaphylactic reactions to neuromuscular blocking agents, including pancuronium bromide, have been reported. These reactions have in some cases been life-threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should be taken in those individuals who have had previous anaphylactic reactions to other neuromuscular blocking agents since cross-reactivity between neuromuscular blocking agents, both depolarizing and non-depolarizing, has been reported in this class of drugs. - In patients who are known to have myasthenia gravis or the myasthenic (Eaton-Lambert) syndrome, small doses of pancuronium bromide may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants. - Benzyl alcohol has been reported to be associated with a fatal “gasping syndrome” in premature infants. - Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to those received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including pancuronium) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of pancuronium bromide for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources. # Adverse Reactions ## Clinical Trials Experience - The most frequent adverse reaction to nondepolarizing blocking agents as a class consists of an extension of the drug’s pharmacological action beyond the time period needed. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiratory insufficiency or apnea. (See Precautions: Pediatric Use). - Inadequate reversal of the neuromuscular blockade is possible with pancuronium bromide as with all curariform drugs. These adverse experiences are managed by manual or mechanical ventilation until recovery is judged adequate. - Prolonged paralysis and/or skeletal muscle weakness have been reported after long-term use to support mechanical ventilation in the intensive care unit. - See discussion of circulatory effects in Clinical pharmacology. - Salivation is sometimes noted during very light anesthesia, especially if no anticholinergic premedication is used. - An occasional transient rash is noted accompanying the use of pancuronium bromide. - Although histamine release is not a characteristic action of pancuronium bromide, rare hypersensitivity reactions such as bronchospasm, flushing, redness, hypotension, tachycardia and other reactions possibly mediated by histamine release have been reported. - There have been post-marketing reports of severe allergic reactions (anaphylactic and anaphylactoid reactions) associated with use of neuromuscular blocking agents, including pancuronium bromide. These reactions, in some cases, have been life threatening and fatal. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency (see Warnings and Precautions). ## Postmarketing Experience There is limited information regarding Pancuronium Postmarketing Experience in the drug label. # Drug Interactions - Prior administration of succinylcholine may enhance the neuromuscular blocking effect of pancuronium and increase its duration of action. If succinylcholine is used before pancuronium bromide, the administration of pancuronium bromide should be delayed until the patient starts recovering from succinylcholine-induced neuromuscular blockade. - If a small dose of pancuronium bromide is given at least 3 minutes prior to the administration of succinylcholine, in order to reduce the incidence and intensity of succinylcholine-induced fasciculations, this dose may induce a degree of neuromuscular block sufficient to cause respiratory depression in some patients. - Other nondepolarizing neuromuscular blocking agents (vecuronium, atracurium, d-tubocurarine, metocurine, and gallamine) behave in a clinically similar fashion to pancuronium bromide. The combination of pancuronium bromide-metocurine and pancuronium bromide-d-tubocurarine are significantly more potent than the additive effects of each of the individual drugs given alone, however, the duration of blockade of these combinations is not prolonged. There are insufficient data to support concomitant use of pancuronium and the other three above mentioned muscle relaxants in the same patient. - Use of volatile inhalational anesthetics such as enflurane, isoflurane, and halothane with pancuronium bromide will enhance neuromuscular blockade. Potentiation is most prominent with use of enflurane and isoflurane. - With the above agents, the intubating dose of pancuronium bromide may be the same as with balanced anesthesia unless the inhalational anesthetic has been administered for a sufficient time at a sufficient dose to have reached clinical equilibrium. The relatively long duration of action of pancuronium should be taken into consideration when the drug is selected for intubation in these circumstances. - Clinical experience and animal experiments suggest that pancuronium should be given with caution to patients receiving chronic tricyclic antidepressant therapy who are anesthetized with halothane because severe ventricular arrhythmias may result from this combination. The severity of the arrhythmias appear in part related to the dose of pancuronium. - Parenteral/intraperitoneal administration of high doses of certain antibiotics may intensify or produce neuromuscular block on their own. The following antibiotics have been associated with various degrees of paralysis: aminoglycosides (such as neomycin, streptomycin, kanamycin, gentamicin, and dihydrostreptomycin); tetracyclines; bacitracin; polymyxin B; colistin; and sodium colistimethate. If these or other newly introduced antibiotics are used preoperatively or in conjunction with pancuronium bromide, unexpected prolongation of neuromuscular block should be considered a possibility. - Experience concerning injection of quinidine during recovery from use of other muscle relaxants suggests that recurrent paralysis may occur. This possibility must also be considered for pancuronium bromide. - Electrolyte imbalance and diseases which lead to electrolyte imbalance, such as adrenal cortical insufficiency, have been shown to alter neuromuscular blockade. Depending on the nature of the imbalance, either enhancement or inhibition may be expected. Magnesium salts, administered for the management of toxemia of pregnancy, may enhance the neuromuscular blockade. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Animal reproduction studies have not been performed. It is not known whether pancuronium bromide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pancuronium bromide should be given to a pregnant woman only if the administering clinician decides that the benefits outweigh the risks. - Pancuronium bromide may be used in operative obstetrics (Caesarean Section), but reversal of pancuronium may be unsatisfactory in patients receiving magnesium sulfate for toxemia of pregnancy because magnesium salts enhance neuromuscular blockade. Dosage should usually be reduced, as indicated, in such cases. It is also recommended that the interval between use of pancuronium and delivery be reasonably short to avoid clinically significant placental transfer. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pancuronium in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Pancuronium during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Pancuronium in women who are nursing. ### Pediatric Use - Dose response studies in children indicate that, with the exception of neonates, dosage requirements are the same as for adults. Neonates are especially sensitive to nondepolarizing neuromuscular blocking agents, such as pancuronium bromide, during the first month of life. It is recommended that a test dose of 0.02 mg/kg be given first in this group to measure responsiveness. - The prolonged use of pancuronium bromide for the management of neonates undergoing mechanical ventilation has been associated in rare cases with severe skeletal muscle weakness that may first be noted during attempts to wean such patients from the ventilator; such patients usually receive other drugs such as antibiotics which may enhance neuromuscular blockade. Microscopic changes consistent with disuse atrophy have been noted at autopsy. Although a cause-and-effect relationship has not been established, the benefits-to-risk ratio must be considered when there is a need for neuromuscular blockade to facilitate long-term mechanical ventilation of neonates. - Rare cases of unexplained, clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included combined use of pancuronium, fentanyl and atropine. A direct cause-and-effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established ### Geriatic Use There is no FDA guidance on the use of Pancuronium in geriatric settings. ### Gender There is no FDA guidance on the use of Pancuronium with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pancuronium with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Pancuronium in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Pancuronium in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pancuronium in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pancuronium in patients who are immunocompromised. # Administration and Monitoring ### Administration - Pancuronium Bromide Injection is for intravenous use only. This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only. Since potent inhalational anesthetics or prior use of succinylcholine may enhance the intensity and duration of pancuronium bromide (see Precautions: Drug Interactions), the lower end of the recommended initial dosage range may suffice when pancuronium bromide is first used after intubation with succinylcholine and/or after maintenance doses of volatile liquid inhalational anesthetics are started. To obtain maximum clinical benefits of Pancuronium Bromide Injection and to minimize the possibility of overdosage, the monitoring of muscle twitch response to a peripheral nerve stimulator is advised. - In adults under balanced anesthesia the initial intravenous dosage range is 0.04 to 0.1 mg/kg. Later incremental doses starting at 0.01 mg/kg may be used. These increments slightly increase the magnitude of the blockade and significantly increase the duration of blockade because a significant number of myoneural junctions are still blocked when there is clinical need for more drug. - If Pancuronium Bromide Injection is used to provide skeletal muscle relaxation for endotracheal intubation, a bolus dose of 0.06 to 0.1 mg/kg is recommended. Conditions satisfactory for intubation are usually present within 2 to 3 minutes (see Precautions). - Dose response studies in children indicate that, with the exception of neonates, dosage requirements are the same as for adults. Neonates are especially sensitive to nondepolarizing neuromuscular blocking agents, such as Pancuronium Bromide Injection, during the first month of life. It is recommended that a test dose of 0.02 mg/kg be given first in this group to measure responsiveness. - The dosage to provide relaxation for intubation and operation is the same as for general surgical procedures. The dosage to provide relaxation, following usage of succinylcholine for intubation (see Precautions: Drug Interactions), is the same as for general surgical procedures. ### Monitoring There is limited information regarding Pancuronium Monitoring in the drug label. # IV Compatibility - Pancuronium Bromide Injection is compatible in solution with: - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - When mixed with the above solutions in glass or plastic containers, Pancuronium Bromide Injection will remain stable in solution for 48 hours with no alteration in potency or pH; no decomposition is observed and there is no absorption to either the glass or plastic container. # Overdosage - The possibility of iatrogenic overdosage can be minimized by carefully monitoring the muscle twitch response to peripheral nerve stimulation. - Excessive doses of pancuronium bromide can be expected to produce enhanced pharmacological effects. Residual neuromuscular blockade beyond the time period needed may occur with pancuronium bromide as with other neuromuscular blockers. This may be manifested by skeletal muscle weakness, decreased respiratory reserve, low tidal volume, or apnea. A peripheral nerve stimulator may be used to assess the degree of residual neuromuscular blockade and help to differentiate residual neuromuscular blockade from other causes of decreased respiratory reserve. - Pyridostigmine bromide, neostigmine, or edrophonium, in conjunction with atropine or glycopyrrolate, will usually antagonize the skeletal muscle relaxant action of pancuronium bromide. Satisfactory reversal can be judged by adequacy of skeletal muscle tone and by adequacy of respiration. A peripheral nerve stimulator may also be used to monitor restoration of twitch response. - Failure of prompt reversal (within 30 minutes) may occur in the presence of extreme debilitation, carcinomatosis, and with concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular blockade or cause respiratory depression of their own. Under such circumstances, the management is the same as that of prolonged neuromuscular blockade. Ventilation must be supported by artificial means until the patient has resumed control of his respiration. Prior to the use of reversal agents, reference should be made to the specific package insert of the reversal agent. # Pharmacology ## Mechanism of Action - Pancuronium bromide is a nondepolarizing neuromuscular blocking agent possessing all of the characteristic pharmacological actions of this class of drugs (curariform). It acts by competing for cholinergic receptors at the motor end-plate. The antagonism to acetylcholine is inhibited; and neuromuscular block is reversed by anticholinesterase agents such as pyridostigmine, neostigmine, and edrophonium. Pancuronium bromide is approximately 1/3 less potent than vecuronium and approximately 5 times as potent as d-tubocurarine: the duration of neuromuscular blockage produced by pancuronium bromide is longer than that of vecuronium at initially equipotent doses. ## Structure - Pancuronium Bromide is a nondepolarizing neuromuscular blocking agent chemically designated as the aminosteroid 2β, 16β - dipiperidino-5α-androstane-3α, 17-β diol diacetate dimethobromide, C35H60Br2N2O4. It is a fine white odorless powder which is soluble in water, alcohol and chloroform. - It has the following structural formula: - Pancuronium Bromide Injection is available in sterile, isotonic, nonpyrogenic solution for injection. Each mL contains pancuronium bromide 1 mg; sodium acetate, anhydrous 1.2 mg; benzyl alcohol 10 mg as preservative. Sodium chloride added to adjust tonicity. May contain acetic acid and/or sodium hydroxide for pH adjustment. pH is 4.0 (3.8 to 4.2). ## Pharmacodynamics The ED95 (dose required to produce 95% suppression of muscle twitch response) is approximately 0.05 mg/kg under balanced anesthesia and 0.03 mg/kg under halothane anesthesia. These doses produce effective skeletal muscle relaxation (as judged by time from maximum effect to 25% recovery of control twitch height) for approximately 22 minutes; the duration from injection to 90% recovery of control twitch height is approximately 65 minutes. The intubating dose of 0.1 mg/kg (balanced anesthesia) will effectively abolish twitch response within approximately 4 minutes; time from injection to 25% recovery from this dose is approximately 100 minutes. - Supplemental doses to maintain muscle relaxation slightly increase the magnitude of block and significantly increase the duration of block. The use of a peripheral nerve stimulator is of benefit in assessing the degree of neuromuscular blockade. - The most characteristic circulatory effects of pancuronium, studied under halothane anesthesia, are a moderate rise in heart rate, mean arterial pressure and cardiac output; systemic vascular resistance is not changed significantly, and central venous pressure may fall slightly. The heart rate rise is inversely related to the rate immediately before administration of pancuronium, is blocked by prior administration of atropine, and appears unrelated to the concentration of halothane or dose of pancuronium. - Data on histamine assays and available clinical experience indicate that hypersensitivity reactions such as bronchospasm, flushing, redness, hypotension, tachycardia, and other reactions commonly associated with histamine release are rare. (See Adverse reactions). ## Pharmacokinetics - The elimination half-life of pancuronium has been reported to range between 89-161 minutes. The volume of distribution ranges from 241-280 mL/kg; and plasma clearance is approximately 1.1−1.9 mL/minute/kg. Approximately 40% of the total dose of pancuronium has been recovered in urine as unchanged pancuronium and its metabolites while approximately 11% has been recovered in bile. As much as 25% of an injected dose may be recovered as 3-hydroxy metabolite, which is half as potent a blocking agent as pancuronium. Less than 5% of the injected dose is recovered as 17-hydroxy metabolite and 3,17-dihydroxy metabolite, which have been judged to be approximately 50 times less potent than pancuronium. Pancuronium exhibits strong binding to gamma globulin and moderate binding to albumin. Approximately 13% is unbound to plasma protein. In patients with cirrhosis the volume of distribution is increased by approximately 50%, the plasma clearance is decreased by approximately 22%, and the elimination half-life is doubled. Similar results were noted in patients with biliary obstruction, except that plasma clearance was less than half the normal rate. The initial total dose to achieve adequate relaxation may, thus, be high in patients with hepatic and/or biliary tract dysfunction, while the duration of action is greater than usual. - The elimination half-life is doubled, and the plasma clearance is reduced by approximately 60% in patients with renal failure. The volume of distribution is variable, and in some cases elevated. The rate of recovery of neuromuscular blockade, as determined by peripheral nerve stimulation is variable and sometimes very much slower than normal. ## Nonclinical Toxicology There is limited information regarding Pancuronium Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Pancuronium Clinical Studies in the drug label. # How Supplied - Pancuronium Bromide Injection is supplied as follows: ## Storage - Store in refrigerator 2° to 8°C (36° to 46°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Pancuronium Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Pancuronium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Pancuronium Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Pancuronium Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Pancuronium
baf0f4a09ca45ab3ec99b9a5d14b9d6c7f093038	wikidoc	Paneth cell	Paneth cell # Overview Paneth cells provide host defense against microbes in the small intestine. They are functionally similar to neutrophils. When exposed to bacteria or bacterial antigens, Paneth cells secrete a number of antimicrobial molecules into the lumen of the crypt, thereby contributing to maintenance of the gastrointestinal barrier. Paneth cells are named after Joseph Paneth (1857–1890), Austrian physician. # Stem cells Small intestinal crypts house stem cells that serve to constantly replenish epithelial cells that die and are lost from the villi. Protection of these stem cells is essential for long-term maintenance of the intestinal epithelium, and the location of Paneth cells adjacent to stem cells suggests that they play a critical role in defending epithelial cell renewal. # Secretions ## Defensins The principal defense molecules secreted by Paneth cells are alpha-defensins, also known as cryptdin. These peptides have hydrophobic and positively-charged domains that can interact with phospholipids in cell membranes. This structure allows defensins to insert into membranes, where they interact with one another to form pores that disrupt membrane function, leading to cell lysis. Due to the higher concentration of negatively-charged phospholipids in bacterial than vertebrate cell membranes, defensins preferentially bind to and disrupt bacterial cells, sparing the cells they are functioning to protect. Paneth cells are stimulated to secrete defensins when exposed to bacteria (both Gram positive and negative types) or such bacterial products as lipopolysaccharide, muramyl dipeptide and lipid A. ## Other secretions In addition to defensins, Paneth cells secrete lysozyme and phospholipase A2, both of which have clear antimicrobial activity. This battery of secretory molecules gives Paneth cells a potent arsenal against a broad spectrum of agents, including bacteria, fungi and even some enveloped viruses.	Paneth cell # Overview Paneth cells provide host defense against microbes in the small intestine. They are functionally similar to neutrophils. When exposed to bacteria or bacterial antigens, Paneth cells secrete a number of antimicrobial molecules into the lumen of the crypt, thereby contributing to maintenance of the gastrointestinal barrier. Paneth cells are named after Joseph Paneth (1857–1890), Austrian physician. # Stem cells Small intestinal crypts house stem cells that serve to constantly replenish epithelial cells that die and are lost from the villi. Protection of these stem cells is essential for long-term maintenance of the intestinal epithelium, and the location of Paneth cells adjacent to stem cells suggests that they play a critical role in defending epithelial cell renewal. # Secretions ## Defensins The principal defense molecules secreted by Paneth cells are alpha-defensins, also known as cryptdin.[1] These peptides have hydrophobic and positively-charged domains that can interact with phospholipids in cell membranes. This structure allows defensins to insert into membranes, where they interact with one another to form pores that disrupt membrane function, leading to cell lysis. Due to the higher concentration of negatively-charged phospholipids in bacterial than vertebrate cell membranes, defensins preferentially bind to and disrupt bacterial cells, sparing the cells they are functioning to protect.[2] Paneth cells are stimulated to secrete defensins when exposed to bacteria (both Gram positive and negative types) or such bacterial products as lipopolysaccharide, muramyl dipeptide and lipid A. ## Other secretions In addition to defensins, Paneth cells secrete lysozyme and phospholipase A2, both of which have clear antimicrobial activity. This battery of secretory molecules gives Paneth cells a potent arsenal against a broad spectrum of agents, including bacteria, fungi and even some enveloped viruses.	https://www.wikidoc.org/index.php/Paneth_cell
a1d18b9ea8fc3935917593df76f92d42a5ac6af0	wikidoc	Panitumumab	Panitumumab # 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 Panitumumab is an Immunological Agent and Monoclonal Antibody that is FDA approved for the treatment of metastatic colorectal cancer with wild-type KRAS (exon 2 in codons 12 or 13) as first-line therapy in combination with FOLFOX, monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash with variable presentations, paronychia, fatigue, nausea, and diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, acneiform dermatitis, pruritus, and dry skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Patient Selection - Prior to initiation of treatment with Panitumumab, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: . ## Recommended Dose - The recommended dose of Panitumumab is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes . - Appropriate medical resources for the treatment of severe infusion reactions should be available during Panitumumab infusions. ## Dose Modifications - Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. - Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Panitumumab. - Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Panitumumab. If the reaction improves to < grade 3, reinitiate Panitumumab at the original dose. - Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Panitumumab. If the reaction improves to < grade 3, reinitiate Panitumumab at 80% of the original dose. - Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Panitumumab. If the reaction improves to < grade 3, reinitiate Panitumumab at 60% of the original dose. - Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Panitumumab. - Permanently discontinue Panitumumab following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. ## Preparation and Administration - Do not administer Panitumumab as an intravenous push or bolus. Prepare the solution for infusion, using aseptic technique, as follows: - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. *Although Panitumumab should be colorless, the solution may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates (which will be removed by filtration; see below). - Do not shake. - Do not administer Panitumumab if discoloration is observed. - Withdraw the necessary amount of Panitumumab for a dose of 6 mg/kg. - Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. - Mix diluted solution by gentle inversion. Do not shake. - Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter. - Panitumumab must be administered via infusion pump. Flush line before and after Panitumumab administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Panitumumab with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab. Infuse doses of 1000 mg or lower over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes. - Flush line before and after Panitumumab administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Panitumumab with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab. - Infuse doses of 1000 mg or lower over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes. - Use the diluted infusion solution of Panitumumab within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36º to 46ºF). DO NOT FREEZE. - Discard any unused portion remaining in the vial. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Panitumumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Panitumumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Panitumumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Panitumumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Panitumumab in pediatric patients. # Contraindications - None. # Warnings ### Dermatologic and Soft Tissue Toxicity - In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Panitumumab The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. - Monitor patients who develop dermatologic or soft tissue toxicities while receiving Panitumumab for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Panitumumab. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Panitumumab It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Panitumumab for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Panitumumab concerning dermatologic toxicity are provided. ### Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS- and KRAS-Mutant mCRC - A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Panitumumab and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory. - Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Panitumumab. Panitumumab is indicated only for the treatment of patients with KRAS wild-type mCRC. Panitumumab is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Panitumumab in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94-1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Panitumumab. ### Electrolyte Depletion/Monitoring - Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Panitumumab treatment, periodically during Panitumumab treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. ### Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). - Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Panitumumab administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. ### Acute Renal Failure in Combination with Chemotherapy - Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Panitumumab in combination with chemotherapy. ### Pulmonary Fibrosis/Interstitial Lung Disease (ILD) - Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Panitumumab. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Panitumumab In the event of acute onset or worsening of pulmonary symptoms, interrupt Panitumumab therapy. Discontinue Panitumumab therapy if ILD is confirmed. - In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Panitumumab versus the risk of pulmonary complications must be carefully considered. ### Photosensitivity - Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Panitumumab. ### Ocular Toxicities - Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Panitumumab use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Panitumumab therapy for acute or worsening keratitis. ### Increased Mortality and Toxicity with Panitumumab in Combination with Bevacizumab and Chemotherapy - In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Panitumumab to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Panitumumab-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). - NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Panitumumab-treated patients (7% vs 3%) and included fatal events in three (< 1%) Panitumumab-treated patients. - As a result of the toxicities experienced, patients randomized to Panitumumab, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. - Safety data are presented from two clinical trials in which patients received Panitumumab: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Panitumumab with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Panitumumab in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. ### Panitumumab Monotherapy - In Study 1, the most common adverse reactions (≥ 20%) with Panitumumab were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. - The most common (> 5%) serious adverse reactions in the Panitumumab arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Panitumumab leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Panitumumab administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). - Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%). - In Study 1, dermatologic toxicities occurred in 90% of patients receiving Panitumumab. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. - In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Panitumumab the median time to most severe skin/ocular toxicity was 15 days after the first dose of Panitumumab and the median time to resolution after the last dose of Panitumumab was 98 days. Severe toxicity necessitated dose interruption in 11% of Panitumumab-treated patients. - Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported. ### Panitumumab in Combination with FOLFOX Chemotherapy - The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Panitumumab (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Panitumumab-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Panitumumab were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Panitumumab. - Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). - Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Panitumumab infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Panitumumab monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Panitumumab was permanently discontinued for a serious infusion reaction. ### Immunogenicity - As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Panitumumab has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Panitumumab. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Panitumumab. - Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Panitumumab. - In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Panitumumab. - The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Panitumumab Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease. - Immune system disorders: Infusion reaction. - Eye disorders: Keratitis/ulcerative keratitis. # Drug Interactions - No formal drug-drug interaction studies have been conducted between Panitumumab and oxaliplatin or fluoropyrimidine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no studies of Panitumumab in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. Panitumumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. - Women who become pregnant during Panitumumab treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Panitumumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Panitumumab during labor and delivery. ### Nursing Mothers - It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Panitumumab 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. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Panitumumab. - Women who are nursing during Panitumumab treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. ### Pediatric Use - The safety and effectiveness of Panitumumab have not been established in pediatric patients. The pharmacokinetic profile of Panitumumab has not been studied in pediatric patients. ### Geriatic Use - Of the 737 patients who received Panitumumab monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Panitumumab monotherapy. - Of the 322 patients in Study 3 who received Panitumumab plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. ### Gender There is no FDA guidance on the use of Panitumumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Panitumumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Panitumumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Panitumumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Panitumumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Panitumumab in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Panitumumab Administration in the drug label. ### Monitoring There is limited information regarding Panitumumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Panitumumab and IV administrations. # Overdosage - Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. # Pharmacology ## Mechanism of Action - The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases, including EGFR, HER2, HER3, and HER4. EGFR is constitutively expressed in normal epithelial tissues, including the skin and hair follicle. EGFR is overexpressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (eg, EGF, transforming growth factor-alpha) leads to phosphorylation and activation of a series of intracellular proteins, which in turn regulate transcription of genes involved with cellular growth and survival, motility, and proliferation. Signal transduction through the EGFR results in activation of the wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the KRAS-mutant protein is continuously active and appears independent of EGFR regulation. - Panitumumab binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of ligands for EGFR. Nonclinical studies show that binding of panitumumab to the EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased proinflammatory cytokine and vascular growth factor production, and internalization of the EGFR. In vitro assays and in vivo animal studies demonstrate that panitumumab inhibits the growth and survival of selected human tumor cell lines expressing EGFR. ## Structure There is limited information regarding Panitumumab Structure in the drug label. ## Pharmacodynamics There is limited information regarding Panitumumab Pharmacodynamics in the drug label. ## Pharmacokinetics - Panitumumab administered as a single agent exhibits nonlinear pharmacokinetics. - Following single-dose administrations of panitumumab as 1-hour infusions, the area under the concentration-time curve (AUC) increased in a greater than dose-proportional manner, and clearance (CL) of panitumumab decreased from 30.6 to 4.6 mL/day/kg as the dose increased from 0.75 to 9 mg/kg. However, at doses above 2 mg/kg, the AUC of panitumumab increased in an approximately dose-proportional manner. - Following the recommended dose regimen (6 mg/kg given once every 2 weeks as a 1-hour infusion), panitumumab concentrations reached steady-state levels by the third infusion with mean (± SD) peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/mL, respectively. The mean (± SD) AUC0-tau and CL were 1306 ± 374 mcgday/mL and 4.9 ± 1.4 mL/kg/day, respectively. The elimination half-life was approximately 7.5 days (range: 3.6 to 10.9 days). - A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates on panitumumab pharmacokinetics. Results suggest that age (21-88 years), gender, race (15% nonwhite), mild-to-moderate renal dysfunction, mild-to-moderate hepatic dysfunction, and EGFR membrane-staining intensity (1+, 2+, and 3+) in tumor cells had no apparent impact on the pharmacokinetics of panitumumab. - No formal pharmacokinetic studies of panitumumab have been conducted in patients with renal impairment or hepatic impairment. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17β-estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment. A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified. The effects of panitumumab on male fertility have not been studied. However, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight). ### Animal Toxicology and/or Pharmacology - Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body weight) than the recommended human dose. ### Reproductive and Developmental Toxicology - Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day 20-50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight). # Clinical Studies ### Recurrent or Refractory mCRC - The safety and efficacy of Panitumumab was demonstrated in Study 1, an open-label, multinational, randomized, controlled trial of 463 patients with EGFR-expressing, metastatic carcinoma of the colon or rectum, and in Study 2, an open-label, multicenter, multinational, randomized trial of 1010 patients with wild-type KRAS mCRC. - Patients in Study 1 were required to have progressed on or following treatment with a regimen(s) containing a fluoropyrimidine, oxaliplatin, and irinotecan; progression was confirmed by an independent review committee (IRC) masked to treatment assignment for 76% of the patients. Patients were randomized (1:1) to receive panitumumab at a dose of 6 mg/kg given once every 2 weeks plus BSC (N = 231) or BSC alone (N = 232) until investigator-determined disease progression. Randomization was stratified based on Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 and 1 vs 2) and geographic region (Western Europe, Eastern/Central Europe, or other). Upon investigator-determined disease progression, patients in the BSC-alone arm were eligible to receive panitumumab and were followed until disease progression was confirmed by the IRC. - Based upon IRC determination of disease progression, a statistically significant prolongation in PFS was observed in patients receiving panitumumab compared to those receiving BSC alone. The mean PFS was 96 days in the panitumumab arm and 60 days in the BSC-alone arm. - The study results were analyzed in the wild-type KRAS subgroup where KRAS status was retrospectively determined using archived paraffin-embedded tumor tissue. KRAS mutation status was determined in 427 patients (92%); of these, 243 (57%) had no detectable KRAS mutations in either codons 12 or 13. The hazard ratio for PFS in patients with wild-type KRAS mCRC was 0.45 (95% CI: 0.34-0.59) favoring the panitumumab arm. The response rate was 17% for the panitumumab arm and 0% for BSC. There were no differences in OS; 77% of patients in the BSC arm received panitumumab at the time of disease progression. - Study 2 was an open-label, multicenter, multinational, randomized (1:1) clinical trial, stratified by region (North America, Western Europe, and Australia versus rest of the world) and ECOG PS (0 and 1 vs 2) in patients with wild-type KRAS mCRC. A total of 1010 patients who received prior treatment with irinotecan, oxaliplatin, and a thymidylate synthase inhibitor were randomized to receive Panitumumab 6 mg/kg intravenously over 60 minutes every 14 days or cetuximab 400 mg/m2 intravenously over 120 minutes on day 1 followed by 250 mg/m2 intravenously over 60 minutes every 7 days. The trial excluded patients with clinically significant cardiac disease and interstitial lung disease. The major efficacy analysis tested whether the OS of Panitumumab was noninferior to cetuximab. Data for investigator-assessed PFS and objective response rate (ORR) were also collected. The criteria for noninferiority was for Panitumumab to retain at least 50% of the OS benefit of cetuximab based on an OS hazard ratio of 0.55 from the NCIC CTG CO.17 study relative to BSC. - In Study 2, 37% of patients were women, 52% were white, 45% were Asian, and 1.3% were Hispanic or Latino. Thirty-one percent of patients were enrolled at sites in North America, Western Europe, or Australia. ECOG performance was 0 in 32% of patients, 1 in 60% of patients, and 2 in 8% of patients. Median age was 61 years. More patients (62%) had colon cancer than rectal cancer (38%). Most patients (74%) had not received prior bevacizumab. - The key efficacy analysis for Study 2 demonstrated that Panitumumab was statistically significantly noninferior to cetuximab for OS. ### First-line in Combination with FOLFOX Chemotherapy - Study 3 was a multicenter, open-label trial that randomized (1:1) patients with mCRC who were previously untreated in the metastatic setting and who had received no prior oxaliplatin to receive Panitumumab every 14 days in combination with FOLFOX or to FOLFOX alone every 14 days. Panitumumab was administered at 6 mg/kg over 60 minutes prior to administration of chemotherapy. The FOLFOX regimen consisted of oxaliplatin 85 mg per m2 IV infusion over 120 minutes and leucovorin (dl-racemic) 200 mg per m2 intravenous infusion over 120 minutes at the same time on day 1 using a Y-line, followed on day 1 by 5-FU 400 mg per m2 intravenous bolus. The 5FU bolus was followed by a continuous infusion of 5-FU 600 mg per m2 over 22 hours. On day 2, patients received leucovorin 200 mg per m2 followed by the bolus dose (400 mg per m2) and continuous infusion of 5FU (600 mg per m2) over 22 hours. Study 3 excluded patients with known central nervous system metastases, clinically significant cardiac disease, interstitial lung disease, or active inflammatory bowel disease. The prespecified major efficacy measure was PFS in patients (n = 656) with wild-type KRAS mCRC as assessed by a blinded independent central review of imaging. Other key efficacy measures included OS and ORR. - In Study 3, in the wild-type KRAS group, 64% of patients were men, 92% white, 2% black, and 4% Hispanic or Latino. Sixty-six percent of patients had colon cancer and 34% had rectal cancer. ECOG performance was 0 in 56% of patients, 1 in 38% of patients, and 2 in 6% of patients. Median age was 61.5 years. - In Study 3, among patients with KRAS-mutant tumors, median PFS was 7.3 months (95% CI: 6.3, 8.0) among 221 patients receiving Panitumumab plus FOLFOX versus 8.8 months (95% CI: 7.7, 9.4) among patients who received FOLFOX alone (HR = 1.29, 95% CI: 1.04, 1.62). Median OS was 15.5 months (95% CI: 13.1, 17.6) among patients receiving Panitumumab plus FOLFOX versus 19.3 months (95% CI: 16.5, 21.8) among patients who received FOLFOX alone (HR = 1.24, 95% CI: 0.98, 1.57). - An exploratory analysis of OS with updated information based on events in 82% of patients with wild-type KRAS mCRC estimated the treatment effect of Panitumumab plus FOLFOX compared with FOLFOX alone on OS (Figure 2). Median OS among 325 patients with wild-type KRAS mCRC who received Panitumumab plus FOLFOX was 23.8 months (95% CI: 20.0, 27.7) versus 19.4 months (95% CI: 17.4, 22.6) among 331 patients who received FOLFOX alone (HR = 0.83, 95% CI: 0.70, 0.98). # How Supplied - Panitumumab is supplied as a sterile, colorless, preservative-free solution containing 20 mg/mL Panitumumab (panitumumab) in a single-use vial. - Panitumumab is provided as one vial per carton: Each 5 mL single-use vial contains 100 mg of panitumumab in 5 mL (20 mg/mL) (NDC 55513-954-01). Each 10 mL single-use vial contains 200 mg of panitumumab in 10 mL (20 mg/mL) (NDC 55513-955-01). Each 20 mL single-use vial contains 400 mg of panitumumab in 20 mL (20 mg/mL) (NDC 55513-956-01). - Each 5 mL single-use vial contains 100 mg of panitumumab in 5 mL (20 mg/mL) (NDC 55513-954-01). - Each 10 mL single-use vial contains 200 mg of panitumumab in 10 mL (20 mg/mL) (NDC 55513-955-01). - Each 20 mL single-use vial contains 400 mg of panitumumab in 20 mL (20 mg/mL) (NDC 55513-956-01). ## Storage Store vials in the original carton under refrigeration at 2º to 8ºC (36º to 46ºF) until time of use. Protect from direct sunlight. DO NOT FREEZE. Since Panitumumab does not contain preservatives, any unused portion remaining in the vial must be discarded. The diluted infusion solution of Panitumumab should be used within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36º to 46ºF). DO NOT FREEZE. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Panitumumab Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Panitumumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Vectibix # Look-Alike Drug Names There is limited information regarding Panitumumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Panitumumab 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. # Black Box Warning # Overview Panitumumab is an Immunological Agent and Monoclonal Antibody that is FDA approved for the treatment of metastatic colorectal cancer with wild-type KRAS (exon 2 in codons 12 or 13) as first-line therapy in combination with FOLFOX, monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash with variable presentations, paronychia, fatigue, nausea, and diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, acneiform dermatitis, pruritus, and dry skin. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ## Patient Selection - Prior to initiation of treatment with Panitumumab, assess KRAS mutational status in colorectal tumors and confirm the absence of a KRAS mutation using an FDA-approved test. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: http://www.fda.gov/CompanionDiagnostics. ## Recommended Dose - The recommended dose of Panitumumab is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration (2.4)]. - Appropriate medical resources for the treatment of severe infusion reactions should be available during Panitumumab infusions. ## Dose Modifications - Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion. - Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Panitumumab. - Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Panitumumab. If the reaction improves to < grade 3, reinitiate Panitumumab at the original dose. - Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Panitumumab. If the reaction improves to < grade 3, reinitiate Panitumumab at 80% of the original dose. - Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Panitumumab. If the reaction improves to < grade 3, reinitiate Panitumumab at 60% of the original dose. - Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Panitumumab. - Permanently discontinue Panitumumab following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses. ## Preparation and Administration - Do not administer Panitumumab as an intravenous push or bolus. Prepare the solution for infusion, using aseptic technique, as follows: - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. *Although Panitumumab should be colorless, the solution may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates (which will be removed by filtration; see below). - Do not shake. - Do not administer Panitumumab if discoloration is observed. - Withdraw the necessary amount of Panitumumab for a dose of 6 mg/kg. - Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. - Mix diluted solution by gentle inversion. Do not shake. - Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter. - Panitumumab must be administered via infusion pump. Flush line before and after Panitumumab administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Panitumumab with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab. Infuse doses of 1000 mg or lower over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes. - Flush line before and after Panitumumab administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Panitumumab with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab. - Infuse doses of 1000 mg or lower over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes. - Use the diluted infusion solution of Panitumumab within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36º to 46ºF). DO NOT FREEZE. - Discard any unused portion remaining in the vial. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Panitumumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Panitumumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Panitumumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Panitumumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Panitumumab in pediatric patients. # Contraindications - None. # Warnings ### Dermatologic and Soft Tissue Toxicity - In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Panitumumab The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. - Monitor patients who develop dermatologic or soft tissue toxicities while receiving Panitumumab for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Panitumumab. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Panitumumab It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Panitumumab for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Panitumumab concerning dermatologic toxicity are provided. ### Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with RAS- and KRAS-Mutant mCRC - A predefined retrospective subset analysis of Study 3 further identified a shortening of progression-free survival (PFS) and overall survival (OS) in patients with RAS-mutant tumors who received Panitumumab and FOLFOX versus FOLFOX alone. Determination of RAS-mutant tumor status should be performed by an experienced laboratory. - Determination of KRAS mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Panitumumab. Panitumumab is indicated only for the treatment of patients with KRAS wild-type mCRC. Panitumumab is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2) as determined by an FDA-approved test for this use. In Study 3, 221 patients with KRAS-mutant mCRC tumors receiving Panitumumab in combination with FOLFOX experienced shorter OS compared to 219 patients receiving FOLFOX alone (HR = 1.16, 95% CI: 0.94-1.41). Perform the assessment for KRAS mutational status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Panitumumab. ### Electrolyte Depletion/Monitoring - Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Panitumumab treatment, periodically during Panitumumab treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate. ### Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). - Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Panitumumab administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. ### Acute Renal Failure in Combination with Chemotherapy - Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Panitumumab in combination with chemotherapy. ### Pulmonary Fibrosis/Interstitial Lung Disease (ILD) - Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Panitumumab. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Panitumumab In the event of acute onset or worsening of pulmonary symptoms, interrupt Panitumumab therapy. Discontinue Panitumumab therapy if ILD is confirmed. - In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Panitumumab versus the risk of pulmonary complications must be carefully considered. ### Photosensitivity - Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Panitumumab. ### Ocular Toxicities - Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Panitumumab use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Panitumumab therapy for acute or worsening keratitis. ### Increased Mortality and Toxicity with Panitumumab in Combination with Bevacizumab and Chemotherapy - In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Panitumumab to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Panitumumab-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). - NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Panitumumab-treated patients (7% vs 3%) and included fatal events in three (< 1%) Panitumumab-treated patients. - As a result of the toxicities experienced, patients randomized to Panitumumab, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy. # Adverse Reactions ## Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. - Safety data are presented from two clinical trials in which patients received Panitumumab: Study 1, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Panitumumab with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 3, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Panitumumab in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 3 are limited to 656 patients with wild-type KRAS mCRC. ### Panitumumab Monotherapy - In Study 1, the most common adverse reactions (≥ 20%) with Panitumumab were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. - The most common (> 5%) serious adverse reactions in the Panitumumab arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Panitumumab leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2). For Study 1, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Panitumumab administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks). - Adverse reactions in Study 1 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%). - In Study 1, dermatologic toxicities occurred in 90% of patients receiving Panitumumab. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. - In Study 1 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Panitumumab the median time to most severe skin/ocular toxicity was 15 days after the first dose of Panitumumab and the median time to resolution after the last dose of Panitumumab was 98 days. Severe toxicity necessitated dose interruption in 11% of Panitumumab-treated patients. - Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported. ### Panitumumab in Combination with FOLFOX Chemotherapy - The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Panitumumab (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 3 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Panitumumab-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Panitumumab were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Panitumumab. - Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%). - Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Panitumumab infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Panitumumab monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Panitumumab was permanently discontinued for a serious infusion reaction. ### Immunogenicity - As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Panitumumab has been evaluated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) detecting high-affinity antibodies and a Biacore® biosensor immunoassay detecting both high- and low-affinity antibodies. For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Panitumumab. In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Panitumumab. - Monotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.4% (5/1123) as detected by the acid dissociation ELISA and 3.2% (36/1123) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting and transient positive patients) was 0.8% (9/1123). There was no evidence of altered pharmacokinetic or safety profiles in patients who developed antibodies to Panitumumab. - In combination with chemotherapy: The incidence of binding anti-panitumumab antibodies (excluding preexisting positive patients) was 0.9% (12/1297) as detected by the acid dissociation ELISA and 0.7% (9/1296) as detected by the Biacore® assay. The incidence of neutralizing anti-panitumumab antibodies (excluding preexisting positive patients) was 0.2% (2/1297). No evidence of an altered safety profile was found in patients who developed antibodies to Panitumumab. - The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of Panitumumab Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Skin and subcutaneous tissue disorders: Skin necrosis, angioedema, life-threatening and fatal bullous mucocutaneous disease. - Immune system disorders: Infusion reaction. - Eye disorders: Keratitis/ulcerative keratitis. # Drug Interactions - No formal drug-drug interaction studies have been conducted between Panitumumab and oxaliplatin or fluoropyrimidine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no studies of Panitumumab in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. Panitumumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. - Women who become pregnant during Panitumumab treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Panitumumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Panitumumab during labor and delivery. ### Nursing Mothers - It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Panitumumab 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. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Panitumumab. - Women who are nursing during Panitumumab treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. ### Pediatric Use - The safety and effectiveness of Panitumumab have not been established in pediatric patients. The pharmacokinetic profile of Panitumumab has not been studied in pediatric patients. ### Geriatic Use - Of the 737 patients who received Panitumumab monotherapy in Study 1 and 2, 36% were 65 and over while 8% were 75 and over. No overall differences in safety or efficacy were observed in elderly patients (≥ 65 years of age) treated with Panitumumab monotherapy. - Of the 322 patients in Study 3 who received Panitumumab plus FOLFOX, 128 (40%) were 65 and over while 8% were 75 and over. Patients older than 65 years of age experienced an increased incidence of serious adverse events (52% vs 36%) and an increased incidence of serious diarrhea (15% vs 5%) as compared to younger patients. ### Gender There is no FDA guidance on the use of Panitumumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Panitumumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Panitumumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Panitumumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Panitumumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Panitumumab in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Panitumumab Administration in the drug label. ### Monitoring There is limited information regarding Panitumumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Panitumumab and IV administrations. # Overdosage - Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue. # Pharmacology ## Mechanism of Action - The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases, including EGFR, HER2, HER3, and HER4. EGFR is constitutively expressed in normal epithelial tissues, including the skin and hair follicle. EGFR is overexpressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (eg, EGF, transforming growth factor-alpha) leads to phosphorylation and activation of a series of intracellular proteins, which in turn regulate transcription of genes involved with cellular growth and survival, motility, and proliferation. Signal transduction through the EGFR results in activation of the wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the KRAS-mutant protein is continuously active and appears independent of EGFR regulation. - Panitumumab binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of ligands for EGFR. Nonclinical studies show that binding of panitumumab to the EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased proinflammatory cytokine and vascular growth factor production, and internalization of the EGFR. In vitro assays and in vivo animal studies demonstrate that panitumumab inhibits the growth and survival of selected human tumor cell lines expressing EGFR. ## Structure There is limited information regarding Panitumumab Structure in the drug label. ## Pharmacodynamics There is limited information regarding Panitumumab Pharmacodynamics in the drug label. ## Pharmacokinetics - Panitumumab administered as a single agent exhibits nonlinear pharmacokinetics. - Following single-dose administrations of panitumumab as 1-hour infusions, the area under the concentration-time curve (AUC) increased in a greater than dose-proportional manner, and clearance (CL) of panitumumab decreased from 30.6 to 4.6 mL/day/kg as the dose increased from 0.75 to 9 mg/kg. However, at doses above 2 mg/kg, the AUC of panitumumab increased in an approximately dose-proportional manner. - Following the recommended dose regimen (6 mg/kg given once every 2 weeks as a 1-hour infusion), panitumumab concentrations reached steady-state levels by the third infusion with mean (± SD) peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/mL, respectively. The mean (± SD) AUC0-tau and CL were 1306 ± 374 mcg•day/mL and 4.9 ± 1.4 mL/kg/day, respectively. The elimination half-life was approximately 7.5 days (range: 3.6 to 10.9 days). - A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates on panitumumab pharmacokinetics. Results suggest that age (21-88 years), gender, race (15% nonwhite), mild-to-moderate renal dysfunction, mild-to-moderate hepatic dysfunction, and EGFR membrane-staining intensity (1+, 2+, and 3+) in tumor cells had no apparent impact on the pharmacokinetics of panitumumab. - No formal pharmacokinetic studies of panitumumab have been conducted in patients with renal impairment or hepatic impairment. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility - No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17β-estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment. A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified. The effects of panitumumab on male fertility have not been studied. However, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight). ### Animal Toxicology and/or Pharmacology - Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body weight) than the recommended human dose. ### Reproductive and Developmental Toxicology - Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20-50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight). # Clinical Studies ### Recurrent or Refractory mCRC - The safety and efficacy of Panitumumab was demonstrated in Study 1, an open-label, multinational, randomized, controlled trial of 463 patients with EGFR-expressing, metastatic carcinoma of the colon or rectum, and in Study 2, an open-label, multicenter, multinational, randomized trial of 1010 patients with wild-type KRAS mCRC. - Patients in Study 1 were required to have progressed on or following treatment with a regimen(s) containing a fluoropyrimidine, oxaliplatin, and irinotecan; progression was confirmed by an independent review committee (IRC) masked to treatment assignment for 76% of the patients. Patients were randomized (1:1) to receive panitumumab at a dose of 6 mg/kg given once every 2 weeks plus BSC (N = 231) or BSC alone (N = 232) until investigator-determined disease progression. Randomization was stratified based on Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 and 1 vs 2) and geographic region (Western Europe, Eastern/Central Europe, or other). Upon investigator-determined disease progression, patients in the BSC-alone arm were eligible to receive panitumumab and were followed until disease progression was confirmed by the IRC. - Based upon IRC determination of disease progression, a statistically significant prolongation in PFS was observed in patients receiving panitumumab compared to those receiving BSC alone. The mean PFS was 96 days in the panitumumab arm and 60 days in the BSC-alone arm. - The study results were analyzed in the wild-type KRAS subgroup where KRAS status was retrospectively determined using archived paraffin-embedded tumor tissue. KRAS mutation status was determined in 427 patients (92%); of these, 243 (57%) had no detectable KRAS mutations in either codons 12 or 13. The hazard ratio for PFS in patients with wild-type KRAS mCRC was 0.45 (95% CI: 0.34-0.59) favoring the panitumumab arm. The response rate was 17% for the panitumumab arm and 0% for BSC. There were no differences in OS; 77% of patients in the BSC arm received panitumumab at the time of disease progression. - Study 2 was an open-label, multicenter, multinational, randomized (1:1) clinical trial, stratified by region (North America, Western Europe, and Australia versus rest of the world) and ECOG PS (0 and 1 vs 2) in patients with wild-type KRAS mCRC. A total of 1010 patients who received prior treatment with irinotecan, oxaliplatin, and a thymidylate synthase inhibitor were randomized to receive Panitumumab 6 mg/kg intravenously over 60 minutes every 14 days or cetuximab 400 mg/m2 intravenously over 120 minutes on day 1 followed by 250 mg/m2 intravenously over 60 minutes every 7 days. The trial excluded patients with clinically significant cardiac disease and interstitial lung disease. The major efficacy analysis tested whether the OS of Panitumumab was noninferior to cetuximab. Data for investigator-assessed PFS and objective response rate (ORR) were also collected. The criteria for noninferiority was for Panitumumab to retain at least 50% of the OS benefit of cetuximab based on an OS hazard ratio of 0.55 from the NCIC CTG CO.17 study relative to BSC. - In Study 2, 37% of patients were women, 52% were white, 45% were Asian, and 1.3% were Hispanic or Latino. Thirty-one percent of patients were enrolled at sites in North America, Western Europe, or Australia. ECOG performance was 0 in 32% of patients, 1 in 60% of patients, and 2 in 8% of patients. Median age was 61 years. More patients (62%) had colon cancer than rectal cancer (38%). Most patients (74%) had not received prior bevacizumab. - The key efficacy analysis for Study 2 demonstrated that Panitumumab was statistically significantly noninferior to cetuximab for OS. ### First-line in Combination with FOLFOX Chemotherapy - Study 3 was a multicenter, open-label trial that randomized (1:1) patients with mCRC who were previously untreated in the metastatic setting and who had received no prior oxaliplatin to receive Panitumumab every 14 days in combination with FOLFOX or to FOLFOX alone every 14 days. Panitumumab was administered at 6 mg/kg over 60 minutes prior to administration of chemotherapy. The FOLFOX regimen consisted of oxaliplatin 85 mg per m2 IV infusion over 120 minutes and leucovorin (dl-racemic) 200 mg per m2 intravenous infusion over 120 minutes at the same time on day 1 using a Y-line, followed on day 1 by 5-FU 400 mg per m2 intravenous bolus. The 5FU bolus was followed by a continuous infusion of 5-FU 600 mg per m2 over 22 hours. On day 2, patients received leucovorin 200 mg per m2 followed by the bolus dose (400 mg per m2) and continuous infusion of 5FU (600 mg per m2) over 22 hours. Study 3 excluded patients with known central nervous system metastases, clinically significant cardiac disease, interstitial lung disease, or active inflammatory bowel disease. The prespecified major efficacy measure was PFS in patients (n = 656) with wild-type KRAS mCRC as assessed by a blinded independent central review of imaging. Other key efficacy measures included OS and ORR. - In Study 3, in the wild-type KRAS group, 64% of patients were men, 92% white, 2% black, and 4% Hispanic or Latino. Sixty-six percent of patients had colon cancer and 34% had rectal cancer. ECOG performance was 0 in 56% of patients, 1 in 38% of patients, and 2 in 6% of patients. Median age was 61.5 years. - In Study 3, among patients with KRAS-mutant tumors, median PFS was 7.3 months (95% CI: 6.3, 8.0) among 221 patients receiving Panitumumab plus FOLFOX versus 8.8 months (95% CI: 7.7, 9.4) among patients who received FOLFOX alone (HR = 1.29, 95% CI: 1.04, 1.62). Median OS was 15.5 months (95% CI: 13.1, 17.6) among patients receiving Panitumumab plus FOLFOX versus 19.3 months (95% CI: 16.5, 21.8) among patients who received FOLFOX alone (HR = 1.24, 95% CI: 0.98, 1.57). - An exploratory analysis of OS with updated information based on events in 82% of patients with wild-type KRAS mCRC estimated the treatment effect of Panitumumab plus FOLFOX compared with FOLFOX alone on OS (Figure 2). Median OS among 325 patients with wild-type KRAS mCRC who received Panitumumab plus FOLFOX was 23.8 months (95% CI: 20.0, 27.7) versus 19.4 months (95% CI: 17.4, 22.6) among 331 patients who received FOLFOX alone (HR = 0.83, 95% CI: 0.70, 0.98). # How Supplied - Panitumumab is supplied as a sterile, colorless, preservative-free solution containing 20 mg/mL Panitumumab (panitumumab) in a single-use vial. - Panitumumab is provided as one vial per carton: Each 5 mL single-use vial contains 100 mg of panitumumab in 5 mL (20 mg/mL) (NDC 55513-954-01). Each 10 mL single-use vial contains 200 mg of panitumumab in 10 mL (20 mg/mL) (NDC 55513-955-01). Each 20 mL single-use vial contains 400 mg of panitumumab in 20 mL (20 mg/mL) (NDC 55513-956-01). - Each 5 mL single-use vial contains 100 mg of panitumumab in 5 mL (20 mg/mL) (NDC 55513-954-01). - Each 10 mL single-use vial contains 200 mg of panitumumab in 10 mL (20 mg/mL) (NDC 55513-955-01). - Each 20 mL single-use vial contains 400 mg of panitumumab in 20 mL (20 mg/mL) (NDC 55513-956-01). ## Storage Store vials in the original carton under refrigeration at 2º to 8ºC (36º to 46ºF) until time of use. Protect from direct sunlight. DO NOT FREEZE. Since Panitumumab does not contain preservatives, any unused portion remaining in the vial must be discarded. The diluted infusion solution of Panitumumab should be used within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36º to 46ºF). DO NOT FREEZE. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Panitumumab Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Panitumumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Vectibix # Look-Alike Drug Names There is limited information regarding Panitumumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Panitumumab
fcb5a6f2517e44933a82fa862fef852a880142ef	wikidoc	Paraldehyde	Paraldehyde Paraldehyde is the cyclic trimer of acetaldehyde molecules. Formally, it is a derivative of 1,3,5-trioxane. The corresponding tetramer is metaldehyde. A colourless liquid, it is sparingly soluble in water and highly soluble in alcohol. Paraldehyde slowly oxidizes in air, turning brown and producing an odour of acetic acid. It quickly reacts with most plastics and rubber. Paraldehyde was first synthesized in 1829 by Wildenbusch. It has uses in industry and medicine. # Stereochemistry Theoretically four stereoisomeric structures are possible. The structures (1) and (2) are known as cis- and trans-paraldehyde. The structures (3) (a conformer of (2)) and (4) (a conformer of (1)) don't exist for steric reasons. # Reactions Heated with catalytic amounts of acid, it depolymerizes back to acetaldehyde: Since paraldehyde has better handling characteristics, it may be used indirectly or directly as a synthetic equivalent of anhydrous acetaldehyde (b.p. 20 °C). For example, it is used as-is in the synthesis of bromal (tribromoacetaldehyde): # Medical applications Paraldehyde was introduced into clinical practice in the UK by the Italian physician Vincenzo Cervello in 1882. It is a central nervous system depressant and was soon found to be an effective anticonvulsant, hypnotic and sedative. It was included in some cough medicines as an expectorant (though there is no known mechanism for this function beyond the placebo effect). Paraldehyde was the last injection given to Edith Alice Morrell in 1950 by the suspected serial killer John Bodkin Adams. He was tried for her murder but acquitted. ## As a hypnotic/sedative It was commonly used to induce sleep in sufferers from delirium tremens but has been replaced by other drugs in this regard. It is one of the safest hypnotics and was regularly given at bedtime in psychiatric hospitals and geriatric wards up to the 1960s. Up to 30% of the dose is excreted via the lungs (the rest via the liver). This contributes to a strong unpleasant odour on the breath. ## As anti-seizure It has been used in the treatment of convulsions. Today, paraldehyde is sometimes used to treat status epilepticus. Unlike diazepam and other benzodiazepines, it does not suppress breathing at therapeutic doses and so is safer when no resuscitation facilities exist or when the patient's breathing is already compromised. This makes it a useful emergency medication for parents and other caretakers of children with epilepsy. Since the dose margin between the anticonvulsant and hypnotic effect is small, paraldehyde treatment usually results in sleep. ## Administration Generic paraldehyde is available in 5ml sealed glass ampoules. Production in the US has been discontinued, but it was previously marketed as Paral. Paraldehyde has been given orally, rectally, intravenously and by intramuscular injection. It reacts with rubber and plastic which limits the time it may safely be kept in contact with some syringes or tubing before administration. - Injection. Intramuscular injection can be very painful and lead to sterile abscesses, nerve damage, and tissue necrosis. Intravenous administration can lead to pulmonary edema, circulatory collapse and other complications. - Oral. Paraldehyde has a hot burning taste and can upset the stomach. It is often mixed with milk or fruit juice in a glass cup and stirred with a metal spoon. - Rectal. It may be mixed 1 part paraldehyde with 9 parts saline or, alternatively, with an equal mixture of peanut or olive oil. # Industrial applications Paraldehyde is used in resin manufacture, as a preservative, and in other processes as a solvent. It has been used in the generation of aldehyde fuchsin.	Paraldehyde Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Paraldehyde is the cyclic trimer of acetaldehyde molecules. Formally, it is a derivative of 1,3,5-trioxane. The corresponding tetramer is metaldehyde. A colourless liquid, it is sparingly soluble in water and highly soluble in alcohol. Paraldehyde slowly oxidizes in air, turning brown and producing an odour of acetic acid. It quickly reacts with most plastics and rubber. Paraldehyde was first synthesized in 1829 by Wildenbusch.[2] It has uses in industry and medicine. # Stereochemistry Theoretically four stereoisomeric structures are possible. The structures (1) and (2) are known as cis- and trans-paraldehyde. The structures (3) (a conformer of (2)) and (4) (a conformer of (1)) don't exist for steric reasons.[3][4] # Reactions Heated with catalytic amounts of acid, it depolymerizes back to acetaldehyde:[5][6] Since paraldehyde has better handling characteristics, it may be used indirectly or directly as a synthetic equivalent of anhydrous acetaldehyde (b.p. 20 °C). For example, it is used as-is in the synthesis of bromal (tribromoacetaldehyde):[7] # Medical applications Paraldehyde was introduced into clinical practice in the UK by the Italian physician Vincenzo Cervello in 1882.[2] It is a central nervous system depressant and was soon found to be an effective anticonvulsant, hypnotic and sedative. It was included in some cough medicines as an expectorant (though there is no known mechanism for this function beyond the placebo effect). Paraldehyde was the last injection given to Edith Alice Morrell in 1950 by the suspected serial killer John Bodkin Adams. He was tried for her murder but acquitted. ## As a hypnotic/sedative It was commonly used to induce sleep in sufferers from delirium tremens but has been replaced by other drugs in this regard. It is one of the safest hypnotics and was regularly given at bedtime in psychiatric hospitals and geriatric wards up to the 1960s. Up to 30% of the dose is excreted via the lungs (the rest via the liver). This contributes to a strong unpleasant odour on the breath. ## As anti-seizure It has been used in the treatment of convulsions.[8] Today, paraldehyde is sometimes used to treat status epilepticus. Unlike diazepam and other benzodiazepines, it does not suppress breathing at therapeutic doses and so is safer when no resuscitation facilities exist or when the patient's breathing is already compromised.[9] This makes it a useful emergency medication for parents and other caretakers of children with epilepsy. Since the dose margin between the anticonvulsant and hypnotic effect is small, paraldehyde treatment usually results in sleep. ## Administration Generic paraldehyde is available in 5ml sealed glass ampoules. Production in the US has been discontinued, but it was previously marketed as Paral. Paraldehyde has been given orally, rectally, intravenously and by intramuscular injection. It reacts with rubber and plastic which limits the time it may safely be kept in contact with some syringes or tubing before administration. - Injection. Intramuscular injection can be very painful and lead to sterile abscesses, nerve damage, and tissue necrosis. Intravenous administration can lead to pulmonary edema, circulatory collapse and other complications. - Oral. Paraldehyde has a hot burning taste and can upset the stomach. It is often mixed with milk or fruit juice in a glass cup and stirred with a metal spoon. - Rectal. It may be mixed 1 part paraldehyde with 9 parts saline or, alternatively, with an equal mixture of peanut or olive oil. # Industrial applications Paraldehyde is used in resin manufacture, as a preservative, and in other processes as a solvent. It has been used in the generation of aldehyde fuchsin.[10]	https://www.wikidoc.org/index.php/Paral
fe91efbea1f0305be791927dd9113e902c6072ea	wikidoc	Paraoxonase	Paraoxonase Paraoxonases are a family of mammalian enzymes with aryldialkylphosphatase activity. There are three paraoxonase isozymes, which were originally discovered for their involvement in the hydrolysis of organophosphates. Research has indicated the enzymatic activity of paraoxonases is more diversified than its activity as an organophosphatase. Esterase and lactonase activity has also been observed from these enzymes and though the physiologically relevant substrates for these enzymes are unknown, it is likely that lactones are the main substrate (although there is a relatively high level of variation in substrate specificity among these enzymes). Most of the studies on the paraoxonase family have specifically looked at the paraoxonase 1 type, leaving much to be learned about the remaining two. The study of this enzyme family has many potential consequences in preventative medicine and toxicology as well as in certain societal contexts. The genes that encode for these enzymes have a number of different polymorphisms, which created additional interest in the study of this enzyme group and its potential ethnic variations. Additional research on the inhibition and selective inhibition, specifically of PON1, has been done to shed some light on the connections between decreases in enzymatic activity of individuals with cardiovascular diseases. Evidence also suggests that this family of enzymes has some role in our innate immune system. # Types There are three known of paraoxonases. They are encoded by the genes PON1, PON2 and PON3, located on the long arm of chromosome 7 in humans. The differences between them lie in their location and activity. - Paraoxonase 1 has gene expression primarily in the liver but has also been expressed in tissue from the kidney and parts of the colon. Paraoxonase 1 that is synthesized in the liver is then transported into the blood stream where it will associate with high-density lipoprotein (HDL). It has been shown to have broad substrate specificity and has proved to protect against exposure to some organophosphates (such as those from insecticides) by hydrolyzing potentially toxic metabolites. Paraoxonase 1 also plays an important role as an antioxidant in preventing the oxidation of low-density lipoproteins (LDL), a process that is directly involved in the development of atherosclerosis. Its serum concentration is influenced by inflammatory changes and the levels of serum oxidised-LDL. - Paraoxonase 2 is a ubiquitously expressed intracellular protein that can protect cells against oxidative damage. While paraoxonase 2 shares similar antioxidant properties with its two enzyme counterparts, it lacks the ability to hydrolyze some of the organophosphate metabolites. - Paraoxonase 3 is similar to type 1 in activity but differs from it in substrate specificity. Serum PON3 activity is 100 times lower than PON1. Additionally, it is not regulated by inflammation and levels of oxidised lipids. Both paraoxonase 1 and 3 are bound to HDL and because of their similar properties as antioxidants, it is possible PON3 also plays a role in the prevention of LDL and HDL oxidation. # Biological function Paraoxonases have been found to perform a number of biological functions, though the primary role of this group of enzymes is still a topic of speculation. Some of the observed roles have revealed activities of anti-inflammatory, anti-oxidative, anti-atherogenic, anti-diabetic, anti-microbial and organophosphate-hydrolyzing properties. Two of the most important known roles that Paraoxonases plays are in functioning as a lactonase and an arylesterase. These properties provide a promising potential for development of new therapeutic interventions to combat a number of health conditions. # Mechanism The study of this family of enzymes has been something of interest for a number of years now; however, the lack of identifying specific natural substrates and numerous physiological roles has made it difficult in determining mechanisms of action for the diverse number of reactions catalyzed by this enzyme family. One of the more studied mechanisms is the lactonase mechanism of Serum Paraoxonase-1. One of the proposed mechanism outlines the hydrolysis of 5-membered ring lactone substrates by serum Paraoxonase-1. PON1, as with PON2 and PON3, utilizes a catalytic calcium ion, which functions as an oxy-anion to stabilize substrate and reaction states. Additionally, this enzyme active site employs two histidine residues (His115 and 134) involved in proton transfers, a glutamic acid (Glu53) to stabilize reactive hydrogens, and an asparagine (Asn168) to stabilize transition states and intermediates in the active site. The exact mechanism is still a subject of further research and it is suggested that the His115 residue is not necessary for the lactonase and arylesterase activity of the enzyme. # Regulation One of the common inhibitors of enzymatic activity (for PON 1 and PON 3) is lipid peroxides found in the plasma. Lipid peroxides can inhibit Paraoxonase activity as an arylesterase and antioxidant, though the specific inhibition is dependent on the type of lipid head group. An important implication of this fact is that, in decreasing the activity of PON1 and PON3, the productivity of preventing oxidation of LDL. Enzyme activity is also regulated by a substrate-dependent polymorphism that occurs at position 192. There are two known isoforms, one having an arginine residue at the 192 position and the other a glutamine, which are associated with high and low enzymatic activity respectively. # Clinical significance The development of atherosclerosis is a complex process, though the main underlying feature is simply an increase in low-density lipoprotein (LDL) oxidation. PON1 and PON3 prevent the formation of atherogenic oxidised-LDL, the form of LDL present in foam cells of an atheromatous plaque. Because of their know association with high-density lipoprotein (HDL) and their effect on oxidized-LDL, PON1 and PON3 are implicated in lowering the risk of developing coronary artery disease and atherosclerosis. # History PON was identified as an enzyme having organophosphates as its substrates. Reports of the geographic differences in population frequencies of paraoxonase activity and genetic analysis led to uncovering the genetic polymorphism. The name paraoxonase was given because of its ability to hydrolyze paraoxon, a toxic metabolite that comes from pesticide parathion. The 3D crystal structure of PON1 was determined in 2004.	Paraoxonase Paraoxonases are a family of mammalian enzymes with aryldialkylphosphatase activity. There are three paraoxonase isozymes, which were originally discovered for their involvement in the hydrolysis of organophosphates.[1] Research has indicated the enzymatic activity of paraoxonases is more diversified than its activity as an organophosphatase. Esterase and lactonase activity has also been observed from these enzymes and though the physiologically relevant substrates for these enzymes are unknown, it is likely that lactones are the main substrate (although there is a relatively high level of variation in substrate specificity among these enzymes). Most of the studies on the paraoxonase family have specifically looked at the paraoxonase 1 type, leaving much to be learned about the remaining two.[2] The study of this enzyme family has many potential consequences in preventative medicine and toxicology as well as in certain societal contexts. The genes that encode for these enzymes have a number of different polymorphisms, which created additional interest in the study of this enzyme group and its potential ethnic variations.[3] Additional research on the inhibition and selective inhibition, specifically of PON1, has been done to shed some light on the connections between decreases in enzymatic activity of individuals with cardiovascular diseases.[4] Evidence also suggests that this family of enzymes has some role in our innate immune system.[5] # Types There are three known of paraoxonases. They are encoded by the genes PON1, PON2 and PON3, located on the long arm of chromosome 7 in humans.[1][6] The differences between them lie in their location and activity. - Paraoxonase 1 has gene expression primarily in the liver but has also been expressed in tissue from the kidney and parts of the colon.[7] Paraoxonase 1 that is synthesized in the liver is then transported into the blood stream where it will associate with high-density lipoprotein (HDL). It has been shown to have broad substrate specificity and has proved to protect against exposure to some organophosphates (such as those from insecticides) by hydrolyzing potentially toxic metabolites.[8][9] Paraoxonase 1 also plays an important role as an antioxidant in preventing the oxidation of low-density lipoproteins (LDL), a process that is directly involved in the development of atherosclerosis. Its serum concentration is influenced by inflammatory changes and the levels of serum oxidised-LDL. - Paraoxonase 2 is a ubiquitously expressed intracellular protein that can protect cells against oxidative damage.[10] While paraoxonase 2 shares similar antioxidant properties with its two enzyme counterparts, it lacks the ability to hydrolyze some of the organophosphate metabolites. - Paraoxonase 3 is similar to type 1 in activity but differs from it in substrate specificity. Serum PON3 activity is 100 times lower than PON1. Additionally, it is not regulated by inflammation and levels of oxidised lipids.[11] Both paraoxonase 1 and 3 are bound to HDL and because of their similar properties as antioxidants, it is possible PON3 also plays a role in the prevention of LDL and HDL oxidation.[12] # Biological function Paraoxonases have been found to perform a number of biological functions, though the primary role of this group of enzymes is still a topic of speculation. Some of the observed roles have revealed activities of anti-inflammatory, anti-oxidative, anti-atherogenic, anti-diabetic, anti-microbial and organophosphate-hydrolyzing properties.[13] Two of the most important known roles that Paraoxonases plays are in functioning as a lactonase and an arylesterase. These properties provide a promising potential for development of new therapeutic interventions to combat a number of health conditions.[14][15] # Mechanism The study of this family of enzymes has been something of interest for a number of years now;[when?] however, the lack of identifying specific natural substrates and numerous physiological roles has made it difficult in determining mechanisms of action for the diverse number of reactions catalyzed by this enzyme family. One of the more studied mechanisms is the lactonase mechanism of Serum Paraoxonase-1. One of the proposed mechanism outlines the hydrolysis of 5-membered ring lactone substrates by serum Paraoxonase-1. PON1, as with PON2 and PON3, utilizes a catalytic calcium ion, which functions as an oxy-anion to stabilize substrate and reaction states. Additionally, this enzyme active site employs two histidine residues (His115 and 134) involved in proton transfers, a glutamic acid (Glu53) to stabilize reactive hydrogens, and an asparagine (Asn168) to stabilize transition states and intermediates in the active site.[15] The exact mechanism is still a subject of further research and it is suggested that the His115 residue is not necessary for the lactonase and arylesterase activity of the enzyme.[13] # Regulation One of the common inhibitors of enzymatic activity (for PON 1 and PON 3) is lipid peroxides found in the plasma. Lipid peroxides can inhibit Paraoxonase activity as an arylesterase and antioxidant, though the specific inhibition is dependent on the type of lipid head group.[4][9] An important implication of this fact is that, in decreasing the activity of PON1 and PON3, the productivity of preventing oxidation of LDL. Enzyme activity is also regulated by a substrate-dependent polymorphism that occurs at position 192. There are two known isoforms, one having an arginine residue at the 192 position and the other a glutamine, which are associated with high and low enzymatic activity respectively.[16][17] # Clinical significance The development of atherosclerosis is a complex process, though the main underlying feature is simply an increase in low-density lipoprotein (LDL) oxidation.[18] PON1 and PON3 prevent the formation of atherogenic oxidised-LDL, the form of LDL present in foam cells of an atheromatous plaque. Because of their know association with high-density lipoprotein (HDL) and their effect on oxidized-LDL, PON1 and PON3 are implicated in lowering the risk of developing coronary artery disease and atherosclerosis. # History PON was identified as an enzyme having organophosphates as its substrates. Reports of the geographic differences in population frequencies of paraoxonase activity and genetic analysis led to uncovering the genetic polymorphism. The name paraoxonase was given because of its ability to hydrolyze paraoxon, a toxic metabolite that comes from pesticide parathion.[3] The 3D crystal structure of PON1 was determined in 2004.[19]	https://www.wikidoc.org/index.php/Paraoxonase
d700592b8c6f0bec4dc2777625c32fc2ab669dc3	wikidoc	Parasitemia	Parasitemia Parasitemia is the quantitative content of parasites in the blood. It is used as a measurement of parasite load in the organism and an indication of the degree of an active parasitic infection. Systematic measurement of parasitemia is important in many phases of the assessment of disease, such as in diagnosis and in the follow-up of therapy, particularly in the chronic phase, when cure depends on ascertaining a parasitemia of zero. The methods to be used for quantifying parasitemia depends on the parasitic species and its life cycle. For instance, in malaria, the number of plasmodia can be counted using an optical microscope, on a special thick film (for low parasitemias) or thin film blood smear (for high parasitemias). The use of molecular biology techniques, such as PCR has been more and more used as a tool to measure parasitemia, specially in patients in the chronic phase of disease. In this technique, blood samples are obtained from the patient, and specific DNA of the parasite is extracted and amplified by PCR.	Parasitemia Parasitemia is the quantitative content of parasites in the blood. It is used as a measurement of parasite load in the organism and an indication of the degree of an active parasitic infection. Systematic measurement of parasitemia is important in many phases of the assessment of disease, such as in diagnosis and in the follow-up of therapy, particularly in the chronic phase, when cure depends on ascertaining a parasitemia of zero. The methods to be used for quantifying parasitemia depends on the parasitic species and its life cycle. For instance, in malaria, the number of plasmodia can be counted using an optical microscope, on a special thick film (for low parasitemias) or thin film blood smear (for high parasitemias). The use of molecular biology techniques, such as PCR has been more and more used as a tool to measure parasitemia, specially in patients in the chronic phase of disease. In this technique, blood samples are obtained from the patient, and specific DNA of the parasite is extracted and amplified by PCR. Template:Abnormal clinical and laboratory findings Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Parasitemia
6283a5ec62a5711de609a674075b15479266cca5	wikidoc	Parasuicide	Parasuicide Parasuicide refers to suicidal gestures, risky behavior likely to result in death, or unsuccessful suicide attempts. Examples of suicidal gestures include cutting in which the cut is not deep enough to cause significant blood loss, or taking a non-lethal overdose of medication. This differs from self-harm in that, in self-harm, the person's primary intention is to injure himself. These gestures are typically done to alert others to the seriousness of the suicidal person's clinical depression and suicidal ideation, as they are usually treated as an actual suicide attempt by others, including hospital staff. Despite the parasuicidal person having no intention of dying, sometimes suicidal gestures result in actual suicide. Risky behaviors such as speeding or disregarding traffic laws, or abusing drugs, are considered parasuicide when the person shows total disregard for whether his actions result in his or her death. Unsuccessful suicide attempts result from either miscalculations in the suicide plan (such as not taking enough pills to reach lethal dose), intervention from others or hospitalization, pure chance, or the suicidal person changing his mind after he has started his suicide attempt. These people are at high risk of attempting suicide again. # Epidemiology Nearly half of all suicides are preceded by an attempt at suicide that does not end in death. Those with a history of such attempts are significantly more likely eventually to end their own lives than those without. A suicidal act that did not end in death is commonly called a "suicide attempt" or a "suicidal gesture", with the distinction being that the goal of a suicide attempt is the death of the individual. Those who attempt to harm themselves are, as a group, quite different from those who actually die from suicide; females attempt suicide much more frequently than males do, but males are four times more likely to die from suicide. Therefore, females commit more parasuicides, at least as far as suicidal gestures and attempts are concerned. Regardless of the intention of the parasuicide, it must be treated seriously, due to the risk of future suicide attempts by these individuals.	Parasuicide Template:Bias Template:Weasel Template:Cleanup Parasuicide refers to suicidal gestures, risky behavior likely to result in death, or unsuccessful suicide attempts. Examples of suicidal gestures include cutting in which the cut is not deep enough to cause significant blood loss, or taking a non-lethal overdose of medication. This differs from self-harm in that, in self-harm, the person's primary intention is to injure himself. These gestures are typically done to alert others to the seriousness of the suicidal person's clinical depression and suicidal ideation, as they are usually treated as an actual suicide attempt by others, including hospital staff. Despite the parasuicidal person having no intention of dying, sometimes suicidal gestures result in actual suicide. Risky behaviors such as speeding or disregarding traffic laws, or abusing drugs, are considered parasuicide when the person shows total disregard for whether his actions result in his or her death. Unsuccessful suicide attempts result from either miscalculations in the suicide plan (such as not taking enough pills to reach lethal dose), intervention from others or hospitalization, pure chance, or the suicidal person changing his mind after he has started his suicide attempt. These people are at high risk of attempting suicide again. # Epidemiology Nearly half of all suicides are preceded by an attempt at suicide that does not end in death. Those with a history of such attempts are significantly more likely eventually to end their own lives than those without.[1] A suicidal act that did not end in death is commonly called a "suicide attempt" or a "suicidal gesture", with the distinction being that the goal of a suicide attempt is the death of the individual. Those who attempt to harm themselves are, as a group, quite different from those who actually die from suicide; females attempt suicide much more frequently than males do, but males are four times more likely to die from suicide. Therefore, females commit more parasuicides, at least as far as suicidal gestures and attempts are concerned. Regardless of the intention of the parasuicide, it must be treated seriously, due to the risk of future suicide attempts by these individuals.	https://www.wikidoc.org/index.php/Parasuicide
c8c83fe35c4fe4dceadf603d4ca22f32440bde9e	wikidoc	Parasystole	Parasystole # Overview Parasystole is a type of arrhythmia caused by the presence and function of a secondary pacemaker in the heart, which works in parallel with the SA node. Parasystolic pacemakers are protected from depolarization by the SA node by some form of entrance block. This block can be complete or incomplete. Parasystolic pacemakers can exist in the atrium or the ventriculus. Atrial parasystolia are characterized by being a type of narrow QRS complexes Arrhythmia. # Historical Perspective - Parasystole was first reported by Schamroth in 1967. - Parasystole as an entity was studied by Kaufmann and Bothberger, but their studies are now interpreted differently. # Classification - Parasystole may be classified according to location of their origin but in literature no such classification mentioned. - Parasystole consists of stimultaneous activity of two (rarely more) independent impulse-forming centers, one of which is "protected" from the other, each competing to activate the atria or ventricles or both. - The parasystolic pacemaker may be located anywhere in the heart but is commonly located in the ventricles, less commonly in the A-V node and rarely in the atria. # Pathophysiology - Parasystole is a result of interaction between two fixed rate pacemakers having different discharge rates. - Parasystolic pacemakers can exist in either the atrium or the ventricle. - The latent pacemaker is protected from being overdriven by the dominant rhythm (usually NSR) by intermittent or constant entrance block (impulses of sinus origin fail to depolarize the latent pacemaker secondary to block in the tissue surrounding the latent pacemaker focus). - The depolarized level of membrane potential at which abnormal automaticity occurs can cause entrance block, leading to parasystole. This would be an example of an arrhythmia caused by a combination of an abnormality of impulse conduction and impulse initiation. - Such block must be unidirectional, so that activity from the ectopic pacemaker can exit and produce depolarization whenever the surrounding myocardium is excitable. - The protected pacemaker is said to be a parasystolic focus. In general, under these conditions, a protected focus of automaticity of this type fires at its own intrinsic frequency, and the intervals between the discharges of each pacemaker are multiples of its intrinsic discharge rate (sometimes described as fixed parasystole). - Therefore on the surface electrocardiogram (ECG) the coupling intervals of the manifest ectopic beats wander through the basic cycle of the sinus rhythm. - The traditional ECG criteria used to recognize the fixed form of parasystole include: The presence of variable coupling intervals of the manifest ectopic beats. Interectopic intervals that are simple multiples of a common denominat. The presence of fusion beats. - The presence of variable coupling intervals of the manifest ectopic beats. - Interectopic intervals that are simple multiples of a common denominat. - The presence of fusion beats. - The parasystolic focus can exhibit exit block, during which it may fail to depolarize excitable myocardium. - The parasystolic focus is protected, it may not be totally immune to the surrounding electrical activity. - The effective electrical communication that permits the emergence of the ectopic discharges can also allow the rhythmic activity of the surrounding tissues to electrotonically influence the periodicity of the pacemaker discharge rate. - Electrotonic influences arriving during the early stage of diastolic depolarization result in a delay in the firing of the parasystolic focus, whereas those arriving late accelerate the discharge of the parasystolic focus. - As a consequence, the dominant pacemaker can entrain the partially protected parasystolic focus and force it to discharge at periods that may be faster or slower than its own intrinsic cycle and give rise to premature discharges whose patterns depend on the degree of modulation and the basic heart rate, occasionally mimic reentry, and occur at fixed coupling intervals. - All these features of abnormal automaticity can be found in the Purkinje fibers that survive in regions of transmural MI and cause ventricular arrhythmias during the subacute phase.. # Clinical Features - Parasystole may feel that heart is racing or beating too slowly. - Heart may not pump effectively due to the fast or slow heartbeat. - These include shortness of breath, weakness, dizziness, lightheadedness, fainting or near fainting, and chest pain or discomfort. # Differentiating from other Diseases The differentiating features are largely based on both EKG findings and cardiovascular examination. - Atrial fibrillation is irregularly irregular, while the other rhythms such as atrial flutter, sinus tachycardia, AV nodal reentry tachycardia and paroxysmal supraventricular tachycardia are all much more regular. - An atrioventricular nodal reentry tachycardia will often break with either carotid sinus massage or AV nodal blocking agents. - If the patient has Wolff-Parkinson-White syndrome there may be much more rapid conduction. The presence of the delta wave on EKG is characteristic. # Epidemiology and Demographics - The incidence of parasystole is approximately 0.13 per cent of all electrocardiograms taken in a general hospital and is seen twice as frequently in males. - In the majority of the cases studied with parasystole there was demonstrated some form of heart disease and 65 per cent of the patients were older than 60 years of age. - The most commonly associated heart diseases were arteriosclerotic heart disease and/or hypertensive cardiovascular disease (60 per cent) and half of these subjects had congestive heart failure. ## Age - Patients of all age groups may develop Parasystole. - Parasystole is more commonly observed among patients older than 60 years old. - Parasystole is more commonly observed among elderly patients. ## Gender - Males are more commonly affected with Parasystole than females. - The male to female ratio is approximately 2 to 1. ## Race - There is no racial predilection for Parasystole. # Risk Factors - Parasystole is a kind of arrhythmia caused by the presence and function of a secondary pacemaker in the heart,so any heart rhythm problem or condition can be a risk factor. - The most commonly associated heart diseases were arteriosclerotic heart disease and/or hypertensive cardiovascular disease (60 per cent) and half of these subjects had congestive heart failure. - Various other acquired and congenital heart diseases were also associated with this arrhythmia but 14 per cent failed to show any evidence of heart disease. # Natural History, Complications and Prognosis - Early clinical features include palpitations, shortness of breath, chest pain. - Although parasystole generally carries a benign prognosis, parasystolic beats may be capable of inducing ventricular tachycardia and ventricular fibrillation on rare occasions. - The prognosis of individuals with arrhythmia is influenced by the presence, absence or status of the underlying heart disease. # Diagnosis - Diagnosis based on EKG. ## Symptoms - Symptoms of may include the following: - Palpitation - Shortness of breath - Chest pain - Syncope ## Laboratory Findings - There are no specific laboratory findings associated with parasystole. ## Imaging Findings - There are no imaging study findings associated with parasystole. # ECG signals On an ECG, parasystole may be recognized by: - spotting ectopic P or QRS waves which either: -ccur at regular intervals the time between them is always exact multiple of the smallest time between such two occurrences - occur at regular intervals - the time between them is always exact multiple of the smallest time between such two occurrences - spotting "fusioned" P or QRS complexes (sometimes rare) Another feature is the varying coupling interval between sinus and ectopic beats. # Treatment ## Medical Therapy - There is no treatment for parasystole, the mainstay of therapy is supportive care. ## Surgery - Surgery is not an option for parasystole. ## Prevention - There are no primary preventive measures available for parasystole.	Parasystole Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammed Salih, MD. # Overview Parasystole is a type of arrhythmia caused by the presence and function of a secondary pacemaker in the heart, which works in parallel with the SA node. Parasystolic pacemakers are protected from depolarization by the SA node by some form of entrance block. This block can be complete or incomplete. Parasystolic pacemakers can exist in the atrium or the ventriculus. Atrial parasystolia are characterized by being a type of narrow QRS complexes Arrhythmia. # Historical Perspective - Parasystole was first reported by Schamroth in 1967. - Parasystole as an entity was studied by Kaufmann and Bothberger, but their studies are now interpreted differently. # Classification - Parasystole may be classified according to location of their origin but in literature no such classification mentioned. - Parasystole consists of stimultaneous activity of two (rarely more) independent impulse-forming centers, one of which is "protected" from the other, each competing to activate the atria or ventricles or both. - The parasystolic pacemaker may be located anywhere in the heart but is commonly located in the ventricles, less commonly in the A-V node and rarely in the atria. # Pathophysiology - Parasystole is a result of interaction between two fixed rate pacemakers having different discharge rates. - Parasystolic pacemakers can exist in either the atrium or the ventricle. - The latent pacemaker is protected from being overdriven by the dominant rhythm (usually NSR) by intermittent or constant entrance block (impulses of sinus origin fail to depolarize the latent pacemaker secondary to block in the tissue surrounding the latent pacemaker focus). - The depolarized level of membrane potential at which abnormal automaticity occurs can cause entrance block, leading to parasystole. This would be an example of an arrhythmia caused by a combination of an abnormality of impulse conduction and impulse initiation. - Such block must be unidirectional, so that activity from the ectopic pacemaker can exit and produce depolarization whenever the surrounding myocardium is excitable. - The protected pacemaker is said to be a parasystolic focus. In general, under these conditions, a protected focus of automaticity of this type fires at its own intrinsic frequency, and the intervals between the discharges of each pacemaker are multiples of its intrinsic discharge rate (sometimes described as fixed parasystole). - Therefore on the surface electrocardiogram (ECG) the coupling intervals of the manifest ectopic beats wander through the basic cycle of the sinus rhythm. - The traditional ECG criteria used to recognize the fixed form of parasystole include: The presence of variable coupling intervals of the manifest ectopic beats. Interectopic intervals that are simple multiples of a common denominat. The presence of fusion beats. - The presence of variable coupling intervals of the manifest ectopic beats. - Interectopic intervals that are simple multiples of a common denominat. - The presence of fusion beats. - The parasystolic focus can exhibit exit block, during which it may fail to depolarize excitable myocardium. - The parasystolic focus is protected, it may not be totally immune to the surrounding electrical activity. - The effective electrical communication that permits the emergence of the ectopic discharges can also allow the rhythmic activity of the surrounding tissues to electrotonically influence the periodicity of the pacemaker discharge rate. - Electrotonic influences arriving during the early stage of diastolic depolarization result in a delay in the firing of the parasystolic focus, whereas those arriving late accelerate the discharge of the parasystolic focus. - As a consequence, the dominant pacemaker can entrain the partially protected parasystolic focus and force it to discharge at periods that may be faster or slower than its own intrinsic cycle and give rise to premature discharges whose patterns depend on the degree of modulation and the basic heart rate, occasionally mimic reentry, and occur at fixed coupling intervals. - All these features of abnormal automaticity can be found in the Purkinje fibers that survive in regions of transmural MI and cause ventricular arrhythmias during the subacute phase.. # Clinical Features - Parasystole may feel that heart is racing or beating too slowly. - Heart may not pump effectively due to the fast or slow heartbeat. - These include shortness of breath, weakness, dizziness, lightheadedness, fainting or near fainting, and chest pain or discomfort. # Differentiating [disease name] from other Diseases The differentiating features are largely based on both EKG findings and cardiovascular examination. - Atrial fibrillation is irregularly irregular, while the other rhythms such as atrial flutter, sinus tachycardia, AV nodal reentry tachycardia and paroxysmal supraventricular tachycardia are all much more regular. - An atrioventricular nodal reentry tachycardia will often break with either carotid sinus massage or AV nodal blocking agents. - If the patient has Wolff-Parkinson-White syndrome there may be much more rapid conduction. The presence of the delta wave on EKG is characteristic. # Epidemiology and Demographics - The incidence of parasystole is approximately 0.13 per cent of all electrocardiograms taken in a general hospital and is seen twice as frequently in males. - In the majority of the cases studied with parasystole there was demonstrated some form of heart disease and 65 per cent of the patients were older than 60 years of age. - The most commonly associated heart diseases were arteriosclerotic heart disease and/or hypertensive cardiovascular disease (60 per cent) and half of these subjects had congestive heart failure. ## Age - Patients of all age groups may develop Parasystole. - Parasystole is more commonly observed among patients older than 60 years old. - Parasystole is more commonly observed among elderly patients. ## Gender - Males are more commonly affected with Parasystole than females. - The male to female ratio is approximately 2 to 1. ## Race - There is no racial predilection for Parasystole. # Risk Factors - Parasystole is a kind of arrhythmia caused by the presence and function of a secondary pacemaker in the heart,so any heart rhythm problem or condition can be a risk factor. - The most commonly associated heart diseases were arteriosclerotic heart disease and/or hypertensive cardiovascular disease (60 per cent) and half of these subjects had congestive heart failure. - Various other acquired and congenital heart diseases were also associated with this arrhythmia but 14 per cent failed to show any evidence of heart disease. # Natural History, Complications and Prognosis - Early clinical features include palpitations, shortness of breath, chest pain. - Although parasystole generally carries a benign prognosis, parasystolic beats may be capable of inducing ventricular tachycardia and ventricular fibrillation on rare occasions. - The prognosis of individuals with arrhythmia is influenced by the presence, absence or status of the underlying heart disease. # Diagnosis - Diagnosis based on EKG. ## Symptoms - Symptoms of may include the following: - Palpitation - Shortness of breath - Chest pain - Syncope ## Laboratory Findings - There are no specific laboratory findings associated with parasystole. ## Imaging Findings - There are no imaging study findings associated with parasystole. # ECG signals On an ECG, parasystole may be recognized by: - spotting ectopic P or QRS waves which either: occur at regular intervals the time between them is always exact multiple of the smallest time between such two occurrences - occur at regular intervals - the time between them is always exact multiple of the smallest time between such two occurrences - spotting "fusioned" P or QRS complexes (sometimes rare) Another feature is the varying coupling interval between sinus and ectopic beats. # Treatment ## Medical Therapy - There is no treatment for parasystole, the mainstay of therapy is supportive care. ## Surgery - Surgery is not an option for parasystole. ## Prevention - There are no primary preventive measures available for parasystole. # External links - ventricular parasystole - atrial parasystole Template:WikiDoc Sources - ↑ Lankveld TA, Zeemering S, Crijns HJ, Schotten U (July 2014). "The ECG as a tool to determine atrial fibrillation complexity". Heart. 100 (14): 1077–84. doi:10.1136/heartjnl-2013-305149. PMID 24837984..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} - ↑ Harris K, Edwards D, Mant J (2012). "How can we best detect atrial fibrillation?". J R Coll Physicians Edinb. 42 Suppl 18: 5–22. doi:10.4997/JRCPE.2012.S02. PMID 22518390. - ↑ Cosío FG (June 2017). "Atrial Flutter, Typical and Atypical: A Review". Arrhythm Electrophysiol Rev. 6 (2): 55–62. doi:10.15420/aer.2017.5.2. PMC 5522718. PMID 28835836. - ↑ Katritsis DG, Josephson ME (August 2016). "Classification, Electrophysiological Features and Therapy of Atrioventricular Nodal Reentrant Tachycardia". Arrhythm Electrophysiol Rev. 5 (2): 130–5. doi:10.15420/AER.2016.18.2. PMC 5013176. PMID 27617092. - ↑ Letsas KP, Weber R, Siklody CH, Mihas CC, Stockinger J, Blum T, Kalusche D, Arentz T (April 2010). "Electrocardiographic differentiation of common type atrioventricular nodal reentrant tachycardia from atrioventricular reciprocating tachycardia via a concealed accessory pathway". Acta Cardiol. 65 (2): 171–6. doi:10.2143/AC.65.2.2047050. PMID 20458824. - ↑ "Atrioventricular Nodal Reentry Tachycardia (AVNRT) - StatPearls - NCBI Bookshelf". - ↑ Schernthaner C, Danmayr F, Strohmer B (2014). "Coexistence of atrioventricular nodal reentrant tachycardia with other forms of arrhythmias". Med Princ Pract. 23 (6): 543–50. doi:10.1159/000365418. PMC 5586929. PMID 25196716. - ↑ Scher DL, Arsura EL (September 1989). "Multifocal atrial tachycardia: mechanisms, clinical correlates, and treatment". Am. Heart J. 118 (3): 574–80. doi:10.1016/0002-8703(89)90275-5. PMID 2570520. - ↑ Goodacre S, Irons R (March 2002). "ABC of clinical electrocardiography: Atrial arrhythmias". BMJ. 324 (7337): 594–7. doi:10.1136/bmj.324.7337.594. PMC 1122515. PMID 11884328. - ↑ Lin CY, Lin YJ, Chen YY, Chang SL, Lo LW, Chao TF, Chung FP, Hu YF, Chong E, Cheng HM, Tuan TC, Liao JN, Chiou CW, Huang JL, Chen SA (August 2015). "Prognostic Significance of Premature Atrial Complexes Burden in Prediction of Long-Term Outcome". J Am Heart Assoc. 4 (9): e002192. doi:10.1161/JAHA.115.002192. PMC 4599506. PMID 26316525. - ↑ Strasburger JF, Cheulkar B, Wichman HJ (December 2007). "Perinatal arrhythmias: diagnosis and management". Clin Perinatol. 34 (4): 627–52, vii–viii. doi:10.1016/j.clp.2007.10.002. PMC 3310372. PMID 18063110. - ↑ Rao AL, Salerno JC, Asif IM, Drezner JA (July 2014). "Evaluation and management of wolff-Parkinson-white in athletes". Sports Health. 6 (4): 326–32. doi:10.1177/1941738113509059. PMC 4065555. PMID 24982705. - ↑ Rosner MH, Brady WJ, Kefer MP, Martin ML (November 1999). "Electrocardiography in the patient with the Wolff-Parkinson-White syndrome: diagnostic and initial therapeutic issues". Am J Emerg Med. 17 (7): 705–14. doi:10.1016/s0735-6757(99)90167-5. PMID 10597097. - ↑ Glinge C, Sattler S, Jabbari R, Tfelt-Hansen J (September 2016). "Epidemiology and genetics of ventricular fibrillation during acute myocardial infarction". J Geriatr Cardiol. 13 (9): 789–797. doi:10.11909/j.issn.1671-5411.2016.09.006. PMC 5122505. PMID 27899944. - ↑ Samie FH, Jalife J (May 2001). "Mechanisms underlying ventricular tachycardia and its transition to ventricular fibrillation in the structurally normal heart". Cardiovasc. Res. 50 (2): 242–50. doi:10.1016/s0008-6363(00)00289-3. PMID 11334828. - ↑ Adabag AS, Luepker RV, Roger VL, Gersh BJ (April 2010). "Sudden cardiac death: epidemiology and risk factors". Nat Rev Cardiol. 7 (4): 216–25. doi:10.1038/nrcardio.2010.3. PMC 5014372. PMID 20142817. - ↑ Koplan BA, Stevenson WG (March 2009). "Ventricular tachycardia and sudden cardiac death". Mayo Clin. Proc. 84 (3): 289–97. doi:10.1016/S0025-6196(11)61149-X. PMC 2664600. PMID 19252119. - ↑ Levis JT (2011). "ECG Diagnosis: Monomorphic Ventricular Tachycardia". Perm J. 15 (1): 65. doi:10.7812/tpp/10-130. PMC 3048638. PMID 21505622.	https://www.wikidoc.org/index.php/Parasystole
fbecf577040574f2050ba3373c6e6b325acdebe2	wikidoc	Pericardium	Pericardium # Overview The pericardium is a double-walled sac that contains the heart and the roots of the great vessels. Morphologically, it is a conical-shaped, double-walled fibro-serous membrane. It rests posteriorly to the sternum at the level of second to sixth costal cartilages and T5-T8 vertebrae. # Layers - The pericardium is made up of two layers: Fibrous pericardium Hard protective external layer Attached to sternum anteriorly by sterno-pericardial ligaments and fused with the central tendon of the diaphragm and great vessels to allow mobility of the pericardial sac against sudden cardiac overfilling Serous pericardium Smooth internal layer made up of 2 components: Parietal: reflects onto fibrous pericardium Visceral: reflects onto heart and great vessels and forms the epicardium, the external layer of the heart wall - Fibrous pericardium Hard protective external layer Attached to sternum anteriorly by sterno-pericardial ligaments and fused with the central tendon of the diaphragm and great vessels to allow mobility of the pericardial sac against sudden cardiac overfilling - Hard protective external layer - Attached to sternum anteriorly by sterno-pericardial ligaments and fused with the central tendon of the diaphragm and great vessels to allow mobility of the pericardial sac against sudden cardiac overfilling - Serous pericardium Smooth internal layer made up of 2 components: Parietal: reflects onto fibrous pericardium Visceral: reflects onto heart and great vessels and forms the epicardium, the external layer of the heart wall - Smooth internal layer made up of 2 components: Parietal: reflects onto fibrous pericardium Visceral: reflects onto heart and great vessels and forms the epicardium, the external layer of the heart wall - Parietal: reflects onto fibrous pericardium - Visceral: reflects onto heart and great vessels and forms the epicardium, the external layer of the heart wall - Pericardial cavity: Potential space between parietal and visceral layers. It contains a serous fluid film that occupies the cavity and functions as lubricant against friction by all chest movements. # Pericardial Sinuses - There are two small chambers or sinuses located where the visceral and parietal pericardia are continuous with one another within the pericardial cavity. - Transverse sinus: Located posterior to the pulmonary trunk and ascending aorta at the level between the superior vena cava and aortic arch Formed after dorsal mesocardium rupture embryonically Functional role is to allow the unhindered expansion of great arteries posteriorly during cardiac systole Utilized surgically to pass surgical clamps or place ligatures around great arteries. - Located posterior to the pulmonary trunk and ascending aorta at the level between the superior vena cava and aortic arch - Formed after dorsal mesocardium rupture embryonically - Functional role is to allow the unhindered expansion of great arteries posteriorly during cardiac systole - Utilized surgically to pass surgical clamps or place ligatures around great arteries. - Oblique sinus: A blind recess (cul-de-sac) posterior to the left atrium between superior vena cava, right and left pulmonary veins inferior to the transverse sinus Formed embryonically by the incorporation of the pulmonary vein tributaries into the left atrium Functional role believed to be the expansion of the left atrium upon normal collapse of the thorax - A blind recess (cul-de-sac) posterior to the left atrium between superior vena cava, right and left pulmonary veins inferior to the transverse sinus - Formed embryonically by the incorporation of the pulmonary vein tributaries into the left atrium - Functional role believed to be the expansion of the left atrium upon normal collapse of the thorax # Diseases of the Pericardium - Pericarditis is an inflammatory condition of the pericardium. - Pericardial effusion is fluid accumulation in the pericardial sac. - Constrictive pericarditis occurs when there is a scar encasing, the heart that chronically constricts the filling of the heart. - Cardiac tamponade is a medical emergency in which fluid in the pericardial sac acutely restricts the filling of the heart. This requires surgical drainage or pericardiocentesis. # Additional Images - The phrenic nerve and its relations with the vagus nerve. - Thoracic portion of the sympathetic trunk. - Liver with the septum transversum. Human embryo 3 mm long. - The thymus of a full-time fetus, exposed in situ.	Pericardium Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Rim Halaby # Overview The pericardium is a double-walled sac that contains the heart and the roots of the great vessels. Morphologically, it is a conical-shaped, double-walled fibro-serous membrane. It rests posteriorly to the sternum at the level of second to sixth costal cartilages and T5-T8 vertebrae. # Layers - The pericardium is made up of two layers: Fibrous pericardium Hard protective external layer Attached to sternum anteriorly by sterno-pericardial ligaments and fused with the central tendon of the diaphragm and great vessels to allow mobility of the pericardial sac against sudden cardiac overfilling Serous pericardium Smooth internal layer made up of 2 components: Parietal: reflects onto fibrous pericardium Visceral: reflects onto heart and great vessels and forms the epicardium, the external layer of the heart wall - Fibrous pericardium Hard protective external layer Attached to sternum anteriorly by sterno-pericardial ligaments and fused with the central tendon of the diaphragm and great vessels to allow mobility of the pericardial sac against sudden cardiac overfilling - Hard protective external layer - Attached to sternum anteriorly by sterno-pericardial ligaments and fused with the central tendon of the diaphragm and great vessels to allow mobility of the pericardial sac against sudden cardiac overfilling - Serous pericardium Smooth internal layer made up of 2 components: Parietal: reflects onto fibrous pericardium Visceral: reflects onto heart and great vessels and forms the epicardium, the external layer of the heart wall - Smooth internal layer made up of 2 components: Parietal: reflects onto fibrous pericardium Visceral: reflects onto heart and great vessels and forms the epicardium, the external layer of the heart wall - Parietal: reflects onto fibrous pericardium - Visceral: reflects onto heart and great vessels and forms the epicardium, the external layer of the heart wall - Pericardial cavity: Potential space between parietal and visceral layers. It contains a serous fluid film that occupies the cavity and functions as lubricant against friction by all chest movements.[1][2][3] # Pericardial Sinuses - There are two small chambers or sinuses located where the visceral and parietal pericardia are continuous with one another within the pericardial cavity. - Transverse sinus: Located posterior to the pulmonary trunk and ascending aorta at the level between the superior vena cava and aortic arch Formed after dorsal mesocardium rupture embryonically Functional role is to allow the unhindered expansion of great arteries posteriorly during cardiac systole Utilized surgically to pass surgical clamps or place ligatures around great arteries. - Located posterior to the pulmonary trunk and ascending aorta at the level between the superior vena cava and aortic arch - Formed after dorsal mesocardium rupture embryonically - Functional role is to allow the unhindered expansion of great arteries posteriorly during cardiac systole - Utilized surgically to pass surgical clamps or place ligatures around great arteries. - Oblique sinus: A blind recess (cul-de-sac) posterior to the left atrium between superior vena cava, right and left pulmonary veins inferior to the transverse sinus Formed embryonically by the incorporation of the pulmonary vein tributaries into the left atrium Functional role believed to be the expansion of the left atrium upon normal collapse of the thorax[4][5][6] - A blind recess (cul-de-sac) posterior to the left atrium between superior vena cava, right and left pulmonary veins inferior to the transverse sinus - Formed embryonically by the incorporation of the pulmonary vein tributaries into the left atrium - Functional role believed to be the expansion of the left atrium upon normal collapse of the thorax[4][5][6] - - # Diseases of the Pericardium - Pericarditis is an inflammatory condition of the pericardium. - Pericardial effusion is fluid accumulation in the pericardial sac. - Constrictive pericarditis occurs when there is a scar encasing, the heart that chronically constricts the filling of the heart. - Cardiac tamponade is a medical emergency in which fluid in the pericardial sac acutely restricts the filling of the heart. This requires surgical drainage or pericardiocentesis. # Additional Images - The phrenic nerve and its relations with the vagus nerve. - Thoracic portion of the sympathetic trunk. - Liver with the septum transversum. Human embryo 3 mm long. - The thymus of a full-time fetus, exposed in situ.	https://www.wikidoc.org/index.php/Parietal_pericardium
9c169f90ead7e48927ac9319b53603cf2f3195d5	wikidoc	Parke-Davis	Parke-Davis Ben Van Cise is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history. Parke-Davis originally was founded in Detroit, Michigan by Hervey Parke and George Davis in 1886. It was once the world's largest pharmaceutical company, and is credited with building the first modern pharmaceutical laboratory and developing the first systematic methods of performing clinical trials of new medications. Parke-Davis was acquired by Warner-Lambert in 1970, which in turn was bought by Pfizer in 2000. One of Parke-Davis' early products was an amylase isolated from Aspergillus oryzae by Dr. Jokichi Takamine. The enzyme was originally intended for use in distilleries, but was more successfully marketed as "Taka-diastase" for dyspepsia. They also develop Ketalar (Ketamine Hydrochlorides), an aneasthesian for horses, and dissociative drug in 1962. Another of the company's products developed by Takamine was a pure form of adrenaline. The compound was patented in 1900 and trademarked as "Adrenalin". Because of the similarity of this name to "Adrenaline", the use of the alternative name "epinephrine" for generics was mandated in the United States and is used to this day. A lawsuit filed by H.K. Mulford challenged the patent on the grounds that it was a natural product and therefore unpatentable. The ruling in favor of Parke-Davis by judge Learned Hand is considered crucial to modern patent law. Before its criminalization, Parke-Davis sold cocaine in various forms, including cigarettes, powder, and even a cocaine mixture that could be injected directly into the user’s veins with the included needle. The company promised that its cocaine products would “supply the place of food, make the coward brave, the silent eloquent and ... render the sufferer insensitive to pain. Phencyclidine (PCP) was first patented in the 1950s by the Parke-Davis pharmaceutical company. PCP is listed as a Schedule II drug in the United States under the Convention on Psychotropic Substances. Parke-Davis marketed the first widely available epilepsy treatment, Dilantin, which was approved in 1939, although it discovered neither the compound nor the application on its own. The first bacterial vaccine was developed by Parke-Davis, and the company was thus known as as a pioneer in the field of Vaccinology. It was also among the five firms contracted to manufacture the Salk vaccine used to eradicate polio A combination of the DPT and polio vaccines, called Quadrigen, was developed in 1954 and approved in 1959. Quadrigen was later removed from the market in 1968 after a series of lawsuits pertaining to adverse effects in vaccinated children. Other products popularized by the company included anti-infectives and brands of combined oral contraceptive pills. # Modern Events In the case of Franklin v. Parke-Davis (2002) the company was accused of illegal marketing practices, including the promotion of off-label uses of its anticonvulsant medication Neurontin. The drug had only been approved for use in patients with epilepsy, but in 2001 over 80% of its $1.8 billion in sales were for indications unapproved by the FDA. In 2004, Pfizer "admitted that aggressively marketed by illicit means for unrelated conditions including bipolar disorder, pain, migraine headaches, and drug and alcohol withdrawal", and consented to $430 million dollars in penalties although it claimed the violations originated in 1996, well before Pfizer's acquisition of Warner-Lambert. As announced on January 22, 2007, Pfizer will close its research facilities in Ann Arbor, MI. # Trivia Actor Calvert DeForest, who appeared multiple times with David Letterman, worked for the company for many years.	Parke-Davis Ben Van Cise is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker,[1] and played an important role in medical history. Parke-Davis originally was founded in Detroit, Michigan by Hervey Parke and George Davis in 1886. It was once the world's largest pharmaceutical company, and is credited with building the first modern pharmaceutical laboratory and developing the first systematic methods of performing clinical trials of new medications. Parke-Davis was acquired by Warner-Lambert in 1970, which in turn was bought by Pfizer in 2000. One of Parke-Davis' early products was an amylase isolated from Aspergillus oryzae by Dr. Jokichi Takamine.[2] The enzyme was originally intended for use in distilleries, but was more successfully marketed as "Taka-diastase" for dyspepsia. They also develop Ketalar (Ketamine Hydrochlorides), an aneasthesian for horses, and dissociative drug in 1962. Another of the company's products developed by Takamine was a pure form of adrenaline. The compound was patented in 1900 and trademarked as "Adrenalin". Because of the similarity of this name to "Adrenaline", the use of the alternative name "epinephrine" for generics was mandated in the United States and is used to this day. A lawsuit filed by H.K. Mulford challenged the patent on the grounds that it was a natural product and therefore unpatentable. The ruling in favor of Parke-Davis by judge Learned Hand is considered crucial to modern patent law. Before its criminalization, Parke-Davis sold cocaine in various forms, including cigarettes, powder, and even a cocaine mixture that could be injected directly into the user’s veins with the included needle. The company promised that its cocaine products would “supply the place of food, make the coward brave, the silent eloquent and ... render the sufferer insensitive to pain. Phencyclidine (PCP) was first patented in the 1950s by the Parke-Davis pharmaceutical company. PCP is listed as a Schedule II drug in the United States under the Convention on Psychotropic Substances. Parke-Davis marketed the first widely available epilepsy treatment, Dilantin, which was approved in 1939, although it discovered neither the compound nor the application on its own.[3] The first bacterial vaccine was developed by Parke-Davis, and the company was thus known as as a pioneer in the field of Vaccinology. It was also among the five firms contracted to manufacture the Salk vaccine used to eradicate polio[4] A combination of the DPT and polio vaccines, called Quadrigen, was developed in 1954 and approved in 1959. Quadrigen was later removed from the market in 1968 after a series of lawsuits pertaining to adverse effects in vaccinated children. Other products popularized by the company included anti-infectives and brands of combined oral contraceptive pills. # Modern Events Template:NPOV-section In the case of Franklin v. Parke-Davis (2002) the company was accused of illegal marketing practices, including the promotion of off-label uses of its anticonvulsant medication Neurontin.[5] The drug had only been approved for use in patients with epilepsy, but in 2001 over 80% of its $1.8 billion in sales were for indications unapproved by the FDA. In 2004, Pfizer "admitted that [Parke-Davis] aggressively marketed [Neurontin] by illicit means for unrelated conditions including bipolar disorder, pain, migraine headaches, and drug and alcohol withdrawal", and consented to $430 million dollars in penalties although it claimed the violations originated in 1996, well before Pfizer's acquisition of Warner-Lambert.[6] As announced on January 22, 2007, Pfizer will close its research facilities in Ann Arbor, MI.[1] # Trivia Actor Calvert DeForest, who appeared multiple times with David Letterman, worked for the company for many years.	https://www.wikidoc.org/index.php/Parke-Davis
eafe31d035395c12250d93ffc656d843429980b3	wikidoc	Webbed toes	Webbed toes # Overview Webbed toes is the common name for syndactyly affecting the feet. It is characterised by the fusion of two or more digits of the feet. # Classification The scientific name for the condition is syndactyly, although this term covers both webbed fingers and webbed toes. There are various levels of webbing, from partial to complete. Most commonly the second and third toes are webbed or joined by skin and flexible tissue. This can reach either part way up or nearly all the way up the toe. # Pathophysiology The exact cause of the condition is unknown. In other cases, no other related persons have this condition. Syndactyly occurs when apoptosis or programmed cell death during gestation is absent or incomplete. Webbed toes occur most commonly in the following circumstances: ## Associated Conditions - Syndactyly or Familial syndactyly - Down syndrome - Acrocallosal syndrome - Apert's syndrome - Aarskog syndrome - Bardet-Biedl syndrome - Carpenter's syndrome - Cornelia de Lange syndrome - Edwards syndrome - Jackson-Weiss syndrome - Fetal hydantoin syndrome - Miller syndrome - Pfeiffer syndrome - Smith-Lemli-Opitz syndrome - Timothy syndrome # Differentiating Syndactyly from other Disorders - Syndactyly is having fused or webbed fingers or toes. - Polydactyly is the presence of more than five digits on the hands or feet. - Adactyly is the absence of fingers or toes. # Risk Factors Smoking: Smoking during pregnancy significantly elevates the risk of having a child with excess, webbed or missing fingers and toes, according to the January issue of Plastic and Reconstructive Surgery, the official medical journal of the American Society of Plastic Surgeons (ASPS). In fact, the study found that smoking just half a pack per day increases the risk of having a child born with a toe or finger defect by 29 percent. # Epidemiology and Demographics Webbed fingers or toes occur one in every 2,000 to 2,500 live births and excess fingers or toes occur one in every 600 live births. ## Gender Webbed fingers or toes occur twice as often in boys. ## Race Webbed toes are more common in Caucasians than African Americans. Excess digits, however, are 10 times more common in African Americans. # Natural History, Complications, and Prognosis Webbed toes is a purely cosmetic condition. This condition does not impair the ability to perform any activity including walking, running, or swimming. There is no evidence that it improves swimming ability. Webbed toes can interfere with the ability to wear toe rings and toe socks. People with webbed toes may have a slight disadvantage for activities that benefit from prehensile toes. Psychological stress may arise from the fear of negative reactions to this condition from people who do not have webbed toes. This may lead some individuals to become extremely self-conscious about their feet and go to great lengths to hide them. They may avoid open-toed footwear and activities such as swimming where their feet may be seen. In reality, other people rarely notice this condition unless the person with this condition makes a deliberate effort to point it out. # Diagnosis This condition is normally discovered at birth. If other symptoms are present, a specific syndrome may be indicated. Diagnosis of a specific syndrome is based on a family history, medical history, and a physical exam. ## Family History In some cases, close family members may share this condition. # Surgery - Partial simple syndactyly before surgery - Partial simple syndactyly, 4 months post-op Webbed toes can be separated through surgery. Surgical separation of webbed toes is an example of body modification. As with any form of surgery, there are risks of complications. The end results depend on the extent of the webbing and underlying bone structure. ## Complications - Scarring: There is usually some degree of scarring, and skin grafts may be required. - Loss of sensation: In rare instances, nerve damage may lead to loss of feeling in the toes. - Recurrence: There are also reports of partial web grow-back. The skin grafts needed to fill in the space between the toes can lead to additional scars in the places where the skin is removed. - Bleeding - Hyperpigmentation of skin graft	Webbed toes Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Webbed toes is the common name for syndactyly affecting the feet. It is characterised by the fusion of two or more digits of the feet. # Classification The scientific name for the condition is syndactyly, although this term covers both webbed fingers and webbed toes. There are various levels of webbing, from partial to complete. Most commonly the second and third toes are webbed or joined by skin and flexible tissue. This can reach either part way up or nearly all the way up the toe. # Pathophysiology The exact cause of the condition is unknown. In other cases, no other related persons have this condition. Syndactyly occurs when apoptosis or programmed cell death during gestation is absent or incomplete. Webbed toes occur most commonly in the following circumstances: ## Associated Conditions - Syndactyly or Familial syndactyly - Down syndrome - Acrocallosal syndrome - Apert's syndrome - Aarskog syndrome - Bardet-Biedl syndrome - Carpenter's syndrome - Cornelia de Lange syndrome - Edwards syndrome - Jackson-Weiss syndrome - Fetal hydantoin syndrome - Miller syndrome - Pfeiffer syndrome - Smith-Lemli-Opitz syndrome - Timothy syndrome # Differentiating Syndactyly from other Disorders - Syndactyly is having fused or webbed fingers or toes. - Polydactyly is the presence of more than five digits on the hands or feet. - Adactyly is the absence of fingers or toes. # Risk Factors Smoking: Smoking during pregnancy significantly elevates the risk of having a child with excess, webbed or missing fingers and toes, according to the January issue of Plastic and Reconstructive Surgery, the official medical journal of the American Society of Plastic Surgeons (ASPS). In fact, the study found that smoking just half a pack per day increases the risk of having a child born with a toe or finger defect by 29 percent.[1][2] # Epidemiology and Demographics Webbed fingers or toes occur one in every 2,000 to 2,500 live births and excess fingers or toes occur one in every 600 live births. ## Gender Webbed fingers or toes occur twice as often in boys. ## Race Webbed toes are more common in Caucasians than African Americans. Excess digits, however, are 10 times more common in African Americans. # Natural History, Complications, and Prognosis Webbed toes is a purely cosmetic condition. This condition does not impair the ability to perform any activity including walking, running, or swimming. There is no evidence that it improves swimming ability. Webbed toes can interfere with the ability to wear toe rings and toe socks. People with webbed toes may have a slight disadvantage for activities that benefit from prehensile toes. Psychological stress may arise from the fear of negative reactions to this condition from people who do not have webbed toes. This may lead some individuals to become extremely self-conscious about their feet and go to great lengths to hide them. They may avoid open-toed footwear and activities such as swimming where their feet may be seen. In reality, other people rarely notice this condition unless the person with this condition makes a deliberate effort to point it out. # Diagnosis This condition is normally discovered at birth. If other symptoms are present, a specific syndrome may be indicated. Diagnosis of a specific syndrome is based on a family history, medical history, and a physical exam. ## Family History In some cases, close family members may share this condition. # Surgery - Partial simple syndactyly before surgery - Partial simple syndactyly, 4 months post-op Webbed toes can be separated through surgery. Surgical separation of webbed toes is an example of body modification. As with any form of surgery, there are risks of complications. The end results depend on the extent of the webbing and underlying bone structure. ## Complications - Scarring: There is usually some degree of scarring, and skin grafts may be required. - Loss of sensation: In rare instances, nerve damage may lead to loss of feeling in the toes. - Recurrence: There are also reports of partial web grow-back. The skin grafts needed to fill in the space between the toes can lead to additional scars in the places where the skin is removed. - Bleeding - Hyperpigmentation of skin graft	https://www.wikidoc.org/index.php/Partial_webbing_of_2nd_and_3rd_toes
dc6f51752d3711c62b6893c02545bf74fbaeb5b2	wikidoc	Parvalbumin	Parvalbumin Parvalbumin is a calcium-binding albumin protein with low molecular weight (typically 9-11 kDa). It has three EF hand motifs and is structurally related to calmodulin and troponin C. Parvalbumin is found in fast-contracting muscles, where its levels are highest, as well as in the brain and some endocrine tissues. Parvalbumin is a small, stable protein containing EF-hand type calcium binding sites. It is involved in calcium signaling. Typically, this protein is broken into three domains, domains AB, CD and EF, each individually containing a helix-loop-helix motif. The AB domain houses a two amino-acid deletion in the loop region, whereas domains CD and EF contain the N-terminal and C-terminal, respectively. Calcium binding proteins like parvalbumin play a role in many physiological processes, namely cell-cycle regulation, second messenger production, muscle contraction, organization of microtubules and phototransduction. Therefore, calcium-binding proteins must distinguish calcium in the presence of high concentrations of other metal ions. The mechanism for the calcium selectivity has been extensively studied. Alterations in the function of parvalbumin-expressing neurons have been implicated in various areas of clinical interest such as Alzheimer's disease, age-related cognitive defects and some forms of cancer. # Location and function Parvalbumin (PV) is present in GABAergic interneurons in the nervous system, especially the reticular thalamus, and expressed predominantly by chandelier and basket cells in the cortex. In the cerebellum, PV is expressed in Purkinje cells and molecular layer interneurons. In the hippocampus, PV+ interneurons are subdivided into basket, axo-axonic, bistratified, and oriens-lacunosum moleculare (O-LM) cells, each subtype targeting distinct domains of pyramidal cells. PV interneurons' connections are mostly perisomatic (around the cell body of neurons). Most of the PV interneurons are fast-spiking. They are also thought to give rise to gamma waves recorded in EEG. PV-expressing interneurons represent approximately 25% of GABAergic cells in the primate DLPFC. Other calcium-binding protein markers are calretinin (most abundant subtype in DLPFC, about 50%) and calbindin. Interneurons are also divided into subgroups by the expression of neuropeptides such as somatostatin, neuropeptide Y, cholecystokinin. # Role in pathology Decreased PV and GAD67 expression was found in PV+ GABAergic interneurons in schizophrenia. PV has been identified as an allergen causing fish allergy.	Parvalbumin Parvalbumin is a calcium-binding albumin protein with low molecular weight (typically 9-11 kDa). It has three EF hand motifs and is structurally related to calmodulin and troponin C. Parvalbumin is found in fast-contracting muscles, where its levels are highest, as well as in the brain and some endocrine tissues. Parvalbumin is a small, stable protein containing EF-hand type calcium binding sites. It is involved in calcium signaling. Typically, this protein is broken into three domains, domains AB, CD and EF, each individually containing a helix-loop-helix motif.[3] The AB domain houses a two amino-acid deletion in the loop region, whereas domains CD and EF contain the N-terminal and C-terminal, respectively.[3] Calcium binding proteins like parvalbumin play a role in many physiological processes, namely cell-cycle regulation, second messenger production, muscle contraction, organization of microtubules and phototransduction.[1] Therefore, calcium-binding proteins must distinguish calcium in the presence of high concentrations of other metal ions. The mechanism for the calcium selectivity has been extensively studied.[1][4] Alterations in the function of parvalbumin-expressing neurons have been implicated in various areas of clinical interest such as Alzheimer's disease,[5] age-related cognitive defects and some forms of cancer.[3] # Location and function Parvalbumin (PV) is present in GABAergic interneurons in the nervous system, especially the reticular thalamus,[6] and expressed predominantly by chandelier and basket cells in the cortex. In the cerebellum, PV is expressed in Purkinje cells and molecular layer interneurons.[7] In the hippocampus, PV+ interneurons are subdivided into basket, axo-axonic, bistratified, and oriens-lacunosum moleculare (O-LM) cells, each subtype targeting distinct domains of pyramidal cells.[8] PV interneurons' connections are mostly perisomatic (around the cell body of neurons). Most of the PV interneurons are fast-spiking. They are also thought to give rise to gamma waves recorded in EEG. PV-expressing interneurons represent approximately 25% of GABAergic cells in the primate DLPFC.[9][10] Other calcium-binding protein markers are calretinin (most abundant subtype in DLPFC, about 50%) and calbindin. Interneurons are also divided into subgroups by the expression of neuropeptides such as somatostatin, neuropeptide Y, cholecystokinin. # Role in pathology Decreased PV and GAD67 expression was found in PV+ GABAergic interneurons in schizophrenia.[11][12] PV has been identified as an allergen causing fish allergy.[13]	https://www.wikidoc.org/index.php/Parvalbumin
8dad2b024307038267937c508af152104537c230	wikidoc	Pasireotide	Pasireotide # 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 Pasireotide is a somatostatin analog that is FDA approved for the treatment of Cushing’s disease for whom pituitary surgery is not an option or has not been curative. Common adverse reactions include diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - SIGNIFOR is indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. - The recommended dosage range of SIGNIFOR is 0.3 to 0.9 mg by subcutaneous injection twice a day. The recommended initial dose is either 0.6 mg or 0.9 mg twice a day. Titrate dose based on response and tolerability. - Patients should be evaluated for a treatment response and should continue receiving therapy with SIGNIFOR as long as benefit is derived. Maximum urinary free cortisol reduction is typically seen by two months of treatment. For patients who are started on 0.6 mg twice a day, a dosage increase to 0.9 mg twice a day may be considered based on the response to the treatment, as long as the 0.6 mg dosage is well tolerated by the patient. - Management of suspected adverse reactions may require temporary dose reduction of SIGNIFOR. Dose reduction by 0.3 mg decrements per injection is suggested. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pasireotide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pasireotide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Pasireotide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pasireotide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pasireotide in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Hypocortisolism - Treatment with SIGNIFOR leads to suppression of adrenocorticotropic hormone (ACTH) secretion in Cushing’s disease. Suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially hypocortisolism. - Monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia or hypoglycemia). If hypocortisolism occurs, consider temporary dose reduction or interruption of treatment with SIGNIFOR, as well as temporary, exogenous glucocorticoid replacement therapy. - Hyperglycemia and Diabetes - Elevations in blood glucose levels have been seen in healthy volunteers and patients treated with SIGNIFOR. In the Phase III trial, the development of pre-diabetes and diabetes was observed. In this trial, nearly all patients—including those with normal glucose status at baseline, pre-diabetes, and diabetes—developed worsening glycemia in the first two weeks of treatment. Cushing’s disease patients with poor glycemic control (as defined by HbA1c values >8% while receiving anti-diabetic therapy) may be at a higher risk of developing severe hyperglycemia and associated complications, e.g. ketoacidosis. - Because of this predictable adverse reaction, the glycemic status ] (FPG) or hemoglobin A1c (HbA1c)] should be assessed prior to starting treatment with SIGNIFOR. In patients with uncontrolled diabetes mellitus intensive anti-diabetic therapy should be initiated prior to treatment with SIGNIFOR. Self-monitoring of blood glucose and/or FPG assessments should be done every week for the first two to three months and periodically thereafter, as clinically appropriate. After treatment discontinuation, glycemic monitoring (e.g. FPG or HbA1c) should be done according to clinical practice. Patients who were initiated on anti-diabetic therapy as a result of SIGNIFOR may require closer monitoring after discontinuation of SIGNIFOR, especially if the anti-diabetic therapy has a risk of causing hypoglycemia. - If hyperglycemia develops in a patient treated with SIGNIFOR, the initiation or adjustment of anti-diabetic treatment is recommended. The optimal treatment for the management of SIGNIFOR-induced hyperglycemia is not known. If uncontrolled hyperglycemia persists, despite appropriate medical management, the dose of SIGNIFOR should be reduced or discontinued. - Bradycardia and QT Prolongation - Bradycardia - Bradycardia has been reported with the use of SIGNIFOR. Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high-grade heart block, or concomitant use of drugs associated with bradycardia, should be carefully monitored. Dose adjustments of beta-blockers, calcium channel blockers, or correction of electrolyte disturbances may be necessary. - QT Prolongation - SIGNIFOR is associated with QT prolongation. In two thorough QT studies with SIGNIFOR, QT prolongation occurred at therapeutic and supra-therapeutic doses. SIGNIFOR should be used with caution in patients who are at significant risk of developing prolongation of QTc, such as those: - with congenital long QT prolongation. with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia. -n anti-arrhythmic therapy or other substances that are known to lead to QT prolongation. with hypokalemia and/or hypomagnesemia. - with congenital long QT prolongation. - with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia. - on anti-arrhythmic therapy or other substances that are known to lead to QT prolongation. - with hypokalemia and/or hypomagnesemia. - A baseline ECG is recommended prior to initiating therapy with SIGNIFOR and monitoring for an effect on the QTc interval is advisable. Hypokalemia and hypomagnesemia must be corrected prior to SIGNIFOR administration and should be monitored periodically during therapy. - Liver Test Elevations - In the Phase III trial, 5% of patients had an ALT or AST level greater than 3 times the upper limit of normal (ULN). In the entire clinical development program of SIGNIFOR, there were 4 cases of concurrent elevations in ALT (alanine aminotransferase) greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing’s disease and three healthy volunteers. In these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation. - Monitoring of liver tests should be done after 1 to 2 weeks on treatment, then monthly for 3 months, and every 6 months thereafter. If ALT is normal at baseline and elevations of ALT of 3-5 times the ULN are observed on treatment, repeat the test within a week or within 48 hours if exceeding 5 times ULN. If ALT is abnormal at baseline and elevations of ALT of 3-5 times the baseline values are observed on treatment, repeat the test within a week or sooner if exceeding 5 times ULN. Tests should be done in a laboratory that can provide same-day results. If the values are confirmed or rising, interrupt SIGNIFOR treatment and investigate for probable cause of the findings, which may or may not be SIGNIFOR-related. Serial measures of ALT, aspartate aminotransferase, alkaline phosphatase, and total bilirubin, should be done weekly, or more frequently, if any value exceeds 5 times the baseline value in case of abnormal baselines or 5 times the ULN in case of normal baselines. If resolution of abnormalities to normal or near normal occurs, resuming treatment with SIGNIFOR may be done cautiously, with close observation, and only if some other likely cause has been found. - Cholelithiasis - Cholelithiasis has been frequently reported in clinical studies with SIGNIFOR. Ultrasonic examination of the gallbladder before, and at 6- to 12-month intervals during SIGNIFOR therapy is recommended. - Monitoring for Deficiency of Pituitary Hormones - As the pharmacological activity of SIGNIFOR mimics that of somatostatin, inhibition of pituitary hormones, other than ACTH, may occur. Monitoring of pituitary function (e.g., TSH/free T4, GH/IGF-1) should occur prior to initiation of therapy with SIGNIFOR and periodically during treatment should be considered as clinically appropriate. Patients who have undergone transsphenoidal surgery and pituitary irradiation are particularly at increased risk for deficiency of pituitary hormones. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. - A total of 162 Cushing’s disease patients were exposed to SIGNIFOR in the Phase III study. At study entry, patients were randomized to receive twice a day (b.i.d.) doses of either 0.6 mg or 0.9 mg of SIGNIFOR given subcutaneously. The mean age of patients was approximately 40 years old with a predominance of female patients (78%). The majority of the patients had persistent or recurrent Cushing’s disease (83%) and few patients (≤ 5%) in either treatment group had received previous pituitary irradiation. The median exposure to the treatment was 10.4 months (0.03-37.8) with 68% of patients having at least six-months exposure. - In the Phase III trial, adverse reactions were reported in 98% of patients. The most common adverse reactions (frequency ≥20% in either group) were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. There were no deaths during the study. Serious adverse events were reported in 25% of patients. Adverse events leading to study discontinuation were reported in 17% of patients. - Adverse reactions with an overall frequency higher than 5% are presented in Table 1 by randomized dose group and overall. Adverse reactions are ranked by frequency, with the most frequent reactions listed first. - Other notable adverse reactions which occurred with a frequency less than 5% were: anemia (4%); blood amylase increased (2%) and prothrombin time prolonged (2%). - Gastrointestinal Disorders - Gastrointestinal disorders, predominantly diarrhea, nausea, abdominal pain and vomiting were reported frequently in the Phase III trial (see Table 1). These events began to develop primarily during the first month of treatment with SIGNIFOR and required no intervention. - Hyperglycemia and Diabetes - Hyperglycemia-related terms were reported frequently in the Phase III trial. For all patients, these terms included: hyperglycemia (40%), diabetes mellitus (18%), increased HbA1c (11%), and type 2 diabetes mellitus (9%). In general, increases in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were seen soon after initiation of SIGNIFOR and were sustained during the treatment period. In the SIGNIFOR 0.6 mg group, mean fasting plasma glucose (FPG) levels increased from 98.6 mg/dL at baseline to 125.1 mg/dL at Month 6. In the SIGNIFOR 0.9 mg group, mean fasting plasma glucose (FPG) levels increased from 97.0 mg/dL at baseline to 128.0 mg/dL at Month 6. In the SIGNIFOR 0.6 mg group, HbA1c increased from 5.8% at baseline to 7.2% at Month 6. In the SIGNIFOR 0.9 mg group, HbA1c increased from 5.8% at baseline to 7.3% at Month . - At one month follow-up visits following discontinuation of SIGNIFOR, mean FPG and HbA1c levels decreased but remained above baseline values. Long-term follow-up data are not available. - Elevated Liver Tests - In the Phase III trial, there were transient mean elevations in aminotransferase values in patients treated with SIGNIFOR. Mean values returned to baseline levels by Month 4 of treatment. The elevations were not associated with clinical symptoms of hepatic disease. - In the clinical development program of SIGNIFOR, there were 4 patients with concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing’s disease and three healthy volunteers. In all four cases, the elevations were noted within the first 10 days of treatment. In all of these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation. The patient with Cushing’s disease developed jaundice. All four cases had resolution of the laboratory abnormalities with discontinuation of SIGNIFOR. - Hypocortisolism - Cases of hypocortisolism were reported in the Phase III study in Cushing’s disease patients. The majority of cases were manageable by reducing the dose of SIGNIFOR and/or adding low-dose, short-term glucocorticoid therapy. - Injection Site Reactions - Injection site reactions were reported in 17% of patients enrolled in the Phase III trial in Cushing’s disease. The events were most frequently reported as local pain, erythema, hematoma, hemorrhage, and pruritus. These events resolved spontaneously and required no intervention. - Thyroid function - Hypothyroidism with the use of SIGNIFOR was reported for seven patients participating in the Phase III study in Cushing’s disease. All seven patients presented with a TSH close to or below the lower limit at study entry which precludes establishing a conclusive relationship between the adverse event and the use of SIGNIFOR. - Other Abnormal Laboratory Findings - Asymptomatic and reversible elevations in lipase and amylase were observed in patients receiving SIGNIFOR in clinical studies. Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogs due to the association between cholelithiasis and acute pancreatitis. - For hemoglobin levels, mean decreases that remained within normal range were observed. Also, post-baseline elevations in PT and PTT were noted in 33% and 47% of patients, respectively. The PT and PTT elevations were minimal. - These laboratory findings are of unclear clinical significance. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Pasireotide in the drug label. # Drug Interactions - Effects of Other Drugs on SIGNIFOR - Anti-Arrhythmic Medicines and Drugs that Prolong QT - Co-administration of drugs that prolong the QT interval with SIGNIFOR may have additive effects on the prolongation of the QT interval. Caution is required when co-administering SIGNIFOR with anti-arrhythmic medicines and other drugs that may prolong the QT interval. - Effects of SIGNIFOR on Other Drugs - Cyclosporine - Concomitant administration of cyclosporine with pasireotide may decrease the relative bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to maintain therapeutic levels may be necessary - Bromocriptine - Co-administration of somatostatin analogues with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits which showed evidence of harm to the fetus due to pasireotide at therapeutic exposures. Animal reproduction studies are not always predictive of human response. This drug should be used during pregnancy only if clearly needed. - Dosing in rats before mating and continuing into gestation at exposures less than the human clinical exposure based on body surface area comparisons across species, resulted in adverse fertility effects including: statistically significant increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites. Abnormal cycles or acyclicity were observed at systemic exposure 5-fold higher than the maximum therapeutic exposure based on surface area, comparisons across species. - In embryofetal development studies in rats given 1, 5, and 10 mg/kg/day subcutaneously throughout organogenesis, maternal toxicity was observed at all doses, including the lowest dose tested which had exposures 4-times higher than that at the maximum therapeutic dose based on AUC comparisons across species. - In embryofetal development studies in rabbits given 0.05, 1, and 5 mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day at an exposure 7-times higher than the maximum therapeutic exposure. Treatment related increased incidence of skeletal malformations were observed at 0.05 mg/kg/day, exposures less than the maximum therapeutic exposure based on AUC comparisons across species. - In pre- and post-natal developmental studies in rats given subcutaneous doses of 2, 5, and 10 mg/kg/day during gestation through lactation and weaning, maternal toxicity was observed at all doses including the lowest dose (12-times higher than the maximum therapeutic dose based on surface area comparisons across species). Retardation of physiological growth, attributed to GH inhibition was observed at 2 mg/kg/day during a pre- and postnatal study in rats. After weaning, body weight gains in the rat pups (F1 generation) exposed to pasireotide were comparable to controls, showing reversibility of this developmental delay. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pasireotide in women who are pregnant. ### Labor and Delivery - No data in humans are available. Studies in rats have shown no effects on 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 SIGNIFOR is administered to a nursing woman. Pasireotide was excreted into rat milk at levels 30% of the plasma level. As a risk to the breastfed child cannot be excluded, SIGNIFOR should not be used by the nursing mother. ### Pediatric Use - Safety and effectiveness of SIGNIFOR have not been established in pediatric patients. ### Geriatic Use - Clinical studies of SIGNIFOR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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 concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Pasireotide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pasireotide with respect to specific racial populations. ### Renal Impairment - No dosage adjustment of SIGNIFOR in patients with impaired renal function is required. ### Hepatic Impairment - Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B). Avoid the use of SIGNIFOR in patients with severe hepatic impairment (Child-Pugh C). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pasireotide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pasireotide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Pasireotide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Pasireotide in the drug label. # Overdosage ## Acute Overdose - No cases of overdosage have been reported in patients with Cushing’s disease receiving SIGNIFOR subcutaneously. Doses up to 2.1 mg b.i.d. have been used in healthy volunteers with adverse reactions of diarrhea being observed at a high frequency. - In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient’s clinical status, until resolution of the symptoms. - Up-to-date information about the treatment of overdose can be obtained from a certified Regional Poison Center. ## Chronic Overdose There is limited information regarding Chronic Overdose of Pasireotide in the drug label. # Pharmacology ## Mechanism of Action - SIGNIFOR is an injectable cyclohexapeptide somatostatin analogue. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (ssts). Five human somatostatin receptor subtypes are known: hsst 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Corticotroph tumor cells from Cushing’s disease patients frequently over-express hsst5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the hsst receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion. - The binding affinities of endogenous somatostatin and pasireotide are shown in Table 2. ## Structure - SIGNIFOR (pasireotide) injection is prepared as a sterile solution of pasireotide diaspartate in a tartaric acid buffer for administration by subcutaneous injection. SIGNIFOR is a somatostatin analog. Pasireotide diaspartate, chemically known as (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester, di salt, is a cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. - The molecular formula of pasireotide diaspartate is C58H66N10O9 - 2 C4H7NO4 and the molecular weight is 1313.41. The structural formula is: - SIGNIFOR is supplied as a sterile solution in a single-dose, 1 mL colorless glass ampule containing pasireotide in 0.3 mg/mL, 0.6 mg/mL, or 0.9 mg/mL strengths for subcutaneous injection. - Each glass ampule contains: ## Pharmacodynamics - Cardiac Electrophysiology - QTcI interval was evaluated in a randomized, blinded, crossover study in healthy subjects investigating pasireotide doses of 0.6 mg b.i.d. and 1.95 mg b.i.d. The maximum mean (95% upper confidence bound) placebo-subtracted QTcI change from baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Both pasireotide doses decreased heart rate, with a maximum mean (95% lower confidence bound) placebo-subtracted change from baseline of -10.9 (-11.9) beats per minute (bpm) observed at 1.5 hours for pasireotide 0.6 mg bid, and -15.2 (-16.5) bpm at 0.5 hours for pasireotide 1.95 mg b.i.d. The supra-therapeutic dose (1.95 mg b.i.d) produced mean steady-state Cmax values 3.3-fold the mean Cmax for the 0.6 mg b.i.d dose in the study. ## Pharmacokinetics - In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for a dose range from 0.0025 to 1.5 mg. In Cushing’s disease patients, pasireotide demonstrates linear dose-exposure relationship in a dose range from 0.3 to 1.2 mg. - Absorption and Distribution: - In healthy volunteers, pasireotide peak plasma concentration is reached within Tmax 0.25-0.5 hour. Cmax and AUC are dose-proportional following administration of single and multiple doses. - No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans. Food effect is unlikely to occur since SIGNIFOR is administered via a parenteral route. - In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (Vz/F >100 L). Distribution between blood and plasma is concentration independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration. - Pasireotide has low passive permeability and is likely to be a substrate of P-gp (P-glycoprotein), but the impact of P-gp on ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. Pasireotide is not a substrate of efflux transporter BCRP (breast cancer resistance protein), influx transporter OCT1 (organic cation transporter 1), or influx transporters OATP (organic anion-transporting polypeptide) 1B1, 1B3, or 2B1. - Metabolism and Excretion: - Pasireotide was shown to be metabolically stable in human liver and kidney microsomes systems. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine and feces. Somatropin may increase CYP450 enzymes and, therefore, suppression of growth hormone secretion by somatostatin analogs including pasireotide may decrease the metabolic clearance of compounds metabolized by CYP450 enzymes. - Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small contribution of the renal route. In a human ADME study 55.9 ± 6.63% of the radioactivity dose was recovered over the first 10 days post dosing, including 48.3 ± 8.16% of the radioactivity in feces and 7.63 ± 2.03% in urine. - The clearance (CL/F) of pasireotide in healthy volunteers and Cushing’s disease patients is ~7.6 liters/h and ~3.8 liters/h, respectively. - Steady-state pharmacokinetics: - Following multiple subcutaneous doses, pasireotide demonstrates linear pharmacokinetics in the dose range of 0.05 to 0.6 mg once a day in healthy volunteers, and 0.3 mg to 1.2 mg twice a day in Cushing’s disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t1/2,eff) in healthy volunteers was approximately 12 hours (on average between 10 and 13 hours for 0.05, 0.2 and 0.6 mg once a day doses). - Special Populations: - Population PK analyses of SIGNIFOR indicates that body weight, age, and gender do not affect pasireotide pharmacokinetics and there is no meaningful difference in pharmacokinetics between Caucasian and non-Caucasian.PK parameters. - Hepatic impairment - In a clinical study in subjects with impaired hepatic function (Child-Pugh A, B and C), subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparison with the control group, AUCinf was increased by 12%, 56% and 42% and Cmax increased by 3%, 46% and 33%, respectively, in the mild, moderate and severe hepatic impairment groups. - Pediatric patients - No studies have been performed in pediatric patients. - Geriatric patients - No clinical pharmacology studies have been performed in geriatric patients. - Renal impairment - Clinical pharmacology studies have not been performed in patients with impaired renal function. However, renal clearance has a minor contribution to the elimination of pasireotide in humans. Renal function is not expected to significantly impact the circulating levels of pasireotide. - Drug Interaction Studies: - There was no significant drug interaction between pasireotide and metformin, nateglinide or liraglutide. ## Nonclinical Toxicology - Carcinogenesis - A life-time carcinogenicity study was conducted in rats and transgenic mice. Rats were given daily subcutaneous doses of pasireotide at 0.01, 0.05, 0.3 mg/kg/day for 104 weeks. There were no drug-related tumors in rats at exposures up to 7-fold higher than the maximum recommended clinical exposure at the 1.8 mg/day dose. Mice were given subcutaneous doses of pasireotide at 0.5, 1.0, 2.5 mg/kg/day for 26 weeks and did not identify any carcinogenic potential. - Mutagenesis - Pasireotide was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella and E coli. and mutation test in human peripheral lymphocytes). Pasireotide was not genotoxic in an in vivo rat bone marrow nucleus test. - Impairment of Fertility - Subcutaneous dosing at 0.1 mg/kg/day before mating and continuing into gestation in rats at exposures less than the human clinical exposure based on body surface area comparisons across species resulted in statistically significant increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites. Abnormal cycles or acyclicity were observed at 1 mg/kg/day (5-fold higher than the maximum therapeutic exposure based on surface area, comparisons across species). # Clinical Studies - A Phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of two dose levels of SIGNIFOR over a 6-month treatment period in Cushing’s disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. - Patients with a baseline 24-hour urine free cortisol (UFC) >1.5 x upper limit of normal (ULN) were randomized to receive a SIGNIFOR dosage of either 0.6 mg subcutaneous b.i.d. or 0.9 mg subcutaneous b.i.d. After three months of treatment, patients with a mean 24-hour UFC ≤ 2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg b.i.d. After the initial six months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3 mg b.i.d. at any time during the study for intolerability. - A total of 162 patients were enrolled in this study. The majority of patients were female (78%) and had persistent or recurrent Cushing’s disease despite pituitary surgery (83%) with a mean age of 40 years. A few patients (4%) in either treatment group received previous pituitary irradiation. The median value of the baseline 24-hour UFC for all patients was 565 nmol/24 hours (normal range 30 to 145 nmol/24 hours). About two-thirds of all randomized patients completed six months of treatment. - The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after six months of treatment and did not dose increase during this period. - 24-Hour Urinary Free Cortisol Results - At Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6 mg b.i.d. and 0.9 mg b.i.d. groups, respectively (Table 3). The percentages of patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 0.6 mg bid and 41% in the 0.9 mg bid groups. Dose increases appeared to have minimal effect on 24-hour UFC response. Mean and median percentage changes in UFC from baseline are presented in Table 3. - SIGNIFOR resulted in a decrease in the mean 24-hour UFC after 1 month of treatment (Figure 1). For patients (n=78) who stayed in the trial, similar UFC lowering was observed at Month 12. - Note: Only patients who completed 6 months of treatment are included in this analysis (n=110). The reference line is the upper limit of normal for UFC, which is 145 nmol/24hour; +/-Standard errors are displayed. - Other endpoints - Decreases from baseline for blood pressure were observed at Month 6, including patients who did not receive any antihypertensive medication. However, due to the fact that the study allowed initiation of antihypertensive medication and dose increases in patients already receiving such medications, the individual contribution of SIGNIFOR or of antihypertensive medication adjustments cannot be clearly established. - The mean decreases from baseline at Month 6 for weight, body mass index and waist circumference were 4.4 kg, 1.6 kg/m2 and 2.6 cm, respectively. Individual patients showed varying degrees of improvement in Cushing's disease manifestations but because of the variability in response and the absence of a control group in this trial, it is uncertain whether these changes could be ascribed to the effects of SIGNIFOR. # How Supplied - SIGNIFOR is supplied as a single dose, colorless glass ampule packaged in a box of 60 ampules, arranged in 10 packs of 6 ampules each. The following packaging configurations are available. - 0.3 mg/1 mL pasireotide (as diaspartate) - Box of 60 ampules NDC# 0078-0633-20 - 0.6 mg/1 mL pasireotide (as diaspartate) - Box of 60 ampules NDC# 0078-0634-20 - 0.9 mg/1 mL pasireotide (as diaspartate) - Box of 60 ampules NDC# 0078-0635-20 - Storage and Handling - Store at 25° C (77°F); excursions permitted to 15°-30°C (59°-86°F), protect from light. ## Storage There is limited information regarding Pasireotide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Counsel patients on the following possible significant adverse reactions: - Hypocortisolism - Hyperglycemia and diabetes - Bradycardia and QT prolongation - Liver test elevations - Cholelithiasis - Pituitary hormone deficiency - Instruct the patients on the proper use of SIGNIFOR, including instructions to: - Carefully review the Medication Guide. - Do not reuse unused portions of SIGNIFOR ampules and properly dispose of the ampules after use. - Avoid multiple injections at or near the same site within short periods of time. # Precautions with Alcohol - Alcohol-Pasireotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SIGNIFOR® # Look-Alike Drug Names There is limited information regarding Pasireotide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Pasireotide 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 Pasireotide is a somatostatin analog that is FDA approved for the treatment of Cushing’s disease for whom pituitary surgery is not an option or has not been curative. Common adverse reactions include diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - SIGNIFOR is indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. - The recommended dosage range of SIGNIFOR is 0.3 to 0.9 mg by subcutaneous injection twice a day. The recommended initial dose is either 0.6 mg or 0.9 mg twice a day. Titrate dose based on response and tolerability. - Patients should be evaluated for a treatment response [clinically meaningful reduction in 24-hour urinary free cortisol (UFC) levels and/or improvement in signs or symptoms of the disease] and should continue receiving therapy with SIGNIFOR as long as benefit is derived. Maximum urinary free cortisol reduction is typically seen by two months of treatment. For patients who are started on 0.6 mg twice a day, a dosage increase to 0.9 mg twice a day may be considered based on the response to the treatment, as long as the 0.6 mg dosage is well tolerated by the patient. - Management of suspected adverse reactions may require temporary dose reduction of SIGNIFOR. Dose reduction by 0.3 mg decrements per injection is suggested. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pasireotide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pasireotide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Pasireotide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pasireotide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pasireotide in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Hypocortisolism - Treatment with SIGNIFOR leads to suppression of adrenocorticotropic hormone (ACTH) secretion in Cushing’s disease. Suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially hypocortisolism. - Monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia or hypoglycemia). If hypocortisolism occurs, consider temporary dose reduction or interruption of treatment with SIGNIFOR, as well as temporary, exogenous glucocorticoid replacement therapy. - Hyperglycemia and Diabetes - Elevations in blood glucose levels have been seen in healthy volunteers and patients treated with SIGNIFOR. In the Phase III trial, the development of pre-diabetes and diabetes was observed. In this trial, nearly all patients—including those with normal glucose status at baseline, pre-diabetes, and diabetes—developed worsening glycemia in the first two weeks of treatment. Cushing’s disease patients with poor glycemic control (as defined by HbA1c values >8% while receiving anti-diabetic therapy) may be at a higher risk of developing severe hyperglycemia and associated complications, e.g. ketoacidosis. - Because of this predictable adverse reaction, the glycemic status [[[fasting plasma glucose]] (FPG) or hemoglobin A1c (HbA1c)] should be assessed prior to starting treatment with SIGNIFOR. In patients with uncontrolled diabetes mellitus intensive anti-diabetic therapy should be initiated prior to treatment with SIGNIFOR. Self-monitoring of blood glucose and/or FPG assessments should be done every week for the first two to three months and periodically thereafter, as clinically appropriate. After treatment discontinuation, glycemic monitoring (e.g. FPG or HbA1c) should be done according to clinical practice. Patients who were initiated on anti-diabetic therapy as a result of SIGNIFOR may require closer monitoring after discontinuation of SIGNIFOR, especially if the anti-diabetic therapy has a risk of causing hypoglycemia. - If hyperglycemia develops in a patient treated with SIGNIFOR, the initiation or adjustment of anti-diabetic treatment is recommended. The optimal treatment for the management of SIGNIFOR-induced hyperglycemia is not known. If uncontrolled hyperglycemia persists, despite appropriate medical management, the dose of SIGNIFOR should be reduced or discontinued. - Bradycardia and QT Prolongation - Bradycardia - Bradycardia has been reported with the use of SIGNIFOR. Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high-grade heart block, or concomitant use of drugs associated with bradycardia, should be carefully monitored. Dose adjustments of beta-blockers, calcium channel blockers, or correction of electrolyte disturbances may be necessary. - QT Prolongation - SIGNIFOR is associated with QT prolongation. In two thorough QT studies with SIGNIFOR, QT prolongation occurred at therapeutic and supra-therapeutic doses. SIGNIFOR should be used with caution in patients who are at significant risk of developing prolongation of QTc, such as those: - with congenital long QT prolongation. with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia. on anti-arrhythmic therapy or other substances that are known to lead to QT prolongation. with hypokalemia and/or hypomagnesemia. - with congenital long QT prolongation. - with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia. - on anti-arrhythmic therapy or other substances that are known to lead to QT prolongation. - with hypokalemia and/or hypomagnesemia. - A baseline ECG is recommended prior to initiating therapy with SIGNIFOR and monitoring for an effect on the QTc interval is advisable. Hypokalemia and hypomagnesemia must be corrected prior to SIGNIFOR administration and should be monitored periodically during therapy. - Liver Test Elevations - In the Phase III trial, 5% of patients had an ALT or AST level greater than 3 times the upper limit of normal (ULN). In the entire clinical development program of SIGNIFOR, there were 4 cases of concurrent elevations in ALT (alanine aminotransferase) greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing’s disease and three healthy volunteers. In these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation. - Monitoring of liver tests should be done after 1 to 2 weeks on treatment, then monthly for 3 months, and every 6 months thereafter. If ALT is normal at baseline and elevations of ALT of 3-5 times the ULN are observed on treatment, repeat the test within a week or within 48 hours if exceeding 5 times ULN. If ALT is abnormal at baseline and elevations of ALT of 3-5 times the baseline values are observed on treatment, repeat the test within a week or sooner if exceeding 5 times ULN. Tests should be done in a laboratory that can provide same-day results. If the values are confirmed or rising, interrupt SIGNIFOR treatment and investigate for probable cause of the findings, which may or may not be SIGNIFOR-related. Serial measures of ALT, aspartate aminotransferase, alkaline phosphatase, and total bilirubin, should be done weekly, or more frequently, if any value exceeds 5 times the baseline value in case of abnormal baselines or 5 times the ULN in case of normal baselines. If resolution of abnormalities to normal or near normal occurs, resuming treatment with SIGNIFOR may be done cautiously, with close observation, and only if some other likely cause has been found. - Cholelithiasis - Cholelithiasis has been frequently reported in clinical studies with SIGNIFOR. Ultrasonic examination of the gallbladder before, and at 6- to 12-month intervals during SIGNIFOR therapy is recommended. - Monitoring for Deficiency of Pituitary Hormones - As the pharmacological activity of SIGNIFOR mimics that of somatostatin, inhibition of pituitary hormones, other than ACTH, may occur. Monitoring of pituitary function (e.g., TSH/free T4, GH/IGF-1) should occur prior to initiation of therapy with SIGNIFOR and periodically during treatment should be considered as clinically appropriate. Patients who have undergone transsphenoidal surgery and pituitary irradiation are particularly at increased risk for deficiency of pituitary hormones. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. - A total of 162 Cushing’s disease patients were exposed to SIGNIFOR in the Phase III study. At study entry, patients were randomized to receive twice a day (b.i.d.) doses of either 0.6 mg or 0.9 mg of SIGNIFOR given subcutaneously. The mean age of patients was approximately 40 years old with a predominance of female patients (78%). The majority of the patients had persistent or recurrent Cushing’s disease (83%) and few patients (≤ 5%) in either treatment group had received previous pituitary irradiation. The median exposure to the treatment was 10.4 months (0.03-37.8) with 68% of patients having at least six-months exposure. - In the Phase III trial, adverse reactions were reported in 98% of patients. The most common adverse reactions (frequency ≥20% in either group) were diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue, and diabetes mellitus. There were no deaths during the study. Serious adverse events were reported in 25% of patients. Adverse events leading to study discontinuation were reported in 17% of patients. - Adverse reactions with an overall frequency higher than 5% are presented in Table 1 by randomized dose group and overall. Adverse reactions are ranked by frequency, with the most frequent reactions listed first. - Other notable adverse reactions which occurred with a frequency less than 5% were: anemia (4%); blood amylase increased (2%) and prothrombin time prolonged (2%). - Gastrointestinal Disorders - Gastrointestinal disorders, predominantly diarrhea, nausea, abdominal pain and vomiting were reported frequently in the Phase III trial (see Table 1). These events began to develop primarily during the first month of treatment with SIGNIFOR and required no intervention. - Hyperglycemia and Diabetes - Hyperglycemia-related terms were reported frequently in the Phase III trial. For all patients, these terms included: hyperglycemia (40%), diabetes mellitus (18%), increased HbA1c (11%), and type 2 diabetes mellitus (9%). In general, increases in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were seen soon after initiation of SIGNIFOR and were sustained during the treatment period. In the SIGNIFOR 0.6 mg group, mean fasting plasma glucose (FPG) levels increased from 98.6 mg/dL at baseline to 125.1 mg/dL at Month 6. In the SIGNIFOR 0.9 mg group, mean fasting plasma glucose (FPG) levels increased from 97.0 mg/dL at baseline to 128.0 mg/dL at Month 6. In the SIGNIFOR 0.6 mg group, HbA1c increased from 5.8% at baseline to 7.2% at Month 6. In the SIGNIFOR 0.9 mg group, HbA1c increased from 5.8% at baseline to 7.3% at Month . - At one month follow-up visits following discontinuation of SIGNIFOR, mean FPG and HbA1c levels decreased but remained above baseline values. Long-term follow-up data are not available. - Elevated Liver Tests - In the Phase III trial, there were transient mean elevations in aminotransferase values in patients treated with SIGNIFOR. Mean values returned to baseline levels by Month 4 of treatment. The elevations were not associated with clinical symptoms of hepatic disease. - In the clinical development program of SIGNIFOR, there were 4 patients with concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN: one patient with Cushing’s disease and three healthy volunteers. In all four cases, the elevations were noted within the first 10 days of treatment. In all of these cases, total bilirubin elevations were seen either concomitantly or preceding the transaminase elevation. The patient with Cushing’s disease developed jaundice. All four cases had resolution of the laboratory abnormalities with discontinuation of SIGNIFOR. - Hypocortisolism - Cases of hypocortisolism were reported in the Phase III study in Cushing’s disease patients. The majority of cases were manageable by reducing the dose of SIGNIFOR and/or adding low-dose, short-term glucocorticoid therapy. - Injection Site Reactions - Injection site reactions were reported in 17% of patients enrolled in the Phase III trial in Cushing’s disease. The events were most frequently reported as local pain, erythema, hematoma, hemorrhage, and pruritus. These events resolved spontaneously and required no intervention. - Thyroid function - Hypothyroidism with the use of SIGNIFOR was reported for seven patients participating in the Phase III study in Cushing’s disease. All seven patients presented with a TSH close to or below the lower limit at study entry which precludes establishing a conclusive relationship between the adverse event and the use of SIGNIFOR. - Other Abnormal Laboratory Findings - Asymptomatic and reversible elevations in lipase and amylase were observed in patients receiving SIGNIFOR in clinical studies. Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogs due to the association between cholelithiasis and acute pancreatitis. - For hemoglobin levels, mean decreases that remained within normal range were observed. Also, post-baseline elevations in PT and PTT were noted in 33% and 47% of patients, respectively. The PT and PTT elevations were minimal. - These laboratory findings are of unclear clinical significance. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Pasireotide in the drug label. # Drug Interactions - Effects of Other Drugs on SIGNIFOR - Anti-Arrhythmic Medicines and Drugs that Prolong QT - Co-administration of drugs that prolong the QT interval with SIGNIFOR may have additive effects on the prolongation of the QT interval. Caution is required when co-administering SIGNIFOR with anti-arrhythmic medicines and other drugs that may prolong the QT interval. - Effects of SIGNIFOR on Other Drugs - Cyclosporine - Concomitant administration of cyclosporine with pasireotide may decrease the relative bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to maintain therapeutic levels may be necessary - Bromocriptine - Co-administration of somatostatin analogues with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Reproduction studies have been performed in rats and rabbits which showed evidence of harm to the fetus due to pasireotide at therapeutic exposures. Animal reproduction studies are not always predictive of human response. This drug should be used during pregnancy only if clearly needed. - Dosing in rats before mating and continuing into gestation at exposures less than the human clinical exposure based on body surface area comparisons across species, resulted in adverse fertility effects including: statistically significant increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites. Abnormal cycles or acyclicity were observed at systemic exposure 5-fold higher than the maximum therapeutic exposure based on surface area, comparisons across species. - In embryofetal development studies in rats given 1, 5, and 10 mg/kg/day subcutaneously throughout organogenesis, maternal toxicity was observed at all doses, including the lowest dose tested which had exposures 4-times higher than that at the maximum therapeutic dose based on AUC comparisons across species. - In embryofetal development studies in rabbits given 0.05, 1, and 5 mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day at an exposure 7-times higher than the maximum therapeutic exposure. Treatment related increased incidence of skeletal malformations were observed at 0.05 mg/kg/day, exposures less than the maximum therapeutic exposure based on AUC comparisons across species. - In pre- and post-natal developmental studies in rats given subcutaneous doses of 2, 5, and 10 mg/kg/day during gestation through lactation and weaning, maternal toxicity was observed at all doses including the lowest dose (12-times higher than the maximum therapeutic dose based on surface area comparisons across species). Retardation of physiological growth, attributed to GH inhibition was observed at 2 mg/kg/day during a pre- and postnatal study in rats. After weaning, body weight gains in the rat pups (F1 generation) exposed to pasireotide were comparable to controls, showing reversibility of this developmental delay. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pasireotide in women who are pregnant. ### Labor and Delivery - No data in humans are available. Studies in rats have shown no effects on 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 SIGNIFOR is administered to a nursing woman. Pasireotide was excreted into rat milk at levels 30% of the plasma level. As a risk to the breastfed child cannot be excluded, SIGNIFOR should not be used by the nursing mother. ### Pediatric Use - Safety and effectiveness of SIGNIFOR have not been established in pediatric patients. ### Geriatic Use - Clinical studies of SIGNIFOR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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 concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Pasireotide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pasireotide with respect to specific racial populations. ### Renal Impairment - No dosage adjustment of SIGNIFOR in patients with impaired renal function is required. ### Hepatic Impairment - Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B). Avoid the use of SIGNIFOR in patients with severe hepatic impairment (Child-Pugh C). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pasireotide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pasireotide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Pasireotide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Pasireotide in the drug label. # Overdosage ## Acute Overdose - No cases of overdosage have been reported in patients with Cushing’s disease receiving SIGNIFOR subcutaneously. Doses up to 2.1 mg b.i.d. have been used in healthy volunteers with adverse reactions of diarrhea being observed at a high frequency. - In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient’s clinical status, until resolution of the symptoms. - Up-to-date information about the treatment of overdose can be obtained from a certified Regional Poison Center. ## Chronic Overdose There is limited information regarding Chronic Overdose of Pasireotide in the drug label. # Pharmacology ## Mechanism of Action - SIGNIFOR is an injectable cyclohexapeptide somatostatin analogue. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (ssts). Five human somatostatin receptor subtypes are known: hsst 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Corticotroph tumor cells from Cushing’s disease patients frequently over-express hsst5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the hsst receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion. - The binding affinities of endogenous somatostatin and pasireotide are shown in Table 2. ## Structure - SIGNIFOR (pasireotide) injection is prepared as a sterile solution of pasireotide diaspartate in a tartaric acid buffer for administration by subcutaneous injection. SIGNIFOR is a somatostatin analog. Pasireotide diaspartate, chemically known as (2-Aminoethyl) carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl ester, di[(S)-2-aminosuccinic acid] salt, is a cyclohexapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. - The molecular formula of pasireotide diaspartate is C58H66N10O9 • 2 C4H7NO4 and the molecular weight is 1313.41. The structural formula is: - SIGNIFOR is supplied as a sterile solution in a single-dose, 1 mL colorless glass ampule containing pasireotide in 0.3 mg/mL, 0.6 mg/mL, or 0.9 mg/mL strengths for subcutaneous injection. - Each glass ampule contains: ## Pharmacodynamics - Cardiac Electrophysiology - QTcI interval was evaluated in a randomized, blinded, crossover study in healthy subjects investigating pasireotide doses of 0.6 mg b.i.d. and 1.95 mg b.i.d. The maximum mean (95% upper confidence bound) placebo-subtracted QTcI change from baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Both pasireotide doses decreased heart rate, with a maximum mean (95% lower confidence bound) placebo-subtracted change from baseline of -10.9 (-11.9) beats per minute (bpm) observed at 1.5 hours for pasireotide 0.6 mg bid, and -15.2 (-16.5) bpm at 0.5 hours for pasireotide 1.95 mg b.i.d. The supra-therapeutic dose (1.95 mg b.i.d) produced mean steady-state Cmax values 3.3-fold the mean Cmax for the 0.6 mg b.i.d dose in the study. ## Pharmacokinetics - In healthy volunteers, pasireotide demonstrates approximately linear pharmacokinetics (PK) for a dose range from 0.0025 to 1.5 mg. In Cushing’s disease patients, pasireotide demonstrates linear dose-exposure relationship in a dose range from 0.3 to 1.2 mg. - Absorption and Distribution: - In healthy volunteers, pasireotide peak plasma concentration is reached within Tmax 0.25-0.5 hour. Cmax and AUC are dose-proportional following administration of single and multiple doses. - No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans. Food effect is unlikely to occur since SIGNIFOR is administered via a parenteral route. - In healthy volunteers, pasireotide is widely distributed with large apparent volume of distribution (Vz/F >100 L). Distribution between blood and plasma is concentration independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration. - Pasireotide has low passive permeability and is likely to be a substrate of P-gp (P-glycoprotein), but the impact of P-gp on ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. Pasireotide is not a substrate of efflux transporter BCRP (breast cancer resistance protein), influx transporter OCT1 (organic cation transporter 1), or influx transporters OATP (organic anion-transporting polypeptide) 1B1, 1B3, or 2B1. - Metabolism and Excretion: - Pasireotide was shown to be metabolically stable in human liver and kidney microsomes systems. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine and feces. Somatropin may increase CYP450 enzymes and, therefore, suppression of growth hormone secretion by somatostatin analogs including pasireotide may decrease the metabolic clearance of compounds metabolized by CYP450 enzymes. - Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small contribution of the renal route. In a human ADME study 55.9 ± 6.63% of the radioactivity dose was recovered over the first 10 days post dosing, including 48.3 ± 8.16% of the radioactivity in feces and 7.63 ± 2.03% in urine. - The clearance (CL/F) of pasireotide in healthy volunteers and Cushing’s disease patients is ~7.6 liters/h and ~3.8 liters/h, respectively. - Steady-state pharmacokinetics: - Following multiple subcutaneous doses, pasireotide demonstrates linear pharmacokinetics in the dose range of 0.05 to 0.6 mg once a day in healthy volunteers, and 0.3 mg to 1.2 mg twice a day in Cushing’s disease patients. Based on the accumulation ratios of AUC, the calculated effective half-life (t1/2,eff) in healthy volunteers was approximately 12 hours (on average between 10 and 13 hours for 0.05, 0.2 and 0.6 mg once a day doses). - Special Populations: - Population PK analyses of SIGNIFOR indicates that body weight, age, and gender do not affect pasireotide pharmacokinetics and there is no meaningful difference in pharmacokinetics between Caucasian and non-Caucasian.PK parameters. - Hepatic impairment - In a clinical study in subjects with impaired hepatic function (Child-Pugh A, B and C), subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparison with the control group, AUCinf was increased by 12%, 56% and 42% and Cmax increased by 3%, 46% and 33%, respectively, in the mild, moderate and severe hepatic impairment groups. - Pediatric patients - No studies have been performed in pediatric patients. - Geriatric patients - No clinical pharmacology studies have been performed in geriatric patients. - Renal impairment - Clinical pharmacology studies have not been performed in patients with impaired renal function. However, renal clearance has a minor contribution to the elimination of pasireotide in humans. Renal function is not expected to significantly impact the circulating levels of pasireotide. - Drug Interaction Studies: - There was no significant drug interaction between pasireotide and metformin, nateglinide or liraglutide. ## Nonclinical Toxicology - Carcinogenesis - A life-time carcinogenicity study was conducted in rats and transgenic mice. Rats were given daily subcutaneous doses of pasireotide at 0.01, 0.05, 0.3 mg/kg/day for 104 weeks. There were no drug-related tumors in rats at exposures up to 7-fold higher than the maximum recommended clinical exposure at the 1.8 mg/day dose. Mice were given subcutaneous doses of pasireotide at 0.5, 1.0, 2.5 mg/kg/day for 26 weeks and did not identify any carcinogenic potential. - Mutagenesis - Pasireotide was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella and E coli. and mutation test in human peripheral lymphocytes). Pasireotide was not genotoxic in an in vivo rat bone marrow nucleus test. - Impairment of Fertility - Subcutaneous dosing at 0.1 mg/kg/day before mating and continuing into gestation in rats at exposures less than the human clinical exposure based on body surface area comparisons across species resulted in statistically significant increased implantation loss and decreased viable fetuses, corpora lutea, and implantation sites. Abnormal cycles or acyclicity were observed at 1 mg/kg/day (5-fold higher than the maximum therapeutic exposure based on surface area, comparisons across species). # Clinical Studies - A Phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of two dose levels of SIGNIFOR over a 6-month treatment period in Cushing’s disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. - Patients with a baseline 24-hour urine free cortisol (UFC) >1.5 x upper limit of normal (ULN) were randomized to receive a SIGNIFOR dosage of either 0.6 mg subcutaneous b.i.d. or 0.9 mg subcutaneous b.i.d. After three months of treatment, patients with a mean 24-hour UFC ≤ 2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg b.i.d. After the initial six months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3 mg b.i.d. at any time during the study for intolerability. - A total of 162 patients were enrolled in this study. The majority of patients were female (78%) and had persistent or recurrent Cushing’s disease despite pituitary surgery (83%) with a mean age of 40 years. A few patients (4%) in either treatment group received previous pituitary irradiation. The median value of the baseline 24-hour UFC for all patients was 565 nmol/24 hours (normal range 30 to 145 nmol/24 hours). About two-thirds of all randomized patients completed six months of treatment. - The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after six months of treatment and did not dose increase during this period. - 24-Hour Urinary Free Cortisol Results - At Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6 mg b.i.d. and 0.9 mg b.i.d. groups, respectively (Table 3). The percentages of patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 0.6 mg bid and 41% in the 0.9 mg bid groups. Dose increases appeared to have minimal effect on 24-hour UFC response. Mean and median percentage changes in UFC from baseline are presented in Table 3. - SIGNIFOR resulted in a decrease in the mean 24-hour UFC after 1 month of treatment (Figure 1). For patients (n=78) who stayed in the trial, similar UFC lowering was observed at Month 12. - Note: Only patients who completed 6 months of treatment are included in this analysis (n=110). The reference line is the upper limit of normal for UFC, which is 145 nmol/24hour; +/-Standard errors are displayed. - Other endpoints - Decreases from baseline for blood pressure were observed at Month 6, including patients who did not receive any antihypertensive medication. However, due to the fact that the study allowed initiation of antihypertensive medication and dose increases in patients already receiving such medications, the individual contribution of SIGNIFOR or of antihypertensive medication adjustments cannot be clearly established. - The mean decreases from baseline at Month 6 for weight, body mass index and waist circumference were 4.4 kg, 1.6 kg/m2 and 2.6 cm, respectively. Individual patients showed varying degrees of improvement in Cushing's disease manifestations but because of the variability in response and the absence of a control group in this trial, it is uncertain whether these changes could be ascribed to the effects of SIGNIFOR. # How Supplied - SIGNIFOR is supplied as a single dose, colorless glass ampule packaged in a box of 60 ampules, arranged in 10 packs of 6 ampules each. The following packaging configurations are available. - 0.3 mg/1 mL pasireotide (as diaspartate) - Box of 60 ampules NDC# 0078-0633-20 - 0.6 mg/1 mL pasireotide (as diaspartate) - Box of 60 ampules NDC# 0078-0634-20 - 0.9 mg/1 mL pasireotide (as diaspartate) - Box of 60 ampules NDC# 0078-0635-20 - Storage and Handling - Store at 25° C (77°F); excursions permitted to 15°-30°C (59°-86°F), protect from light. ## Storage There is limited information regarding Pasireotide Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Counsel patients on the following possible significant adverse reactions: - Hypocortisolism - Hyperglycemia and diabetes - Bradycardia and QT prolongation - Liver test elevations - Cholelithiasis - Pituitary hormone deficiency - Instruct the patients on the proper use of SIGNIFOR, including instructions to: - Carefully review the Medication Guide. - Do not reuse unused portions of SIGNIFOR ampules and properly dispose of the ampules after use. - Avoid multiple injections at or near the same site within short periods of time. # Precautions with Alcohol - Alcohol-Pasireotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SIGNIFOR®[1] # Look-Alike Drug Names There is limited information regarding Pasireotide Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Pasireotide
4a19eed7f6098f649712acb1710409bb5ef01d25	wikidoc	Passivation	Passivation # Overview Passivation is the process of making a material "passive" in relation to another material prior to using the materials together. For example, prior to storing hydrogen peroxide in an aluminium container, the container can be passivated by rinsing it with a dilute solution of nitric acid and peroxide alternating with deionized water. The nitric acid and peroxide oxidizes and dissolves any impurities on the inner surface of the container, and the deionized water rinses away the acid and oxidized impurities. Another typical passivation process of cleaning stainless steel tanks involves cleaning with NaOH and citric acid followed by nitric acid (up to 20% at 120F) and a complete water rinse. This process will restore the film, remove metal particles, dirt, and welding generated compounds (e.g. oxides). In the context of corrosion, passivation is the spontaneous formation of a hard non-reactive surface film that inhibits further corrosion. This layer is usually an oxide or nitride that is a few atoms thick. # Mechanisms of passivation Under normal conditions of pH and oxygen concentration, passivation is seen in such materials as aluminium, iron, zinc, magnesium, copper, stainless steel, titanium, and silicon. Ordinary steel can form a passivating layer in alkali environments, as rebar does in concrete. The conditions necessary for passivation are recorded in Pourbaix diagrams. Some corrosion inhibitors help the formation of a passivation layer on the surface of the metals to which they are applied. # Electrochemical passivation processes Some compounds, dissolving in solutions (chromates, molybdates) form non-reactive and low solubility films on metal surfaces. # Passivation of specific materials Aluminium may be protected from oxidation by anodizing and/or allodizing (sometimes called Alodining), or any of an assortment of similar processes. (See terminology, below.) In addition, stacked passivation techniques are often used for protecting aluminium. For example, chromating is often used as a sealant to a previously-anodized surface, to increase resistance to salt-water exposure of aluminium parts by nearly a factor of 2 versus simply relying on anodizing. Iron based (ferrous) materials, including steel, may be somewhat protected by promoting oxidation ("rust") and then converting the oxidation to a metalophosphate by using phosphoric acid and further protected by surface coating. As the uncoated surface is water-soluble a preferred method is to form manganese or zinc compounds by a process commonly known as Parkerizing. Older, less-effective but chemically-similar electrochemical conversion coatings included bluing, also known as black oxide. Nickel can be used for handling elemental fluorine, thanks to a passivation layer of nickel fluoride.' # Terminology for assorted passivation processes Bluing, also known as black oxide, and sometimes called browning when used in reference to historical processes dating from the 18th Century, is a passivation coating for the surfaces of iron and steel objects. It is one of the oldest passivation processes. Newer, proprietary (and/or trademarked) processes for conversion coatings include Parkerized for passivating steel, dating to roughly 1912, and Alodine for passivating aluminium; both are trademarked processes and are now owned by Henkel Surface Technologies. , Chem film is any generic chromate conversion coating used to passivate aluminium. One such example is U.S. Patent 5,304,257. In general, however, chromate can also mean any of several chromate conversion coatings that can be applied to a much wider range of metals and alloys than just to aluminium. In recent years, chromate coatings have become less popular due to concerns over environmental pollution from using such processes. Iridite is another trademarked name of a whole family of proprietary conversion coatings owned by MacDermid. A competing conversion coating used on aluminium, that somewhat ameliorates the environmental pollution concerns caused by chromate coatings, it often appears as a slightly yellowish coating, of roughly the same color as a yellow highlighting pen used to mark text on paper. # Rationale for passivating aluminium Aluminium naturally forms an oxide almost immediately that protects it from further oxidation in many environments. This naturally-occurring oxide provides no protection during exposure to any saltwater spray environments, such as occurs in areas near bodies of saltwater. In such coastal environments, unprotected aluminium will turn white, corrode, and largely vanish over periods of exposure as short as a few years. The only way to prevent this from occurring is to use a more robust conversion coating on aluminium surfaces that will not be affected by the saltwater atmosphere. Alodine, Iridite, and chem film coatings can provide varying amounts of protection for aluminium surfaces. # Further reading ASTM A967 provides advice for the passivation of stainless steel parts. Chromate Conversion Coat (Chemical Film) Per MIL-C-5541 For Aluminum and Aluminum Alloy Parts	Passivation # Overview Passivation is the process of making a material "passive" in relation to another material prior to using the materials together. For example, prior to storing hydrogen peroxide in an aluminium container, the container can be passivated by rinsing it with a dilute solution of nitric acid and peroxide alternating with deionized water. The nitric acid and peroxide oxidizes and dissolves any impurities on the inner surface of the container, and the deionized water rinses away the acid and oxidized impurities. Another typical passivation process of cleaning stainless steel tanks involves cleaning with NaOH and citric acid followed by nitric acid (up to 20% at 120F) and a complete water rinse. This process will restore the film, remove metal particles, dirt, and welding generated compounds (e.g. oxides). In the context of corrosion, passivation is the spontaneous formation of a hard non-reactive surface film that inhibits further corrosion. This layer is usually an oxide or nitride that is a few atoms thick. # Mechanisms of passivation Under normal conditions of pH and oxygen concentration, passivation is seen in such materials as aluminium, iron, zinc, magnesium, copper, stainless steel, titanium, and silicon. Ordinary steel can form a passivating layer in alkali environments, as rebar does in concrete. The conditions necessary for passivation are recorded in Pourbaix diagrams. Some corrosion inhibitors help the formation of a passivation layer on the surface of the metals to which they are applied. # Electrochemical passivation processes Some compounds, dissolving in solutions (chromates, molybdates) form non-reactive and low solubility films on metal surfaces. # Passivation of specific materials Aluminium may be protected from oxidation by anodizing and/or allodizing (sometimes called Alodining), or any of an assortment of similar processes. (See terminology, below.) In addition, stacked passivation techniques are often used for protecting aluminium. For example, chromating is often used as a sealant to a previously-anodized surface, to increase resistance to salt-water exposure of aluminium parts by nearly a factor of 2 versus simply relying on anodizing. Iron based (ferrous) materials, including steel, may be somewhat protected by promoting oxidation ("rust") and then converting the oxidation to a metalophosphate by using phosphoric acid and further protected by surface coating. As the uncoated surface is water-soluble a preferred method is to form manganese or zinc compounds by a process commonly known as Parkerizing. Older, less-effective but chemically-similar electrochemical conversion coatings included bluing, also known as black oxide. Nickel can be used for handling elemental fluorine, thanks to a passivation layer of nickel fluoride.' # Terminology for assorted passivation processes Bluing, also known as black oxide, and sometimes called browning when used in reference to historical processes dating from the 18th Century, is a passivation coating for the surfaces of iron and steel objects. It is one of the oldest passivation processes. Newer, proprietary (and/or trademarked) processes for conversion coatings include Parkerized for passivating steel, dating to roughly 1912, and Alodine for passivating aluminium; both are trademarked processes and are now owned by Henkel Surface Technologies. [1],[2] Chem film is any generic chromate conversion coating used to passivate aluminium. One such example is U.S. Patent 5,304,257. In general, however, chromate can also mean any of several chromate conversion coatings that can be applied to a much wider range of metals and alloys than just to aluminium. In recent years, chromate coatings have become less popular due to concerns over environmental pollution from using such processes. Iridite is another trademarked name of a whole family of proprietary conversion coatings owned by MacDermid. A competing conversion coating used on aluminium, that somewhat ameliorates the environmental pollution concerns caused by chromate coatings, it often appears as a slightly yellowish coating, of roughly the same color as a yellow highlighting pen used to mark text on paper. [3] # Rationale for passivating aluminium Aluminium naturally forms an oxide almost immediately that protects it from further oxidation in many environments. This naturally-occurring oxide provides no protection during exposure to any saltwater spray environments, such as occurs in areas near bodies of saltwater. In such coastal environments, unprotected aluminium will turn white, corrode, and largely vanish over periods of exposure as short as a few years. The only way to prevent this from occurring is to use a more robust conversion coating on aluminium surfaces that will not be affected by the saltwater atmosphere. Alodine, Iridite, and chem film coatings can provide varying amounts of protection for aluminium surfaces. # Further reading ASTM A967 provides advice for the passivation of stainless steel parts. Chromate Conversion Coat (Chemical Film) Per MIL-C-5541 For Aluminum and Aluminum Alloy Parts	https://www.wikidoc.org/index.php/Passivation
400ce307e0fc109ced05d845a7a26a54141b47be	wikidoc	Pat Simmons	Pat Simmons Dr. Pat Simmons (born November 21, 1974 in Moose Jaw, Saskatchewan) is a Canadian curler. Simmons has skipped team Saskatchewan in four straight the Brier from 2005 to 2008. Simmons made it to his first Brier in 2005 after winning his first provincial championship. He skipped Saskatchewan to a 6-5 finish, in a four-way tie for fifth place, out of the playoffs. In 2006, Simmons skipped Saskatchewan to a 5-6 finish at the Brier, out of the playoffs, tied for eighth place. In 2007, Simmons had a much better record, finishing 7-4, but narrowly missed the playoffs once again, finishing in fifth place. In 2008, Simmons finally skipped Saskatchewan to a playoff spot at the Brier, finishing the round robin in second place with a 9-2 record. However, he lost in the semi-final in an extra end to Ontario, skipped by Glenn Howard	Pat Simmons Template:Infobox curler Dr. Pat Simmons (born November 21, 1974 in Moose Jaw, Saskatchewan) is a Canadian curler. Simmons has skipped team Saskatchewan in four straight the Brier from 2005 to 2008. Simmons made it to his first Brier in 2005 after winning his first provincial championship. He skipped Saskatchewan to a 6-5 finish, in a four-way tie for fifth place, out of the playoffs. In 2006, Simmons skipped Saskatchewan to a 5-6 finish at the Brier, out of the playoffs, tied for eighth place. In 2007, Simmons had a much better record, finishing 7-4, but narrowly missed the playoffs once again, finishing in fifth place. In 2008, Simmons finally skipped Saskatchewan to a playoff spot at the Brier, finishing the round robin in second place with a 9-2 record. However, he lost in the semi-final in an extra end to Ontario, skipped by Glenn Howard # External links - teamsimmons.ca Template:Curling-stub Template:ATTRIB	https://www.wikidoc.org/index.php/Pat_Simmons
b931bcfa4d8990174c35ec53ee9b0d2ff46bae99	wikidoc	Patch Adams	Patch Adams # Overview Hunter Campbell "Patch" Adams (born May 28 1945 in Washington, District of Columbia) founded the Gesundheit! Institute in 1972. Patch Adams is a social activist, citizen diplomat, professional clown, performer, and author. Each year he organizes a group of volunteers from around the world to travel to Russia as clowns, to bring hope and joy to orphans, patients, and the people. In 1998 he also visited Bosnia, one of the Balkan Peninsula countries torn apart by the war that started after the break-up of Yugoslavia. His life was the template for the plot of the movie Patch Adams, starring Robin Williams. Adams is currently based in Arlington, Virginia, where he promotes alternative health care in collaboration with the institute. # Early career After attending Wakefield High School in 1963, Patch Adams completed pre-med coursework at the George Washington University. He began medical school without an undergraduate degree, and earned his Doctor of Medicine degree at the Medical College of Virginia, Health Sciences Division of Virginia Commonwealth University in 1973. In the late 60s, one of his closest friends (not his girlfriend as seen in the movie) was murdered. Convinced of the powerful connection between environment and wellness, he believes the health of an individual cannot be separated from the health of the family, community, and the world. While working in an adolescent clinic at MCV, in his final year of med school, he met Linda Edquist, a volunteer in the clinic and student at VCU. Soon after graduation, Patch, Linda, and friends founded the Gesundheit! Institute (originally known to many as the Zanies), which ran as a free community hospital for 12 years. He and Linda later would have two children and separated in 1997. The eldest, Atomic Zagnut Adams, was given a name indicative of Patch and his close friend Leo's personal laugh with life. His younger son's name is Lars Zig Edquist Adams; since the fall 2007 he is a junior at Guilford College in Greensboro, North Carolina. # Gesundheit! Institute A revamped Gesundheit! Institute, envisioned as a free, full-scale hospital and health care eco-community, is planned on 316 acres in Pocahontas County in West Virginia. Its goal is to integrate a traditional hospital with alternative medicine--acupuncture, homeopathy, etc. Care will combine integrative medicine with performing arts, crafts, nature, agriculture, and recreation. The West Virginia location accepts seasonal volunteers through the website. The new hospital has not been built as Patch continues to seek funding. The current caretaker staff at the West Virginia land is actively developing educational programs in sustainable systems design targeted to medical students, university alternative break groups, and the general public. Several videos and books have also been produced including Patch Adams. Since the 1990s Adams has supported the Ithaca Health Alliance (IHA), originally founded as the Ithaca Health Fund (IHF) by Paul Glover. In January 2006 IHA launched the Ithaca Free Clinic, bringing to life key aspects of Adams' vision. Patch Adams has also given strong praise to Health Democracy, a book written and published the same year. In October of 2007, Patch Adams and the Gesundheit Board unveiled its campaign to raise $1 million dollars towards building a Teaching Center and Clinic on its land in West Virginia. The Center and Clinic will enable Gesundheit to see patients and teach health care design.	Patch Adams # Overview Hunter Campbell "Patch" Adams (born May 28 1945 in Washington, District of Columbia) founded the Gesundheit! Institute in 1972. Patch Adams is a social activist, citizen diplomat, professional clown, performer, and author. Each year he organizes a group of volunteers from around the world to travel to Russia as clowns, to bring hope and joy to orphans, patients, and the people. In 1998 he also visited Bosnia, one of the Balkan Peninsula countries torn apart by the war that started after the break-up of Yugoslavia. His life was the template for the plot of the movie Patch Adams, starring Robin Williams. Adams is currently based in Arlington, Virginia, where he promotes alternative health care in collaboration with the institute. # Early career After attending Wakefield High School in 1963, Patch Adams completed pre-med coursework at the George Washington University. He began medical school without an undergraduate degree, and earned his Doctor of Medicine degree at the Medical College of Virginia, Health Sciences Division of Virginia Commonwealth University in 1973. In the late 60s, one of his closest friends (not his girlfriend as seen in the movie) was murdered. Convinced of the powerful connection between environment and wellness, he believes the health of an individual cannot be separated from the health of the family, community, and the world. While working in an adolescent clinic at MCV, in his final year of med school, he met Linda Edquist, a volunteer in the clinic and student at VCU. Soon after graduation, Patch, Linda, and friends founded the Gesundheit! Institute (originally known to many as the Zanies), which ran as a free community hospital for 12 years. He and Linda later would have two children and separated in 1997. The eldest, Atomic Zagnut Adams, was given a name indicative of Patch and his close friend Leo's personal laugh with life. His younger son's name is Lars Zig Edquist Adams; since the fall 2007 he is a junior at Guilford College in Greensboro, North Carolina. # Gesundheit! Institute A revamped Gesundheit! Institute, envisioned as a free, full-scale hospital and health care eco-community, is planned on 316 acres in Pocahontas County in West Virginia. Its goal is to integrate a traditional hospital with alternative medicine--acupuncture, homeopathy, etc. Care will combine integrative medicine with performing arts, crafts, nature, agriculture, and recreation. The West Virginia location accepts seasonal volunteers through the website. The new hospital has not been built as Patch continues to seek funding. The current caretaker staff at the West Virginia land is actively developing educational programs in sustainable systems design targeted to medical students, university alternative break groups, and the general public. Several videos and books have also been produced including Patch Adams. Since the 1990s Adams has supported [1] the Ithaca Health Alliance (IHA), originally founded as the Ithaca Health Fund (IHF) by Paul Glover. In January 2006 IHA launched the Ithaca Free Clinic, bringing to life key aspects of Adams' vision. Patch Adams has also given strong praise to Health Democracy, a book written and published the same year. In October of 2007, Patch Adams and the Gesundheit Board unveiled its campaign to raise $1 million dollars towards building a Teaching Center and Clinic on its land in West Virginia. The Center and Clinic will enable Gesundheit to see patients and teach health care design. # External links - Patch Adams official website - MindFreedom.org - 'President Bush and the Shrinking of the USA: Coalition of Advocacy Groups Says: "Start With the Top. Test President Bush for 'Mental Illness' First: "The "Real" Patch Adams Volunteers' (press release), MindFreedom.org, (August 16, 2004) - Holistic World.org- Holistic World Expo - Adams brings his take on state of medicine to students - Article on the speech that included the controversial statements - Joy to the world! (Interview with Patch Adams) de:Patch Adams it:Patch Adams he:פאץ' אדאמס nl:Patch Adams Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Patch_Adams
7ae477b84347e538b0b65921396a80a802dcdde2	wikidoc	Pearson's r	Pearson's r In statistics, the Pearson product-moment correlation coefficient (sometimes referred to as the MCV or PMCC) (r) is a common measure of the correlation between two variables X and Y. When measured in a population the Pearson Product Moment correlation is designated by the Greek letter rho (ρ). When computed in a sample, it is designated by the letter r and is sometimes called "Pearson's r." Pearson's correlation reflects the degree of linear relationship between two variables. It ranges from +1 to -1. A correlation of +1 means that there is a perfect positive linear relationship between variables. A correlation of -1 means that there is a perfect negative linear relationship between variables. A correlation of 0 means there is no linear relationship between the two variables. Correlations are rarely if ever 0, 1, or -1. A certain outcome could indicate whether correlations are negative or positive. The statistic is defined as the sum of the products of the standard scores of the two measures divided by the degrees of freedom.. If the data comes from a sample, then where are the standard score, sample mean, and sample standard deviation (calculated using n − 1 in the denominator). If the data comes from a population, then where are the standard score, population mean, and population standard deviation (calculated using n in the denominator). The result obtained is equivalent to dividing the covariance between the two variables by the product of their standard deviations. The coefficient ranges from −1 to 1. A value of 1 shows that a linear equation describes the relationship perfectly and positively, with all data points lying on the same line and with Y increasing with X. A score of −1 shows that all data points lie on a single line but that Y increases as X decreases. A value of 0 shows that a linear model is inappropriate – that there is no linear relationship between the variables. The Pearson coefficient is a statistic which estimates the correlation of the two given random variables. The linear equation that best describes the relationship between X and Y can be found by linear regression. This equation can be used to "predict" the value of one measurement from knowledge of the other. That is, for each value of X the equation calculates a value which is the best estimate of the values of Y corresponding the specific value. We denote this predicted variable by Y'. Any value of Y can therefore be defined as the sum of Y′ and the difference between Y and Y′: The variance of Y is equal to the sum of the variance of the two components of Y: Since the coefficient of determination implies that sy.x2 = sy2(1 − r2) we can derive the identity The square of r is conventionally used as a measure of the association between X and Y. For example, if r2 is 0.90, then 90% of the variance of Y can be "accounted for" by changes in X and the linear relationship between X and Y.	Pearson's r Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] In statistics, the Pearson product-moment correlation coefficient (sometimes referred to as the MCV or PMCC) (r) is a common measure of the correlation between two variables X and Y. When measured in a population the Pearson Product Moment correlation is designated by the Greek letter rho (ρ). When computed in a sample, it is designated by the letter r and is sometimes called "Pearson's r." Pearson's correlation reflects the degree of linear relationship between two variables. It ranges from +1 to -1. A correlation of +1 means that there is a perfect positive linear relationship between variables. A correlation of -1 means that there is a perfect negative linear relationship between variables. A correlation of 0 means there is no linear relationship between the two variables. Correlations are rarely if ever 0, 1, or -1. A certain outcome could indicate whether correlations are negative or positive.[1] The statistic is defined as the sum of the products of the standard scores of the two measures divided by the degrees of freedom.[1]. If the data comes from a sample, then where are the standard score, sample mean, and sample standard deviation (calculated using n − 1 in the denominator).[1] If the data comes from a population, then where are the standard score, population mean, and population standard deviation (calculated using n in the denominator). The result obtained is equivalent to dividing the covariance between the two variables by the product of their standard deviations. The coefficient ranges from −1 to 1. A value of 1 shows that a linear equation describes the relationship perfectly and positively, with all data points lying on the same line and with Y increasing with X. A score of −1 shows that all data points lie on a single line but that Y increases as X decreases. A value of 0 shows that a linear model is inappropriate – that there is no linear relationship between the variables.[1] The Pearson coefficient is a statistic which estimates the correlation of the two given random variables. The linear equation that best describes the relationship between X and Y can be found by linear regression. This equation can be used to "predict" the value of one measurement from knowledge of the other. That is, for each value of X the equation calculates a value which is the best estimate of the values of Y corresponding the specific value. We denote this predicted variable by Y'. Any value of Y can therefore be defined as the sum of Y′ and the difference between Y and Y′: The variance of Y is equal to the sum of the variance of the two components of Y: Since the coefficient of determination implies that sy.x2 = sy2(1 − r2) we can derive the identity The square of r is conventionally used as a measure of the association between X and Y. For example, if r2 is 0.90, then 90% of the variance of Y can be "accounted for" by changes in X and the linear relationship between X and Y.[1]	https://www.wikidoc.org/index.php/Pearson%27s_r
d9c1613be9c2317ce295434c8cfcf520a7613a00	wikidoc	Pedodontics	Pedodontics # Overview 'Pediatric Dentistry', formerly known as pedodontics, is a specialized branch of dentistry for the treatment of children. # Dental Care for Young Children: Summary of Best Practice Recommendations When should parents begin to clean their baby’s teeth? “The sooner, the better!” The states that parents should begin dental cleaning at birth, by cleaning their child’s gums with a soft infant toothbrush and water. Unless it is advised by your child’s pediatric dentist, fluoridated toothpaste is not recommended until 2-3 years of age. When should children first visit a dentist? "First visit by first birthday" According to the children should first visit the dentist when they receive their first tooth or by the child’s first birthday. Early dental care is important for dental prevention in the future. However, dental problems can begin early. A major dental concern for young children is Early Childhood Caries, also known as baby bottle tooth decay or nursing caries. How can I prevent tooth decay from a bottle or nursing?To prevent tooth decay in young children, the recommends that children be encouraged to begin drinking from a cup as they approach their first birthday. At nap times or at night, children should not fall asleep with a bottle. It is recommended that nighttime breast-feeding be avoided after the first primary (baby) teeth begin to erupt. Drinking juice or other sugary drinks from a bottle should always be avoided. When such drinks are offered, they should be served in a cup. What is the importance of baby teeth anyway? Primary teeth serve three important functions: they allow children to chew their food, aiding in proper digestion; they serve in proper pronunciation of sounds and formation of speech; and they establish and preserve the space and create the architecture for the developing adult teeth, which form as buds off of primary teeth.	Pedodontics Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview 'Pediatric Dentistry', formerly known as pedodontics, is a specialized branch of dentistry for the treatment of children. # Dental Care for Young Children: Summary of Best Practice Recommendations When should parents begin to clean their baby’s teeth? “The sooner, the better!” The [American Academy of Pediatric Dentistry; http://aapd.org] states that parents should begin dental cleaning at birth, by cleaning their child’s gums with a soft infant toothbrush and water. Unless it is advised by your child’s pediatric dentist, fluoridated toothpaste is not recommended until 2-3 years of age. When should children first visit a dentist? "First visit by first birthday" According to the [American Academy of Pediatric Dentistry; http://aapd.org] children should first visit the dentist when they receive their first tooth or by the child’s first birthday. Early dental care is important for dental prevention in the future. However, dental problems can begin early. A major dental concern for young children is Early Childhood Caries, also known as baby bottle tooth decay or nursing caries. How can I prevent tooth decay from a bottle or nursing?To prevent tooth decay in young children, the [American Academy of Pediatric Dentistry; http://aapd.org] recommends that children be encouraged to begin drinking from a cup as they approach their first birthday. At nap times or at night, children should not fall asleep with a bottle. It is recommended that nighttime breast-feeding be avoided after the first primary (baby) teeth begin to erupt. Drinking juice or other sugary drinks from a bottle should always be avoided. When such drinks are offered, they should be served in a cup. What is the importance of baby teeth anyway? Primary teeth serve three important functions: they allow children to chew their food, aiding in proper digestion; they serve in proper pronunciation of sounds and formation of speech; and they establish and preserve the space and create the architecture for the developing adult teeth, which form as buds off of primary teeth. # External links - FAQ from the American Academy of Pediatric Dentistry Template:Dentistry Template:WH Template:WS	https://www.wikidoc.org/index.php/Pediatric_dentistry
6df27b4d5100e0c286c94974d2c9de1e59bf2ebb	wikidoc	Peer review	Peer review Peer review (also known as refereeing) is the process of subjecting an author's scholarly work, research or ideas to the scrutiny of others who are experts in the same field. Peer review requires a community of experts in a given (and often narrowly defined) field, who are qualified and able to perform impartial review. Impartial review, especially of work in less narrowly defined or inter-disciplinary fields may be difficult to accomplish, and the significance (good or bad) of an idea may never be widely appreciated among its contemporaries. Peer review has been criticized as ineffective and misunderstood. Pragmatically, peer review refers to the work done during the screening of submitted manuscripts and funding applications. This normative process encourages authors to meet the accepted standards of their discipline and prevents the dissemination of unwarranted claims, unacceptable interpretations and personal views. Publications that have not undergone peer review are likely to be regarded with suspicion by scholars and professionals. # Reasons for peer review It is difficult for an individual author or research team to spot every mistake or flaw in a complicated piece of work. This is not because deficiencies represent "needles in a haystack" that are difficult to locate, but because with a new and perhaps eclectic subject, an opportunity for improvement may be more obvious to someone with special expertise or experience. Therefore, showing work to others increases the probability that weaknesses will be identified, and, with advice and encouragement, fixed. For both grant-funding and publication in a scholarly journal, it is also normally a requirement that the subject is both novel and substantial. Reviewers are typically anonymous and independent, to help foster unvarnished criticism, and to discourage cronyism in funding and publication decisions. However, US government guidelines governing peer review for federal regulatory agencies require that reviewer's identity be disclosed under some circumstances. Since reviewers are normally selected from experts in the fields discussed in the article, the process of peer review is considered critical to establishing a reliable body of research and knowledge. Scholars reading the published articles can only be expert in a limited area; they rely, to some degree, on the peer-review process to provide reliable and credible research that they can build upon for subsequent or related research. As a result, significant scandal ensues when an author is found to have falsified the research included in an article, as many other scholars, and the field of study itself, may have relied upon the original research (see Peer review and fraud below). # How it works In the case of proposed publications, an editor sends advance copies of an author's work or ideas to researchers or scholars who are experts in the field (known as "referees" or "reviewers"), nowadays normally by e-mail or through a web-based manuscript processing system. Usually, there are two or three referees for a given article. These referees each return an evaluation of the work to the editor, including noting weaknesses or problems along with suggestions for improvement. Typically, most of the referees' comments are eventually seen by the author; scientific journals observe this convention universally. The editor, usually familiar with the field of the manuscript (although typically not in as much depth as the referees, who are specialists), then evaluates the referees' comments, her or his own opinion of the manuscript, and the context of the scope of the journal or level of the book and readership, before passing a decision back to the author(s), usually with the referees' comments. Referees' evaluations usually include an explicit recommendation of what to do with the manuscript or proposal, often chosen from options provided by the journal or funding agency. Most recommendations are along the lines of the following: - to unconditionally accept the manuscript or proposal, - to accept it in the event that its authors improve it in certain ways, - to reject it, but encourage revision and invite resubmission, - to reject it outright. During this process, the role of the referees is advisory, and the editor is typically under no formal obligation to accept the opinions of the referees. Furthermore, in scientific publication, the referees do not act as a group, do not communicate with each other, and typically are not aware of each other's identities or evaluations. There is usually no requirement that the referees achieve consensus. Thus the group dynamics are substantially different from that of a jury. In situations where the referees disagree substantially about the quality of a work, there are a number of strategies for reaching a decision. When an editor receives very positive and very negative reviews for the same manuscript, the editor often will solicit one or more additional reviews as a tie-breaker. As another strategy in the case of ties, editors may invite authors to reply to a referee's criticisms and permit a compelling rebuttal to break the tie. If an editor does not feel confident to weigh the persuasiveness of a rebuttal, the editor may solicit a response from the referee who made the original criticism. In rare instances, an editor will convey communications back and forth between authors and a referee, in effect allowing them to debate a point. Even in these cases, however, editors do not allow referees to confer with each other, and the goal of the process is explicitly not to reach consensus or to convince anyone to change their opinions. Some medical journals, however (usually following the open access model), have begun posting on the Internet the pre-publication history of each individual article, from the original submission to reviewers' reports, authors' comments, and revised manuscripts. Traditionally, reviewers would remain anonymous to the authors, but this standard is slowly changing. In some academic fields, most journals now offer the reviewer the option of remaining anonymous or not, or a referee may opt to sign a review, thereby relinquishing anonymity. Published papers sometimes contain, in the acknowledgements section, thanks to anonymous or named referees who helped improve the paper. Some university presses undertake peer review of books. After positive review by two or three independent referees, a university press sends the manuscript to the press's editorial board, a committee of faculty members, for final approval. Such a review process is a requirement for full membership of the Association of American University Presses. In some disciplines there exist refereed venues (such as conferences and workshops). To be admitted to speak, scholars and scientists must submit papers (generally short, often 15 pages or less) in advance. These papers are reviewed by a "program committee" (the equivalent of an editorial board), which generally requests inputs from referees. The hard deadlines set by the conferences tend to limit the options to either accept or reject the paper. # Recruiting referees At a journal or book publisher, the task of picking reviewers typically falls to an editor. When a manuscript arrives, an editor solicits reviews from scholars or other experts who may or may not have already expressed a willingness to referee for that journal or book division. Granting agencies typically recruit a panel or committee of reviewers in advance of the arrival of applications. Typically referees are not selected from among the authors' close colleagues, students, or friends. Referees are supposed to inform the editor of any conflict of interests that might arise. Journals or individual editors often invite a manuscript's authors to name people whom they consider qualified to referee their work. Indeed, for a number of journals this is a requirement of submission. Authors are sometimes also invited to name natural candidates who should be disqualified, in which case they may be asked to provide justification (typically expressed in terms of conflict of interest). In some disciplines, scholars listed in an "acknowledgements" section are not allowed to serve as referees (hence the occasional practice of using this section to disqualify potentially negative reviewers). Recruiting referees is a political art, because referees, and often editors, are usually not paid, and reviewing takes time away from the referee's main activities, such as his or her own research. To the would-be recruiter's advantage, most potential referees are authors themselves, or at least readers, who know that the publication system requires that experts donate their time. Referees also have the opportunity to prevent work that does not meet the standards of the field from being published, which is a position of some responsibility. Editors are at a special advantage in recruiting a scholar when they have overseen the publication of his or her work, or if the scholar is one who hopes to submit manuscripts to that editor's publication in the future. Granting agencies, similarly, tend to seek referees among their present or former grantees. Serving as a referee can even be a condition of a grant, or professional association membership. Another difficulty that peer-review organizers face is that, with respect to some manuscripts or proposals, there may be few scholars who truly qualify as experts. Such a circumstance often frustrates the goals of reviewer anonymity and the avoidance of conflicts of interest. It also increases the chances that an organizer will not be able to recruit true experts – people who have themselves done work similar to that under review, and who can read between the lines. Low-prestige or local journals and granting agencies that award little money are especially handicapped with regard to recruiting experts. Finally, anonymity adds to the difficulty in finding reviewers in another way. In scientific circles, credentials and reputation are important, and while being a referee for a prestigious journal is considered an honor, the anonymity restrictions make it impossible to publicly state that one was a referee for a particular article. However, credentials and reputation are principally established by publications, not by refereeing; and in some fields refereeing may not be anonymous. The process of peer review does not end after a paper completes the peer review process. After being put to press, and after 'the ink is dry', the process of peer review continues in journal clubs. Here groups of colleagues review literature and discuss the value and implications it presents. Journal clubs will often send letters to the editor of a journal, or correspond with the editor via an on-line journal club. In this way, all 'peers' may offer review and critique of published literature. # Different styles of review Peer review can be rigorous, in terms of the skill brought to bear, without being highly stringent. An agency may be flush with money to give away, for example, or a journal may have few impressive manuscripts to choose from, so there may be little incentive for selection. Conversely, when either funds or publication space is limited, peer review may be used to select an extremely small number of proposals or manuscripts. Often the decision of what counts as "good enough" falls entirely to the editor or organizer of the review. In other cases, referees will each be asked to make the call, with only general guidance from the coordinator on what stringency to apply. Very general journals such as Science and Nature have extremely stringent standards for publication, and will reject papers that report good quality scientific work if editors feel the work is not a breakthrough in the field. Such journals generally have a two-tier reviewing system. In the first stage, members of the editorial board verify that the paper's findings — if correct — would be ground-breaking enough to warrant publication in Science or Nature. Most papers are rejected at this stage. Papers that do pass this 'pre-reviewing' are sent out for in-depth review to outside referees. Even after all reviewers recommend publication and all reviewer criticisms/suggestions for changes have been met, papers may still be returned to the authors for shortening to meet the journal's length limits. With the advent of electronic journal editions, overflow material may be stored in the journal's online Electronic Supporting Information archive. A similar emphasis on novelty exists in general area journals such as the Journal of the American Chemical Society (JACS). However, these journals generally send out all papers (except blatantly inappropriate ones) for peer reviewing to multiple reviewers. The reviewers are specifically queried not just on the scientific quality and correctness, but also on whether the findings are of interest to the general area readership (chemists of all disciplines, in the case of JACS) or only to a specialist subgroup. In the latter case, the recommendation is usually for publication in a more specialized journal. The editor may offer to authors the option of having the manuscript and reviews forwarded to such a journal with the same publishers (e.g., in the example given, Journal of Organic Chemistry, Journal of Physical Chemistry, Inorganic Chemistry,...) if the reviewer reports warrant such a decision (i.e., they boil down to "Great work, but too specialized for JACS: publish in ..."), the editor of such a journal may accept the forwarded manuscript without further reviewing. Some general area journals, such as Physical Review Letters, have strict length limitations. Others, such as JACS, have Letters and Full Papers sections: the Letters sections have strict length limits (two journal pages in the case of JACS) and special novelty requirements. In contrast, online-only journals may have no space limitations. More specialized scientific journals such as the aforementioned chemistry journals, Astrophysical Journal, and the Physical Review series use peer review primarily to filter out obvious mistakes and incompetence, as well as plagiarism, overly derivative work, and straightforward applications of known methods. Different publication rates reflect these different criteria: Nature publishes about 5 percent of received papers, while Astrophysical Journal publishes about 70 percent. The different publication rates are also reflected in the size of the journals. PLoS ONE was launched by the Public Library of Science in 2006 with the aim to "concentrate on technical rather than subjective concerns", and to publish articles from across science, regardless of the field.. Another open access journal, Biology Direct, has the policy of making the reviewers' reports public by publishing the reports together with the manuscripts. Screening by peers may be more or less laissez-faire depending on the discipline. Physicists, for example, tend to think that decisions about the worthiness of an article are best left to the marketplace. Yet even within such a culture peer review serves to ensure high standards in what is published. Outright errors are detected and authors receive both edits and suggestions. To preserve the integrity of the peer-review process, submitting authors may not be informed of who reviews their papers; sometimes, they might not even know the identity of the associate editor who is responsible for the paper. In many cases, alternatively called "masked" or "double-masked" review (or "blind" or "double-blind" review), the identity of the authors is concealed from the reviewers, lest the knowledge of authorship bias their review; in such cases, however, the associate editor responsible for the paper does know who the author is. Sometimes the scenario where the reviewers do know who the authors are is called "single-masked" to distinguish it from the "double-masked" process. In double-masked review, the authors are required to remove any reference that may point to them as the authors of the paper. While the anonymity of reviewers is almost universally preserved, double-masked review (where authors are also anonymous to reviewers) is still relatively rarely employed. Critics of the double-masked process point out that, despite the extra editorial effort to ensure anonymity, the process often fails to do so, since certain approaches, methods, writing styles, notations, etc., may point to a certain group of people in a research stream, and even to a particular person., Proponents of double-masked review argue that it performs at least as well as the traditional one and that it generates a better perception of fairness and equality in global scientific funding and publishing. Proponents of the double-masked process argue that if the reviewers of a paper are unknown to each other, the associate editor responsible for the paper can easily verify the objectivity of the reviews. Single-masked review is thus strongly dependent upon the goodwill of the participants. A conflict of interest arises when a reviewer and author have a disproportionate amount of respect (or disrespect) for each other. As an alternative to single-masked and double-masked review, authors and reviewers are encouraged to declare their conflicts of interest when the names of authors and sometimes reviewers are known to the other. When conflicts are reported, the conflicting reviewer is prohibited from reviewing and discussing the manuscript. The incentive for reviewers to declare their conflicts of interest is a matter of professional ethics and individual integrity. While their reviews are not public, these reviews are a matter of record and the reviewer's credibility depends upon how they represent themselves among their peers. Some software engineering journals, such as the IEEE Transactions on Software Engineering, use non-blind reviews with reporting to editors of conflicts of interest by both authors and reviewers. A more rigorous standard of accountability is known as an audit. Because reviewers are not paid, they cannot be expected to put as much time and effort into a review as an audit requires. Most journals (and grant agencies like NSF) have a policy that authors must archive their data and methods in the event another researcher wishes to replicate or audit the research after publication. Unfortunately, the archiving policies are sometimes ignored by researchers. # Criticisms of peer review One of the most common complaints about the peer review process is that it is slow, and that it typically takes several months or even several years in some fields for a submitted paper to appear in print. In practice, much of the communication about new results in some fields such as astronomy no longer takes place through peer reviewed papers, but rather through preprints submitted onto electronic servers such as arXiv.org. However, such preprints are often also submitted to refereed journals, and in many cases have, at the time of electronic submission, already passed through the peer review process and been accepted for publication. While passing the peer-review process is often considered in the scientific community to be a certification of validity, it is not without its problems. Drummond Rennie, deputy editor of Journal of the American Medical Association is an organizer of the International Congress on Peer Review and Biomedical Publication, which has been held every four years since 1986. He remarks, "There seems to be no study too fragmented, no hypothesis too trivial, no literature too biased or too egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure, and too contradictory, no analysis too self-serving, no argument too circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print." Richard Horton, editor of the British medical journal The Lancet, has said that "The mistake, of course, is to have thought that peer review was any more than a crude means of discovering the acceptability — not the validity — of a new finding. Editors and scientists alike insist on the pivotal importance of peer review. We portray peer review to the public as a quasi-sacred process that helps to make science our most objective truth teller. But we know that the system of peer review is biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong." ## Allegations of bias and suppression The interposition of editors and reviewers between authors and readers always raises the possibility that the intermediators may serve as gatekeepers. Some sociologists of science argue that peer review makes the ability to publish susceptible to control by elites and to personal jealousy. The peer review process may suppress dissent against "mainstream" theories. Reviewers tend to be especially critical of conclusions that contradict their own views, and lenient towards those that accord with them. At the same time, elite scientists are more likely than less established ones to be sought out as referees, particularly by high-prestige journals or publishers. As a result, it has been argued, ideas that harmonize with the elite's are more likely to see print and to appear in premier journals than are iconoclastic or revolutionary ones, which accords with Thomas Kuhn's well-known observations regarding scientific revolutions. Others have pointed out that there is a very large number of scientific journals in which one can publish, making total control of information difficult. In addition, the decision-making process of peer review, in which each referee gives their opinion separately and without consultation with the other referees, is intended to mitigate some of these problems. Some have suggested that: Nonetheless, while it is generally possible to publish results somewhere, in order for scientists in many fields to attract and maintain funding it is necessary to publish in prestigious journals. Such journals are generally identified by their impact factor. The small number of high-impact journals is susceptible to control by an elite group of anonymous reviewers. Results published in low-impact journals are usually ignored by most scientists in any field. This has led to calls for the removal of reviewer anonymity (especially at high-impact journals) and for the introduction of author anonymity (so that reviewers cannot tell whether the author is a member of any elite). # Peer review failures The Committee on Publication Ethics (COPE) has created the COPE Ethical Guidelines for Peer Reviewers. Peer review failures occur when a peer-reviewed article contains obvious fundamental errors that undermines at least one of its main conclusions. Peer review is not considered a failure in cases of deliberate fraud by authors. Letters-to-the-editor that correct major errors in articles are a common indication of peer review failures. Many journals have no procedure to deal with peer review failures beyond publishing letters. Some do not even publish letters. The author of a disputed article is allowed a published reply to a critical letter. Neither the letter nor the reply is usually peer-reviewed, and typically the author rebuts the criticisms. Thus, the readers are left to decide for themselves if there was a peer review failure. Peer review, in scientific journals, assumes that the article reviewed has been honestly written, and the process is not designed to detect fraud. The reviewers usually do not have full access to the data from which the paper has been written and some elements have to be taken on trust. It is not usually practical for the reviewer to reproduce the author's work, unless the paper deals with purely theoretical problems which the reviewer can follow in a step-by-step manner. The number and proportion of articles which are detected as fraudulent at review stage is unknown. Some instances of outright scientific fraud and scientific misconduct have gone through review and were detected only after other groups tried and failed to replicate the published results. An example is the case of Jan Hendrik Schön, in which a total of fifteen papers were accepted for publication in the top ranked journals Nature and Science following the usual peer review process. All fifteen were found to be fraudulent and were subsequently withdrawn. The fraud was eventually detected, not by peer review, but after publication when other groups tried and failed to reproduce the results of the paper. The International Committee for Medical Journal Editors' Uniform Requirements for Manuscripts Submitted to Biomedical Journals have a duty to investigate allegations of misconduct. A study published in the peer reviewed Lancet Journal associating long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) with a lower risk of oral cancer, was shown to be "completely fabricated" , after which the journal published a retraction, and acknowledged that the study "contains fabricated data." Although it is often argued that fraud cannot be detected during peer review, the Journal of Cell Biology uses an image screening process that it claims could have identified the apparently manipulated figures published in Science by Woo-Suk Hwang. ## Peer review and plagiarism A few cases of plagiarism by historians have been widely publicized. A poll of 3,247 scientists funded by the U.S. National Institutes of Health found 0.3% admitted faking data, 1.4% admitted plagiarism, and 4.7% admitted to autoplagiarism. Autoplagiarism involves an author republishing the same material or data without citing their earlier work. An author often uses autoplagiarism to pad their list of publications. Sometimes reviewers detect cases of likely plagiarism and bring them to the attention of the editor. Reviewers generally lack access to raw data, but do see the full text of the manuscript. Thus, they are in a better position to detect plagiarism or autoplagiarism of prose than fraudulent data. Although it is more common than plagiarism, journals and employers often do not punish authors for autoplagiarism. Autoplagiarism is against the rules of most peer-reviewed journals, which usually require that only unpublished material be submitted. ## Abuse of inside information by reviewers A related form of professional misconduct that is sometimes reported is a reviewer using the not-yet-published information from a manuscript or grant application for personal or professional gain. The frequency with which this happens is of course unknown, but the United States Office of Research Integrity has sanctioned reviewers who have been caught exploiting knowledge they gained as reviewers. A possible defense (for authors) against this form of misconduct on the part of reviewers is to pre-publish their work in the form of a preprint or technical report on a public system such as arXiv. The preprint can later be used to establish priority. # Proposals to improve peer review ## Open peer review It has been suggested that traditional anonymous peer review lacks accountability, can lead to abuse by reviewers, and may be biased and inconsistent, alongside other flaws. In response to these criticisms, other systems of peer review with various degrees of "openness" have been suggested. In 1996, the Journal of Interactive Media in Education launched using open peer review. Reviewers' names are made public and they are therefore accountable for their review, but they also have their contribution acknowledged. Authors have the right of reply, and other researchers have the chance to comment prior to publication. In 1999, the open access journal Journal of Medical Internet Research was launched, which from its inception decided to publish the names of the reviewers at the bottom of each published article. Also in 1999, the British Medical Journal moved to an open peer review system, revealing reviewers' identities to the authors (but not the readers), and in 2000, the medical journals in the open access BMC series published by BioMed Central, launched using open peer review. As with the BMJ, the reviewers' names are included on the peer review reports. In addition, if the article is published the reports are made available online as part of the 'pre-publication history'. Several of the other journals published by the BMJ group allow optional open peer review, as do PLoS Medicine, published by the Public Library of Science. The evidence of the effect of open peer review upon the quality of reviews, the tone and the time spent on reviewing is mixed, although it does seem that under open peer review, more of those who are invited to review decline to do so. In June 2006, the high impact journal Nature launched an experiment in parallel open peer review — some articles that had been submitted to the regular anonymous process were also available online for open, identified public comment. The results were less than encouraging — only 5% of authors agreed to participate in the experiment, and only 54% of those articles received comments. The editors have suggested that researchers may have been too busy to take part and were reluctant to make their names public. The knowledge that articles were simultaneously being subjected to anonymous peer review may also have affected the uptake. In 2006, a group of UK academics launched the online journal Philica, which tries to redress many of the problems of traditional peer review. Unlike in a normal journal, all articles submitted to Philica are published immediately and the review process takes place afterwards. Reviews are still anonymous, but instead of reviewers being chosen by an editor, any researcher who wishes to review an article can do so. Reviews are displayed at the end of each article, and so are used to give the reader criticism or guidance about the work, rather than to decide whether it is published or not. This means that reviewers cannot suppress ideas if they disagree with them. Readers use reviews to guide what they read, and particularly popular or unpopular work is easy to identify. ## Dynamic and self-organizing peer review Another approach that is similar in spirit to Philica is that of a dynamical peer review site, Naboj. Unlike Philica, Naboj is not a full-fledged online journal, but rather it provides an opportunity for users to write peer reviews of preprints at arXiv.org. The review system is modeled on Amazon and users have an opportunity to evaluate the reviews as well as the articles. That way, with a sufficient number of users and reviewers, there should be a convergence towards a higher quality review process. In February 2006, the journal Biology Direct was launched by Eugene Koonin, Laura Landweber, and David Lipman, providing another alternative to the traditional model of peer review. If authors can find three members of the Editorial Board who will each return a report or will themselves solicit an external review, then the article will be published. As with Philica, reviewers cannot suppress publication, but in contrast to Philica, no reviews are anonymous and no article is published without being reviewed. Authors have the opportunity to withdraw their article, to revise it in response to the reviews, or to publish it without revision. If the authors proceed with publication of their article despite critical comments, readers can clearly see any negative comments along with the names of the reviewers. An extension of peer review beyond the date of publication is Open Peer Commentary, whereby expert commentaries are solicited on published articles, and the authors are encouraged to respond. The BMJ's Rapid Responses allow ongoing debate and criticism following publication. By 2005, the editors found it necessary to more rigorously enforce the criteria for acceptance of Rapid Responses, to weed out the "bores". Volunteer peer review of preprints has been proposed # Peer review of policy The technique of peer review is also used to improve government policy. In particular, the European Union uses it as a tool in the 'Open Method of Co-ordination' of policies in the fields of employment and social inclusion. A programme of peer reviews in active labour market policy started in 1999, and was followed in 2004 by one in social inclusion. Each programme sponsors about eight peer review meetings in each year, in which a 'host country' lays a given policy or initiative open to examination by half a dozen other countries and relevant European-level NGOs. These usually meet over two days and include visits to local sites where the policy can be seen in operation. The meeting is preceded by the compilation of an expert report on which participating 'peer countries' submit comments. The results are published on the web. ## U.S. government peer review policies # History of peer review The first recorded peer review process was at The Royal Society in 1665 by the founding editor of Philosophical Transactions of the Royal Society, Henry Oldenburg. According to the common definition of a peer review, the first peer review was the Medical Essays and Observations published by the Royal Society of Edinburgh in 1731. The present-day peer review system evolved from this 18th century process. A practice similar to a peer review process is found in the Ethics of the Physician written by Ishaq bin Ali al-Rahwi (854–931) of al-Raha, Syria. His work, as well as later Arabic medical manuals, state that a visiting physician must always make duplicate notes of a patient's condition on every visit. When the patient was cured or had died, the notes of the physician were examined by a local medical council of other physicians, who would review the practising physician's notes to decide whether his/her performance have met the required standards of medical care. If their reviews were negative, the practicing physician could face a lawsuit from a maltreated patient. Peer review has been a touchstone of modern scientific method only since the middle of the 20th century, the only exception being medicine. Before then, its application was lax in other scientific fields. For example, Albert Einstein's revolutionary "Annus Mirabilis" papers in the 1905 issue of Annalen der Physik were not peer-reviewed by anyone other than the journal's editor in chief, Max Planck (the father of quantum theory), and its co-editor, Wilhelm Wien. Although clearly peers (both won Nobel prizes in physics), a formal panel of reviewers was not sought, as is done for many scientific journals today. Established authors and editors were given more latitude in their journalistic discretion, back then. In a recent editorial in Nature, it was stated that "in journals in those days, the burden of proof was generally on the opponents rather than the proponents of new ideas." # Peer review of software development	Peer review Peer review (also known as refereeing) is the process of subjecting an author's scholarly work, research or ideas to the scrutiny of others who are experts in the same field. Peer review requires a community of experts in a given (and often narrowly defined) field, who are qualified and able to perform impartial review. Impartial review, especially of work in less narrowly defined or inter-disciplinary fields may be difficult to accomplish, and the significance (good or bad) of an idea may never be widely appreciated among its contemporaries. Peer review has been criticized as ineffective and misunderstood. Pragmatically, peer review refers to the work done during the screening of submitted manuscripts and funding applications. This normative process encourages authors to meet the accepted standards of their discipline and prevents the dissemination of unwarranted claims, unacceptable interpretations and personal views. Publications that have not undergone peer review are likely to be regarded with suspicion by scholars and professionals. # Reasons for peer review It is difficult for an individual author or research team to spot every mistake or flaw in a complicated piece of work. This is not because deficiencies represent "needles in a haystack" that are difficult to locate, but because with a new and perhaps eclectic subject, an opportunity for improvement may be more obvious to someone with special expertise or experience. Therefore, showing work to others increases the probability that weaknesses will be identified, and, with advice and encouragement, fixed. For both grant-funding and publication in a scholarly journal, it is also normally a requirement that the subject is both novel and substantial.[citation needed] Reviewers are typically anonymous and independent, to help foster unvarnished criticism, and to discourage cronyism in funding and publication decisions. However, US government guidelines governing peer review for federal regulatory agencies require that reviewer's identity be disclosed under some circumstances. Since reviewers are normally selected from experts in the fields discussed in the article, the process of peer review is considered critical to establishing a reliable body of research and knowledge. Scholars reading the published articles can only be expert in a limited area; they rely, to some degree, on the peer-review process to provide reliable and credible research that they can build upon for subsequent or related research. As a result, significant scandal ensues when an author is found to have falsified the research included in an article, as many other scholars, and the field of study itself, may have relied upon the original research (see Peer review and fraud below). # How it works In the case of proposed publications, an editor sends advance copies of an author's work or ideas to researchers or scholars who are experts in the field (known as "referees" or "reviewers"), nowadays normally by e-mail or through a web-based manuscript processing system. Usually, there are two or three referees for a given article. These referees each return an evaluation of the work to the editor, including noting weaknesses or problems along with suggestions for improvement. Typically, most of the referees' comments are eventually seen by the author; scientific journals observe this convention universally. The editor, usually familiar with the field of the manuscript (although typically not in as much depth as the referees, who are specialists), then evaluates the referees' comments, her or his own opinion of the manuscript, and the context of the scope of the journal or level of the book and readership, before passing a decision back to the author(s), usually with the referees' comments. Referees' evaluations usually include an explicit recommendation of what to do with the manuscript or proposal, often chosen from options provided by the journal or funding agency. Most recommendations are along the lines of the following: - to unconditionally accept the manuscript or proposal, - to accept it in the event that its authors improve it in certain ways, - to reject it, but encourage revision and invite resubmission, - to reject it outright. During this process, the role of the referees is advisory, and the editor is typically under no formal obligation to accept the opinions of the referees. Furthermore, in scientific publication, the referees do not act as a group, do not communicate with each other, and typically are not aware of each other's identities or evaluations. There is usually no requirement that the referees achieve consensus. Thus the group dynamics are substantially different from that of a jury. In situations where the referees disagree substantially about the quality of a work, there are a number of strategies for reaching a decision. When an editor receives very positive and very negative reviews for the same manuscript, the editor often will solicit one or more additional reviews as a tie-breaker. As another strategy in the case of ties, editors may invite authors to reply to a referee's criticisms and permit a compelling rebuttal to break the tie. If an editor does not feel confident to weigh the persuasiveness of a rebuttal, the editor may solicit a response from the referee who made the original criticism. In rare instances, an editor will convey communications back and forth between authors and a referee, in effect allowing them to debate a point. Even in these cases, however, editors do not allow referees to confer with each other, and the goal of the process is explicitly not to reach consensus or to convince anyone to change their opinions. Some medical journals, however (usually following the open access model), have begun posting on the Internet the pre-publication history of each individual article, from the original submission to reviewers' reports, authors' comments, and revised manuscripts. Traditionally, reviewers would remain anonymous to the authors, but this standard is slowly changing. In some academic fields, most journals now offer the reviewer the option of remaining anonymous or not, or a referee may opt to sign a review, thereby relinquishing anonymity. Published papers sometimes contain, in the acknowledgements section, thanks to anonymous or named referees who helped improve the paper. Some university presses undertake peer review of books. After positive review by two or three independent referees, a university press sends the manuscript to the press's editorial board, a committee of faculty members, for final approval.[1] Such a review process is a requirement for full membership of the Association of American University Presses.[2] In some disciplines there exist refereed venues (such as conferences and workshops). To be admitted to speak, scholars and scientists must submit papers (generally short, often 15 pages or less) in advance. These papers are reviewed by a "program committee" (the equivalent of an editorial board), which generally requests inputs from referees. The hard deadlines set by the conferences tend to limit the options to either accept or reject the paper. # Recruiting referees At a journal or book publisher, the task of picking reviewers typically falls to an editor.[3] When a manuscript arrives, an editor solicits reviews from scholars or other experts who may or may not have already expressed a willingness to referee for that journal or book division. Granting agencies typically recruit a panel or committee of reviewers in advance of the arrival of applications. Typically referees are not selected from among the authors' close colleagues, students, or friends. Referees are supposed to inform the editor of any conflict of interests that might arise. Journals or individual editors often invite a manuscript's authors to name people whom they consider qualified to referee their work. Indeed, for a number of journals this is a requirement of submission. Authors are sometimes also invited to name natural candidates who should be disqualified, in which case they may be asked to provide justification (typically expressed in terms of conflict of interest). In some disciplines, scholars listed in an "acknowledgements" section are not allowed to serve as referees (hence the occasional practice of using this section to disqualify potentially negative reviewers). Editors solicit author input in selecting referees because academic writing typically is very specialized. Editors often oversee many specialities, and may not be experts in any of them, since editors may be full time professionals with no time for scholarship. But after an editor selects referees from the pool of candidates, the editor typically is obliged not to disclose the referees' identities to the authors, and in scientific journals, to each other. Policies on such matters differ among academic disciplines. Recruiting referees is a political art, because referees, and often editors, are usually not paid, and reviewing takes time away from the referee's main activities, such as his or her own research. To the would-be recruiter's advantage, most potential referees are authors themselves, or at least readers, who know that the publication system requires that experts donate their time. Referees also have the opportunity to prevent work that does not meet the standards of the field from being published, which is a position of some responsibility. Editors are at a special advantage in recruiting a scholar when they have overseen the publication of his or her work, or if the scholar is one who hopes to submit manuscripts to that editor's publication in the future. Granting agencies, similarly, tend to seek referees among their present or former grantees. Serving as a referee can even be a condition of a grant, or professional association membership. Another difficulty that peer-review organizers face is that, with respect to some manuscripts or proposals, there may be few scholars who truly qualify as experts. Such a circumstance often frustrates the goals of reviewer anonymity and the avoidance of conflicts of interest. It also increases the chances that an organizer will not be able to recruit true experts – people who have themselves done work similar to that under review, and who can read between the lines. Low-prestige or local journals and granting agencies that award little money are especially handicapped with regard to recruiting experts. Finally, anonymity adds to the difficulty in finding reviewers in another way. In scientific circles, credentials and reputation are important, and while being a referee for a prestigious journal is considered an honor, the anonymity restrictions make it impossible to publicly state that one was a referee for a particular article. However, credentials and reputation are principally established by publications, not by refereeing; and in some fields refereeing may not be anonymous. The process of peer review does not end after a paper completes the peer review process. After being put to press, and after 'the ink is dry', the process of peer review continues in journal clubs. Here groups of colleagues review literature and discuss the value and implications it presents. Journal clubs will often send letters to the editor of a journal, or correspond with the editor via an on-line journal club. In this way, all 'peers' may offer review and critique of published literature. # Different styles of review Peer review can be rigorous, in terms of the skill brought to bear, without being highly stringent. An agency may be flush with money to give away, for example, or a journal may have few impressive manuscripts to choose from, so there may be little incentive for selection. Conversely, when either funds or publication space is limited, peer review may be used to select an extremely small number of proposals or manuscripts. Often the decision of what counts as "good enough" falls entirely to the editor or organizer of the review. In other cases, referees will each be asked to make the call, with only general guidance from the coordinator on what stringency to apply. Very general journals such as Science and Nature have extremely stringent standards for publication, and will reject papers that report good quality scientific work if editors feel the work is not a breakthrough in the field. Such journals generally have a two-tier reviewing system. In the first stage, members of the editorial board verify that the paper's findings — if correct — would be ground-breaking enough to warrant publication in Science or Nature. Most papers are rejected at this stage. Papers that do pass this 'pre-reviewing' are sent out for in-depth review to outside referees. Even after all reviewers recommend publication and all reviewer criticisms/suggestions for changes have been met, papers may still be returned to the authors for shortening to meet the journal's length limits. With the advent of electronic journal editions, overflow material may be stored in the journal's online Electronic Supporting Information archive. A similar emphasis on novelty exists in general area journals such as the Journal of the American Chemical Society (JACS). However, these journals generally send out all papers (except blatantly inappropriate ones) for peer reviewing to multiple reviewers. The reviewers are specifically queried not just on the scientific quality and correctness, but also on whether the findings are of interest to the general area readership (chemists of all disciplines, in the case of JACS) or only to a specialist subgroup. In the latter case, the recommendation is usually for publication in a more specialized journal. The editor may offer to authors the option of having the manuscript and reviews forwarded to such a journal with the same publishers (e.g., in the example given, Journal of Organic Chemistry, Journal of Physical Chemistry, Inorganic Chemistry,...) if the reviewer reports warrant such a decision (i.e., they boil down to "Great work, but too specialized for JACS: publish in ..."), the editor of such a journal may accept the forwarded manuscript without further reviewing. Some general area journals, such as Physical Review Letters, have strict length limitations. Others, such as JACS, have Letters and Full Papers sections: the Letters sections have strict length limits (two journal pages in the case of JACS) and special novelty requirements. In contrast, online-only journals may have no space limitations.[4] More specialized scientific journals such as the aforementioned chemistry journals, Astrophysical Journal, and the Physical Review series use peer review primarily to filter out obvious mistakes and incompetence, as well as plagiarism, overly derivative work, and straightforward applications of known methods. Different publication rates reflect these different criteria: Nature publishes about 5 percent of received papers, while Astrophysical Journal publishes about 70 percent. The different publication rates are also reflected in the size of the journals. PLoS ONE was launched by the Public Library of Science in 2006 with the aim to "concentrate on technical rather than subjective concerns", and to publish articles from across science, regardless of the field.[5]. Another open access journal, Biology Direct, has the policy of making the reviewers' reports public by publishing the reports together with the manuscripts. Screening by peers may be more or less laissez-faire depending on the discipline. Physicists, for example, tend to think that decisions about the worthiness of an article are best left to the marketplace. Yet even within such a culture peer review serves to ensure high standards in what is published. Outright errors are detected and authors receive both edits and suggestions. To preserve the integrity of the peer-review process, submitting authors may not be informed of who reviews their papers; sometimes, they might not even know the identity of the associate editor who is responsible for the paper. In many cases, alternatively called "masked" or "double-masked" review (or "blind" or "double-blind" review), the identity of the authors is concealed from the reviewers, lest the knowledge of authorship bias their review; in such cases, however, the associate editor responsible for the paper does know who the author is. Sometimes the scenario where the reviewers do know who the authors are is called "single-masked" to distinguish it from the "double-masked" process. In double-masked review, the authors are required to remove any reference that may point to them as the authors of the paper. While the anonymity of reviewers is almost universally preserved, double-masked review (where authors are also anonymous to reviewers) is still relatively rarely employed. Critics of the double-masked process point out that, despite the extra editorial effort to ensure anonymity, the process often fails to do so, since certain approaches, methods, writing styles, notations, etc., may point to a certain group of people in a research stream, and even to a particular person.[6],[7] Proponents of double-masked review argue that it performs at least as well as the traditional one and that it generates a better perception of fairness and equality in global scientific funding and publishing.[8] Proponents of the double-masked process argue that if the reviewers of a paper are unknown to each other, the associate editor responsible for the paper can easily verify the objectivity of the reviews. Single-masked review is thus strongly dependent upon the goodwill of the participants. A conflict of interest arises when a reviewer and author have a disproportionate amount of respect (or disrespect) for each other. As an alternative to single-masked and double-masked review, authors and reviewers are encouraged to declare their conflicts of interest when the names of authors and sometimes reviewers are known to the other. When conflicts are reported, the conflicting reviewer is prohibited from reviewing and discussing the manuscript. The incentive for reviewers to declare their conflicts of interest is a matter of professional ethics and individual integrity. While their reviews are not public, these reviews are a matter of record and the reviewer's credibility depends upon how they represent themselves among their peers. Some software engineering journals, such as the IEEE Transactions on Software Engineering, use non-blind reviews with reporting to editors of conflicts of interest by both authors and reviewers. A more rigorous standard of accountability is known as an audit. Because reviewers are not paid, they cannot be expected to put as much time and effort into a review as an audit requires. Most journals (and grant agencies like NSF) have a policy that authors must archive their data and methods in the event another researcher wishes to replicate or audit the research after publication. Unfortunately, the archiving policies are sometimes ignored by researchers. # Criticisms of peer review One of the most common complaints about the peer review process is that it is slow, and that it typically takes several months or even several years in some fields for a submitted paper to appear in print. In practice, much of the communication about new results in some fields such as astronomy no longer takes place through peer reviewed papers, but rather through preprints submitted onto electronic servers such as arXiv.org. However, such preprints are often also submitted to refereed journals, and in many cases have, at the time of electronic submission, already passed through the peer review process and been accepted for publication. While passing the peer-review process is often considered in the scientific community to be a certification of validity, it is not without its problems. Drummond Rennie, deputy editor of Journal of the American Medical Association is an organizer of the International Congress on Peer Review and Biomedical Publication, which has been held every four years since 1986.[9] He remarks, "There seems to be no study too fragmented, no hypothesis too trivial, no literature too biased or too egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure, and too contradictory, no analysis too self-serving, no argument too circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print."[10] Richard Horton, editor of the British medical journal The Lancet, has said that "The mistake, of course, is to have thought that peer review was any more than a crude means of discovering the acceptability — not the validity — of a new finding. Editors and scientists alike insist on the pivotal importance of peer review. We portray peer review to the public as a quasi-sacred process that helps to make science our most objective truth teller. But we know that the system of peer review is biased, unjust, unaccountable, incomplete, easily fixed, often insulting, usually ignorant, occasionally foolish, and frequently wrong." [11] ## Allegations of bias and suppression The interposition of editors and reviewers between authors and readers always raises the possibility that the intermediators may serve as gatekeepers. Some sociologists of science argue that peer review makes the ability to publish susceptible to control by elites and to personal jealousy.[12] The peer review process may suppress dissent against "mainstream" theories.[13][14][15] Reviewers tend to be especially critical of conclusions that contradict their own views, and lenient towards those that accord with them. At the same time, elite scientists are more likely than less established ones to be sought out as referees, particularly by high-prestige journals or publishers. As a result, it has been argued, ideas that harmonize with the elite's are more likely to see print and to appear in premier journals than are iconoclastic or revolutionary ones, which accords with Thomas Kuhn's well-known observations regarding scientific revolutions.[16] Others have pointed out that there is a very large number of scientific journals in which one can publish, making total control of information difficult. In addition, the decision-making process of peer review, in which each referee gives their opinion separately and without consultation with the other referees, is intended to mitigate some of these problems. Some have suggested that: Nonetheless, while it is generally possible to publish results somewhere, in order for scientists in many fields to attract and maintain funding it is necessary to publish in prestigious journals. Such journals are generally identified by their impact factor. The small number of high-impact journals is susceptible to control by an elite group of anonymous reviewers.[citation needed] Results published in low-impact journals are usually ignored by most scientists in any field. This has led to calls for the removal of reviewer anonymity (especially at high-impact journals) and for the introduction of author anonymity (so that reviewers cannot tell whether the author is a member of any elite).[citation needed] # Peer review failures The Committee on Publication Ethics (COPE) has created the COPE Ethical Guidelines for Peer Reviewers. Peer review failures occur when a peer-reviewed article contains obvious fundamental errors that undermines at least one of its main conclusions. Peer review is not considered a failure in cases of deliberate fraud by authors. Letters-to-the-editor that correct major errors in articles are a common indication of peer review failures. Many journals have no procedure to deal with peer review failures beyond publishing letters.[18] Some do not even publish letters. The author of a disputed article is allowed a published reply to a critical letter. Neither the letter nor the reply is usually peer-reviewed, and typically the author rebuts the criticisms. Thus, the readers are left to decide for themselves if there was a peer review failure. Peer review, in scientific journals, assumes that the article reviewed has been honestly written, and the process is not designed to detect fraud. The reviewers usually do not have full access to the data from which the paper has been written and some elements have to be taken on trust. It is not usually practical for the reviewer to reproduce the author's work, unless the paper deals with purely theoretical problems which the reviewer can follow in a step-by-step manner. The number and proportion of articles which are detected as fraudulent at review stage is unknown. Some instances of outright scientific fraud and scientific misconduct have gone through review and were detected only after other groups tried and failed to replicate the published results. An example is the case of Jan Hendrik Schön, in which a total of fifteen papers were accepted for publication in the top ranked journals Nature and Science following the usual peer review process. All fifteen were found to be fraudulent and were subsequently withdrawn. The fraud was eventually detected, not by peer review, but after publication when other groups tried and failed to reproduce the results of the paper. The International Committee for Medical Journal Editors' Uniform Requirements for Manuscripts Submitted to Biomedical Journals[19] states that "if a fraudulent paper has been published, the journal must print a retraction",[20] and gives guidelines on investigating alleged fraud. Members of the UK-based Committee on Publication Ethics[21](COPE) have a duty to investigate allegations of misconduct.[22] A study published in the peer reviewed Lancet Journal associating long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) with a lower risk of oral cancer, was shown to be "completely fabricated"[23] , after which the journal published a retraction, and acknowledged that the study "contains fabricated data." [24] Although it is often argued that fraud cannot be detected during peer review, the Journal of Cell Biology uses an image screening process that it claims could have identified the apparently manipulated figures published in Science by Woo-Suk Hwang.[25] ## Peer review and plagiarism A few cases of plagiarism by historians have been widely publicized.[26] A poll of 3,247 scientists funded by the U.S. National Institutes of Health found 0.3% admitted faking data, 1.4% admitted plagiarism, and 4.7% admitted to autoplagiarism.[27] Autoplagiarism involves an author republishing the same material or data without citing their earlier work. An author often uses autoplagiarism to pad their list of publications. Sometimes reviewers detect cases of likely plagiarism and bring them to the attention of the editor. Reviewers generally lack access to raw data, but do see the full text of the manuscript. Thus, they are in a better position to detect plagiarism or autoplagiarism of prose than fraudulent data. Although it is more common than plagiarism, journals and employers often do not punish authors for autoplagiarism. Autoplagiarism is against the rules of most peer-reviewed journals, which usually require that only unpublished material be submitted. ## Abuse of inside information by reviewers A related form of professional misconduct that is sometimes reported is a reviewer using the not-yet-published information from a manuscript or grant application for personal or professional gain. The frequency with which this happens is of course unknown, but the United States Office of Research Integrity has sanctioned reviewers who have been caught exploiting knowledge they gained as reviewers. A possible defense (for authors) against this form of misconduct on the part of reviewers is to pre-publish their work in the form of a preprint or technical report on a public system such as arXiv. The preprint can later be used to establish priority. # Proposals to improve peer review ## Open peer review Template:Splitsection It has been suggested that traditional anonymous peer review lacks accountability, can lead to abuse by reviewers, and may be biased and inconsistent,[28] alongside other flaws.[29][30] In response to these criticisms, other systems of peer review with various degrees of "openness" have been suggested. In 1996, the Journal of Interactive Media in Education[31] launched using open peer review.[32] Reviewers' names are made public and they are therefore accountable for their review, but they also have their contribution acknowledged. Authors have the right of reply, and other researchers have the chance to comment prior to publication. In 1999, the open access journal Journal of Medical Internet Research[33] was launched, which from its inception decided to publish the names of the reviewers at the bottom of each published article. Also in 1999, the British Medical Journal[34] moved to an open peer review system, revealing reviewers' identities to the authors (but not the readers),[35] and in 2000, the medical journals in the open access BMC series[36] published by BioMed Central, launched using open peer review. As with the BMJ, the reviewers' names are included on the peer review reports. In addition, if the article is published the reports are made available online as part of the 'pre-publication history'. Several of the other journals published by the BMJ group[37] allow optional open peer review,[38][39][40] as do PLoS Medicine, published by the Public Library of Science[41][42]. The evidence of the effect of open peer review upon the quality of reviews, the tone and the time spent on reviewing is mixed, although it does seem that under open peer review, more of those who are invited to review decline to do so.[43][44] In June 2006, the high impact journal Nature launched an experiment in parallel open peer review — some articles that had been submitted to the regular anonymous process were also available online for open, identified public comment.[45] The results were less than encouraging — only 5% of authors agreed to participate in the experiment, and only 54% of those articles received comments.[46][47] The editors have suggested that researchers may have been too busy to take part and were reluctant to make their names public. The knowledge that articles were simultaneously being subjected to anonymous peer review may also have affected the uptake. In 2006, a group of UK academics launched the online journal Philica, which tries to redress many of the problems of traditional peer review. Unlike in a normal journal, all articles submitted to Philica are published immediately and the review process takes place afterwards. Reviews are still anonymous, but instead of reviewers being chosen by an editor, any researcher who wishes to review an article can do so. Reviews are displayed at the end of each article, and so are used to give the reader criticism or guidance about the work, rather than to decide whether it is published or not. This means that reviewers cannot suppress ideas if they disagree with them. Readers use reviews to guide what they read, and particularly popular or unpopular work is easy to identify. ## Dynamic and self-organizing peer review Another approach that is similar in spirit to Philica is that of a dynamical peer review site, Naboj.[48] Unlike Philica, Naboj is not a full-fledged online journal, but rather it provides an opportunity for users to write peer reviews of preprints at arXiv.org. The review system is modeled on Amazon and users have an opportunity to evaluate the reviews as well as the articles. That way, with a sufficient number of users and reviewers, there should be a convergence towards a higher quality review process. In February 2006, the journal Biology Direct[49] was launched by Eugene Koonin, Laura Landweber, and David Lipman, providing another alternative to the traditional model of peer review. If authors can find three members of the Editorial Board who will each return a report or will themselves solicit an external review, then the article will be published. As with Philica, reviewers cannot suppress publication, but in contrast to Philica, no reviews are anonymous and no article is published without being reviewed. Authors have the opportunity to withdraw their article, to revise it in response to the reviews, or to publish it without revision. If the authors proceed with publication of their article despite critical comments, readers can clearly see any negative comments along with the names of the reviewers.[50] An extension of peer review beyond the date of publication is Open Peer Commentary, whereby expert commentaries are solicited on published articles, and the authors are encouraged to respond. The BMJ's Rapid Responses[51] allow ongoing debate and criticism following publication.[52] By 2005, the editors found it necessary to more rigorously enforce the criteria for acceptance of Rapid Responses, to weed out the "bores".[53] Volunteer peer review of preprints has been proposed </ref>. # Peer review of policy The technique of peer review is also used to improve government policy. In particular, the European Union uses it as a tool in the 'Open Method of Co-ordination' of policies in the fields of employment and social inclusion. A programme of peer reviews in active labour market policy[54] started in 1999, and was followed in 2004 by one in social inclusion.[55] Each programme sponsors about eight peer review meetings in each year, in which a 'host country' lays a given policy or initiative open to examination by half a dozen other countries and relevant European-level NGOs. These usually meet over two days and include visits to local sites where the policy can be seen in operation. The meeting is preceded by the compilation of an expert report on which participating 'peer countries' submit comments. The results are published on the web. ## U.S. government peer review policies # History of peer review The first recorded peer review process was at The Royal Society in 1665 by the founding editor of Philosophical Transactions of the Royal Society, Henry Oldenburg.[56][57] According to the common definition of a peer review, the first peer review was the Medical Essays and Observations published by the Royal Society of Edinburgh in 1731. The present-day peer review system evolved from this 18th century process.[58] A practice similar to a peer review process is found in the Ethics of the Physician written by Ishaq bin Ali al-Rahwi (854–931) of al-Raha, Syria. His work, as well as later Arabic medical manuals, state that a visiting physician must always make duplicate notes of a patient's condition on every visit. When the patient was cured or had died, the notes of the physician were examined by a local medical council of other physicians, who would review the practising physician's notes to decide whether his/her performance have met the required standards of medical care. If their reviews were negative, the practicing physician could face a lawsuit from a maltreated patient.[59] Peer review has been a touchstone of modern scientific method only since the middle of the 20th century, the only exception being medicine. Before then, its application was lax in other scientific fields. For example, Albert Einstein's revolutionary "Annus Mirabilis" papers in the 1905 issue of Annalen der Physik were not peer-reviewed by anyone other than the journal's editor in chief, Max Planck (the father of quantum theory), and its co-editor, Wilhelm Wien. Although clearly peers (both won Nobel prizes in physics), a formal panel of reviewers was not sought, as is done for many scientific journals today. Established authors and editors were given more latitude in their journalistic discretion, back then. In a recent editorial in Nature, it was stated that "in journals in those days, the burden of proof was generally on the opponents rather than the proponents of new ideas."[60] # Peer review of software development	https://www.wikidoc.org/index.php/Peer_review
ad1f4d0c830990819bf38da3d9206334a56ce2ac	wikidoc	Pegloticase	Pegloticase # 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 Pegloticase is a PEGylated uric acid specific enzyme that is FDA approved for the treatment of chronic gout in adult patients refractory to conventional therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose and regimen of KRYSTEXXA for adult patients is 8 mg (uricase protein) given as an intravenous infusion every two weeks. - The optimal treatment duration with KRYSTEXXA has not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pegloticase in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegloticase in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Pegloticase in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pegloticase in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegloticase in pediatric patients. # Contraindications - Glucose-6-phosphate dehydrogenase (G6PD) deficiency - KRYSTEXXA is contraindicated in patients with G6PD deficiency due to the risk of hemolysis and methemoglobinemia. It is recommended that patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) be screened for G6PD deficiency before starting KRYSTEXX # Warnings ### Precautions - Anaphylaxis - During pre-marketing controlled clinical trials, anaphylaxis was reported with a frequency of 6.5% of patients treated with KRYSTEXXA every 2 weeks, compared to none with placebo. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate. - KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed type hypersensitivity reactions have also been reported. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting. - The risk of anaphylaxis is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA. - Infusion Reactions - During pre-marketing controlled clinical trials, infusion reactions were reported in 26% of patients treated with KRYSTEXXA 8 mg every 2 weeks, and 41% of patients treated with KRYSTEXXA 8 mg every 4 weeks, compared to 5% of patients treated with placebo. These infusion reactions occurred in patients being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate. - KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate. - The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA. - Gout Flares - Gout flares may occur after initiation of KRYSTEXXA. An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated. KRYSTEXXA does not need to be discontinued because of a gout flare. The gout flare should be managed concurrently as appropriate for the individual patient. - Congestive Heart Failure - KRYSTEXXA has not been formally studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion. - Re-treatment with KRYSTEXXA - No controlled trial data are available on the safety and efficacy of re-treatment with KRYSTEXXA after stopping treatment for longer than 4 weeks. Due to the immunogenicity of KRYSTEXXA, patients receiving re-treatment may be at increased risk of anaphylaxis and infusion reactions. Therefore, patients receiving re-treatment after a drug-free interval should be monitored carefully. # Adverse Reactions ## Clinical Trials Experience - The data described below reflect exposure to KRYSTEXXA in patients with chronic gout refractory to conventional therapy in two replicate randomized, placebo-controlled, double-blind 6-month clinical trials: 85 patients were treated with KRYSTEXXA 8 mg every 2 weeks; 84 patients were treated with KRYSTEXXA 8 mg every 4 weeks; and 43 patients were treated with placebo. These patients were between the ages of 23 and 89 years (average 55 years); 173 patients were male and 39 were female; and 143 patients were White/Caucasian, 27 were Black/African American, 24 were Hispanic/Latino and 18 were all other ethnicities. Common co-morbid conditions among the enrolled patients included hypertension (72%), dyslipidemia (49%), chronic kidney disease (28%), diabetes (24%), coronary artery disease (18%), arrhythmia (16%), and cardiac failure/left ventricular dysfunction (12%). - Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice. - Anaphylaxis: - Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA or placebo injection with no other identifiable cause. Using these clinical criteria, anaphylaxis was identified in 14 (5.1%) of 273 total patients studied in the clinical program of IV KRYSTEXXA. The frequency was 6.5% for the every 2-week dosing regimen (8 of 123 patients), and 4.8% for the 4-week dosing frequency (6 of 126) of KRYSTEXXA. There were no cases of anaphylaxis in patients receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment. This occurred with patients being pre-treated with an oral antihistamine, intravenous corticosteroid, and acetaminophen. - Infusion Reactions: - Infusion reactions occurred in 26% of patients in the 2 week dosing regimen group and 41% of patients in the 4 week dosing regimen group, compared to 5% of placebo-treated patients. Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion, and approximately 91% occurred during the time of infusion. Some infusion reaction manifestations were reduced with slowing the rate of infusion, or stopping the infusion and restarting the infusion at a slower rate. These infusion reactions occurred with all patients being pre-treated with an oral antihistamine, intravenous corticosteroid and acetaminophen. - Gout Flares: - Gout flares were common in the study patients before randomization to treatment, with patients experiencing an average of 10 flares in the preceding 18 months prior to study entry. During the controlled treatment period with KRYSTEXXA or placebo, the frequencies of gout flares were high in all treatment groups, but more so with KRYSTEXXA treatment during the first 3 months of treatment, which seemed to decrease in the subsequent 3 months of treatment. The percentages of patients with any flare for the first 3 months were 74%, 81%, and 51%, for KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. The percentages of patients with any flare for the subsequent 3 months were 41%, 57%, and 67%, for KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. Patients received gout flare prophylaxis with colchicine and/or nonsteroidal anti-inflammatory drugs (NSAIDs) starting at least one week before receiving KRYSTEXXA. - Congestive Heart Failure: - Two cases of congestive heart failure exacerbation occurred during the trials in patients receiving treatment with KRYSTEXXA 8 mg every 2 weeks. No cases were reported in placebo-treated patients. Four subjects had exacerbations of pre-existing congestive heart failure while receiving KRYSTEXXA 8 mg every 2 weeks during the open-label extension study. - Other Adverse Reactions: - The most commonly reported adverse reactions that occurred in greater than or equal to 5% of patients treated with KRYSTEXXA 8 mg every 2 weeks are provided in Table 1. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Pegloticase in the drug label. # Drug Interactions - No studies of interactions of KRYSTEXXA with other drugs have been conducted. - Because anti-pegloticase antibodies appear to bind to the PEG portion of the drug, there may be potential for binding with other PEGylated products. The impact of anti-PEG antibodies on patients' responses to other PEG-containing therapeutics is unknown. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - A complete evaluation of the reproductive and developmental toxicity of pegloticase has not been completed. Adequate animal reproduction studies have not been conducted with KRYSTEXXA. It is not known whether KRYSTEXXA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled studies in pregnant women. KRYSTEXXA should be used during pregnancy only if clearly needed. - Pegloticase was not teratogenic in rats administered 0, 5, 10, or 40 mg/kg twice weekly by the intravenous route on gestation days 6 through 16 (the doses are approximately 6-fold to 50-fold higher than the maximum recommended human dose (MRHD) of 8 mg (0.133 mg/kg based on a 60 kg person) every 2 weeks based on a mg/m2 comparison). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pegloticase in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Pegloticase 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, it is not recommended to administer KRYSTEXXA to a nursing mother. ### Pediatric Use - The safety and effectiveness of KRYSTEXXA in pediatric patients less than 18 years of age have not been established. ### Geriatic Use - Of the total number of patients treated with KRYSTEXXA 8 mg every 2 weeks in the controlled studies, 34% (29 of 85) were 65 years of age and older and 12% (10 of 85) were 75 years of age and older. No overall differences in safety or effectiveness were observed between older and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is needed for patients 65 years of age and older. ### Gender There is no FDA guidance on the use of Pegloticase with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pegloticase with respect to specific racial populations. ### Renal Impairment - No dose adjustment is required for patients with renal impairment. A total of 32% (27 of 85) of patients treated with KRYSTEXXA 8 mg every 2 weeks had a creatinine clearance of ≤62.5 mL/min. No overall differences in efficacy were observed. ### Hepatic Impairment There is no FDA guidance on the use of Pegloticase in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pegloticase in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pegloticase in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Pegloticase in the drug label. # IV Compatibility - Visually inspect KRYSTEXXA for particulate matter and discoloration before administration, whenever solution and container permit. Do not use vials if either is present. - Use appropriate aseptic technique. Withdraw 1 mL of KRYSTEXXA from the vial into a sterile syringe. Discard any unused portion of product remaining in the 2 mL vial. Inject into a single 250 mL bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP for intravenous infusion. Do not mix or dilute with other drugs. - Invert the infusion bag containing the dilute KRYSTEXXA solution a number of times to ensure thorough mixing. Do not shake. - KRYSTEXXA diluted in infusion bags is stable for 4 hours at 2° to 8°C (36° to 46°F) and at room temperature (20° to 25°C, 68° to 77°F). However it is recommended that diluted solutions be stored under refrigeration, not frozen, protected from light, and used within 4 hours of dilution. - Before administration, allow the diluted solution of KRYSTEXXA to reach room temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid should never be subjected to artificial heating (e.g., hot water, microwave). # Overdosage ## Acute Overdose - No reports of overdosage with KRYSTEXXA have been reported. The maximum dose that has been administered as a single intravenous dose is 12 mg as uricase protein. - Patients suspected of receiving an overdose should be monitored, and general supportive measures should be initiated as no specific antidote has been identified. ## Chronic Overdose There is limited information regarding Chronic Overdose of Pegloticase in the drug label. # Pharmacology ## Mechanism of Action - KRYSTEXXA is a uric acid specific enzyme which is a recombinant uricase and achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Allantoin is an inert and water soluble purine metabolite. It is readily eliminated, primarily by renal excretion. ## Structure - KRYSTEXXA (pegloticase) is a uric acid specific enzyme which is a PEGylated product that consists of recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of Escherichia coli. Uricase is covalently conjugated to monomethoxypoly(ethylene glycol) (10 kDa molecular weight). The cDNA coding for uricase is based on mammalian sequences. Each uricase subunit has a molecular weight of approximately 34 kDa per subunit. The average molecular weight of pegloticase (tetrameric enzyme conjugated to mPEG) is approximately 540 kDa. - KRYSTEXXA is intended for intravenous infusion. - KRYSTEXXA is a sterile, clear, colorless solution containing 8 mg/mL pegloticase in phosphate-buffered saline. - KRYSTEXXA (pegloticase) concentrations are expressed as concentrations of uricase protein. Each mL of KRYSTEXXA contains 8 mg of uricase protein (conjugated to 24 mg of 10 kDa mPEG), 2.18 mg Disodium Hydrogen Phosphate Dihydrate (Na2HPO42H2O), 8.77 mg Sodium Chloride (NaCl), 0.43 mg Sodium Dihydrogen Phosphate Dihydrate (NaH2PO42H2O), and Water for Injection to deliver 8 mg of pegloticase (as uricase protein). ## Pharmacodynamics - Approximately 24 hours following the first dose of KRYSTEXXA, mean plasma uric acid levels for subjects in the KRYSTEXXA groups were 0.7 mg/dL for the KRYSTEXXA 8 mg every 2 weeks group. In comparison, the mean plasma uric acid level for the placebo group was 8.2 mg/dL. - In a single-dose, dose-ranging trial, following 1-hour intravenous infusions of 0.5, 1, 2, 4, 8 or 12 mg of pegloticase in 24 patients with symptomatic gout (n=4 subjects/dose group), plasma uric acid decreased with increasing pegloticase dose or concentrations. The duration of suppression of plasma uric acid appeared to be positively associated with pegloticase dose. Sustained decrease in plasma uric acid below the solubility concentration of 6 mg/dL for more than 300 hours was observed with doses of 8 mg and 12 mg. ## Pharmacokinetics - Pegloticase levels were determined in serum based on measurements of uricase enzyme activity. - Following single intravenous infusions of 0.5 mg to 12 mg pegloticase in 23 patients with symptomatic gout, maximum serum concentrations of pegloticase increased in proportion to the dose administered. - The population pharmacokinetic analysis showed that age, sex, weight, and creatinine clearance did not influence the pharmacokinetics of pegloticase. Significant covariates included in the model for determining clearance and volume of distribution were found to be body surface area and anti-pegloticase antibodies. - The pharmacokinetics of pegloticase has not been studied in children and adolescents. - No formal studies were conducted to examine the effects of either renal or hepatic impairment on pegloticase pharmacokinetics. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term animal studies have not been performed to evaluate the carcinogenic potential of pegloticase. - The genotoxic potential of pegloticase has not been evaluated. - Fertility studies in animals have not been performed. - Animal Toxicology and/or Pharmacology - In a 12-week intravenous repeat-dose study in dogs, there was a dose-dependent increase in vacuolated macrophages in the spleen. The presence of vacuolated macrophages likely reflects accumulated removal of injected pegloticase (foreign) material from the circulation. There was no evidence of degeneration, inflammation, or necrosis associated with the vacuoles findings, however there was evidence of decreased functional response to liposaccharides. - In a 39-week, repeat dose dog study, there was a dose dependent increase in vacuolated cells in several organs, including the spleen, adrenal gland, liver, heart, duodenum and jejunum. In the spleen, liver, duodenum and jejunum, these vacuoles were within macrophages and most likely represented phagocytic removal of pegloticase from the circulation. However, the vacuolated cells in the heart and adrenal gland did not stain as macrophages. In the aortic outflow tract of the heart, vacuoles were in the cytoplasm of endothelial cells in the intimal lining of the aorta. In the adrenal gland, vacuoles were located within cortical cells in the zona reticularis and zona fasciculata. The clinical significance of these findings and the functional consequences are unknown. # Clinical Studies - The efficacy of KRYSTEXXA was studied in adult patients with chronic gout refractory to conventional therapy in two replicate, multicenter, randomized, double-blind, placebo-controlled studies of six months duration: Trial 1 and Trial 2. Patients were randomized to receive KRYSTEXXA 8 mg every 2 weeks or every 4 weeks or placebo in a 2:2:1 ratio. Studies were stratified for the presence of tophi. Seventy-one percent (71%) of patients had baseline tophi. All patients were prophylaxed with an oral antihistamine, intravenous corticosteroid and acetaminophen. Patients also received prophylaxis for gout flares with non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine, or both, beginning at least one week before KRYSTEXXA treatment unless medically contraindicated or not tolerated. Patients who completed the randomized clinical trials were eligible to enroll in a 2-year open label extension study. - Entry criteria for patients to be eligible for the trials were: baseline serum uric acid (SUA) of at least 8 mg/dL; had symptomatic gout with at least 3 gout flares in the previous 18 months or at least 1 gout tophus or gouty arthritis; and had a self-reported medical contraindication to allopurinol or medical history of failure to normalize uric acid (to less than 6 mg/dL) with at least 3 months of allopurinol treatment at the maximum medically appropriate dose. - The mean age of study subjects was 55 years (23-89); 82% were male, mean body mass index (BMI) was 33 kg/m2, mean duration of gout was 15 years, and mean baseline SUA was 10 mg/dL. - To assess the efficacy of KRYSTEXXA in lowering uric acid, the primary endpoint in both trials was the proportion of patients who achieved plasma uric acid (PUA) less than 6 mg/dL for at least 80% of the time during Month 3 and Month 6. As shown in Table 2, a greater proportion of patients treated with KRYSTEXXA every 2 weeks achieved urate lowering to below 6 mg/dL than patients receiving placebo. Although the 4 week regimen also demonstrated efficacy for the primary endpoint, this regimen was associated with increased frequency of anaphylaxis and infusion reactions and less efficacy with respect to tophi. - The effect of treatment on tophi was a secondary efficacy endpoint and was assessed using standardized digital photography, image analysis, and a Central Reader blinded to treatment assignment. Approximately 70% of patients had tophi at baseline. A pooled analysis of data from Trial 1 and Trial 2 was performed as pre-specified in the protocols. At Month 6, the percentage of patients who achieved a complete response (defined as 100% resolution of at least one target tophus, no new tophi appear and no single tophus showing progression) was 45%, 26%, and 8%, with KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. The difference between KRYSTEXXA and placebo was statistically significant for the every 2 week dosing regimen, but not for the every 4 week dosing regimen. # How Supplied - KRYSTEXXA is supplied as a clear, colorless, sterile solution in phosphate buffered saline intended for intravenous infusion after dilution. KRYSTEXXA is supplied in a single-use 2 mL glass vial with a Teflon® coated (latex-free) rubber injection stopper to deliver KRYSTEXXA as 8 mg of uricase protein in 1 mL volume. - Storage and Handling - Before the preparation for use, KRYSTEXXA must be stored in the carton and maintained at all times under refrigeration between 2° to 8°C (36° to 46°F). Protect from light. Do not shake or freeze. - Do not use beyond the expiration date stamped. ## Storage There is limited information regarding Pegloticase Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - General Information - Provide and instruct patients to read the accompanying Medication Guide before starting treatment and before each subsequent treatment. - Anaphylaxis and Infusion Reactions - Anaphylaxis and infusion reactions can occur at any infusion while on therapy. Counsel patients on the importance of adhering to any prescribed medications to help prevent or lessen the severity of these reactions. - Educate patients on the signs and symptoms of anaphylaxis, including wheezing, peri-oral or lingual edema, hemodynamic instability, and rash or urticaria. - Educate patients on the most common signs and symptoms of an infusion reaction, including urticaria (skin rash), erythema (redness of the skin), dyspnea (difficulty breathing), flushing, chest discomfort, chest pain, and rash. - Advise patients to seek medical care immediately if they experience any symptoms of an allergic reaction during or at any time after the infusion of KRYSTEXXA. - Advise patients to discontinue any oral urate-lowering agents before starting on KRYSTEXXA and not to take any oral urate-lowering agents while on KRYSTEXXA. - Glucose-6-phosphate dehydrogenase (G6PD) Deficiency - Inform patients not to take KRYSTEXXA if they have a condition known as G6PD deficiency. Explain to patients that G6PD deficiency is more frequently found in individuals of African or Mediterranean ancestry and that they may be tested to determine if they have G6PD deficiency, unless already known. - Gout Flares - Explain to patients that gout flares may initially increase when starting treatment with KRYSTEXXA, and that medications to help reduce flares may need to be taken regularly for the first few months after KRYSTEXXA is started. Advise patients that they should not stop KRYSTEXXA therapy if they have a flare. # Precautions with Alcohol - Alcohol-Pegloticase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - KRYSTEXXA® # Look-Alike Drug Names There is limited information regarding Pegloticase Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Pegloticase 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. # Black Box Warning # Overview Pegloticase is a PEGylated uric acid specific enzyme that is FDA approved for the treatment of chronic gout in adult patients refractory to conventional therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include gout flares, infusion reactions, nausea, contusion or ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis and vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The recommended dose and regimen of KRYSTEXXA for adult patients is 8 mg (uricase protein) given as an intravenous infusion every two weeks. - The optimal treatment duration with KRYSTEXXA has not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pegloticase in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegloticase in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Pegloticase in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pegloticase in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegloticase in pediatric patients. # Contraindications - Glucose-6-phosphate dehydrogenase (G6PD) deficiency - KRYSTEXXA is contraindicated in patients with G6PD deficiency due to the risk of hemolysis and methemoglobinemia. It is recommended that patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) be screened for G6PD deficiency before starting KRYSTEXX # Warnings ### Precautions - Anaphylaxis - During pre-marketing controlled clinical trials, anaphylaxis was reported with a frequency of 6.5% of patients treated with KRYSTEXXA every 2 weeks, compared to none with placebo. Manifestations included wheezing, peri-oral or lingual edema, or hemodynamic instability, with or without rash or urticaria. Cases occurred in patients being pre-treated with one or more doses of an oral antihistamine, an intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of anaphylaxis and therefore the reported frequency may be an underestimate. - KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage anaphylaxis. Patients should be pre-treated with antihistamines and corticosteroids. Anaphylaxis may occur with any infusion, including a first infusion, and generally manifests within 2 hours of the infusion. However, delayed type hypersensitivity reactions have also been reported. Patients should be closely monitored for an appropriate period of time for anaphylaxis after administration of KRYSTEXXA. Patients should be informed of the symptoms and signs of anaphylaxis and instructed to seek immediate medical care should anaphylaxis occur after discharge from the healthcare setting. - The risk of anaphylaxis is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA. - Infusion Reactions - During pre-marketing controlled clinical trials, infusion reactions were reported in 26% of patients treated with KRYSTEXXA 8 mg every 2 weeks, and 41% of patients treated with KRYSTEXXA 8 mg every 4 weeks, compared to 5% of patients treated with placebo. These infusion reactions occurred in patients being pre-treated with an oral antihistamine, intravenous corticosteroid and/or acetaminophen. This pre-treatment may have blunted or obscured symptoms or signs of infusion reactions and therefore the reported frequency may be an underestimate. - KRYSTEXXA should be administered in a healthcare setting by healthcare providers prepared to manage infusion reactions. Patients should be pre-treated with antihistamines and corticosteroids. KRYSTEXXA should be infused slowly over no less than 120 minutes. In the event of an infusion reaction, the infusion should be slowed, or stopped and restarted at a slower rate. - The risk of infusion reaction is higher in patients whose uric acid level increases to above 6 mg/dL, particularly when 2 consecutive levels above 6 mg/dL are observed. Monitor serum uric acid levels prior to infusions and consider discontinuing treatment if levels increase to above 6 mg/dL. Because of the possibility that concomitant use of oral urate-lowering therapy and KRYSTEXXA may potentially blunt the rise of serum uric acid levels, it is recommended that before starting KRYSTEXXA patients discontinue oral urate-lowering medications and not institute therapy with oral urate-lowering agents while taking KRYSTEXXA. - Gout Flares - Gout flares may occur after initiation of KRYSTEXXA. An increase in gout flares is frequently observed upon initiation of anti-hyperuricemic therapy, due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits. Gout flare prophylaxis with a non-steroidal anti-inflammatory drug (NSAID) or colchicine is recommended starting at least 1 week before initiation of KRYSTEXXA therapy and lasting at least 6 months, unless medically contraindicated or not tolerated. KRYSTEXXA does not need to be discontinued because of a gout flare. The gout flare should be managed concurrently as appropriate for the individual patient. - Congestive Heart Failure - KRYSTEXXA has not been formally studied in patients with congestive heart failure, but some patients in the clinical trials experienced exacerbation. Exercise caution when using KRYSTEXXA in patients who have congestive heart failure and monitor patients closely following infusion. - Re-treatment with KRYSTEXXA - No controlled trial data are available on the safety and efficacy of re-treatment with KRYSTEXXA after stopping treatment for longer than 4 weeks. Due to the immunogenicity of KRYSTEXXA, patients receiving re-treatment may be at increased risk of anaphylaxis and infusion reactions. Therefore, patients receiving re-treatment after a drug-free interval should be monitored carefully. # Adverse Reactions ## Clinical Trials Experience - The data described below reflect exposure to KRYSTEXXA in patients with chronic gout refractory to conventional therapy in two replicate randomized, placebo-controlled, double-blind 6-month clinical trials: 85 patients were treated with KRYSTEXXA 8 mg every 2 weeks; 84 patients were treated with KRYSTEXXA 8 mg every 4 weeks; and 43 patients were treated with placebo. These patients were between the ages of 23 and 89 years (average 55 years); 173 patients were male and 39 were female; and 143 patients were White/Caucasian, 27 were Black/African American, 24 were Hispanic/Latino and 18 were all other ethnicities. Common co-morbid conditions among the enrolled patients included hypertension (72%), dyslipidemia (49%), chronic kidney disease (28%), diabetes (24%), coronary artery disease (18%), arrhythmia (16%), and cardiac failure/left ventricular dysfunction (12%). - Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice. - Anaphylaxis: - Diagnostic criteria of anaphylaxis were skin or mucosal tissue involvement, and, either airway compromise, and/or reduced blood pressure with or without associated symptoms, and a temporal relationship to KRYSTEXXA or placebo injection with no other identifiable cause. Using these clinical criteria, anaphylaxis was identified in 14 (5.1%) of 273 total patients studied in the clinical program of IV KRYSTEXXA. The frequency was 6.5% for the every 2-week dosing regimen (8 of 123 patients), and 4.8% for the 4-week dosing frequency (6 of 126) of KRYSTEXXA. There were no cases of anaphylaxis in patients receiving placebo. Anaphylaxis generally occurred within 2 hours after treatment. This occurred with patients being pre-treated with an oral antihistamine, intravenous corticosteroid, and acetaminophen. - Infusion Reactions: - Infusion reactions occurred in 26% of patients in the 2 week dosing regimen group and 41% of patients in the 4 week dosing regimen group, compared to 5% of placebo-treated patients. Manifestations of these reactions included urticaria (frequency of 10.6%), dyspnea (frequency of 7.1%), chest discomfort (frequency of 9.5%), chest pain (frequency of 9.5%), erythema (frequency of 9.5%), and pruritus (frequency of 9.5%). These manifestations overlap with the symptoms of anaphylaxis, but in a given patient did not occur together to satisfy the clinical criteria for diagnosing anaphylaxis. Infusion reactions are thought to result from release of various mediators, such as cytokines. Infusion reactions occurred at any time during a course of treatment with approximately 3% occurring with the first infusion, and approximately 91% occurred during the time of infusion. Some infusion reaction manifestations were reduced with slowing the rate of infusion, or stopping the infusion and restarting the infusion at a slower rate. These infusion reactions occurred with all patients being pre-treated with an oral antihistamine, intravenous corticosteroid and acetaminophen. - Gout Flares: - Gout flares were common in the study patients before randomization to treatment, with patients experiencing an average of 10 flares in the preceding 18 months prior to study entry. During the controlled treatment period with KRYSTEXXA or placebo, the frequencies of gout flares were high in all treatment groups, but more so with KRYSTEXXA treatment during the first 3 months of treatment, which seemed to decrease in the subsequent 3 months of treatment. The percentages of patients with any flare for the first 3 months were 74%, 81%, and 51%, for KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. The percentages of patients with any flare for the subsequent 3 months were 41%, 57%, and 67%, for KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. Patients received gout flare prophylaxis with colchicine and/or nonsteroidal anti-inflammatory drugs (NSAIDs) starting at least one week before receiving KRYSTEXXA. - Congestive Heart Failure: - Two cases of congestive heart failure exacerbation occurred during the trials in patients receiving treatment with KRYSTEXXA 8 mg every 2 weeks. No cases were reported in placebo-treated patients. Four subjects had exacerbations of pre-existing congestive heart failure while receiving KRYSTEXXA 8 mg every 2 weeks during the open-label extension study. - Other Adverse Reactions: - The most commonly reported adverse reactions that occurred in greater than or equal to 5% of patients treated with KRYSTEXXA 8 mg every 2 weeks are provided in Table 1. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Pegloticase in the drug label. # Drug Interactions - No studies of interactions of KRYSTEXXA with other drugs have been conducted. - Because anti-pegloticase antibodies appear to bind to the PEG portion of the drug, there may be potential for binding with other PEGylated products. The impact of anti-PEG antibodies on patients' responses to other PEG-containing therapeutics is unknown. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - A complete evaluation of the reproductive and developmental toxicity of pegloticase has not been completed. Adequate animal reproduction studies have not been conducted with KRYSTEXXA. It is not known whether KRYSTEXXA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled studies in pregnant women. KRYSTEXXA should be used during pregnancy only if clearly needed. - Pegloticase was not teratogenic in rats administered 0, 5, 10, or 40 mg/kg twice weekly by the intravenous route on gestation days 6 through 16 (the doses are approximately 6-fold to 50-fold higher than the maximum recommended human dose (MRHD) of 8 mg (0.133 mg/kg based on a 60 kg person) every 2 weeks based on a mg/m2 comparison). Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pegloticase in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Pegloticase 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, it is not recommended to administer KRYSTEXXA to a nursing mother. ### Pediatric Use - The safety and effectiveness of KRYSTEXXA in pediatric patients less than 18 years of age have not been established. ### Geriatic Use - Of the total number of patients treated with KRYSTEXXA 8 mg every 2 weeks in the controlled studies, 34% (29 of 85) were 65 years of age and older and 12% (10 of 85) were 75 years of age and older. No overall differences in safety or effectiveness were observed between older and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is needed for patients 65 years of age and older. ### Gender There is no FDA guidance on the use of Pegloticase with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pegloticase with respect to specific racial populations. ### Renal Impairment - No dose adjustment is required for patients with renal impairment. A total of 32% (27 of 85) of patients treated with KRYSTEXXA 8 mg every 2 weeks had a creatinine clearance of ≤62.5 mL/min. No overall differences in efficacy were observed. ### Hepatic Impairment There is no FDA guidance on the use of Pegloticase in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pegloticase in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pegloticase in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Pegloticase in the drug label. # IV Compatibility - Visually inspect KRYSTEXXA for particulate matter and discoloration before administration, whenever solution and container permit. Do not use vials if either is present. - Use appropriate aseptic technique. Withdraw 1 mL of KRYSTEXXA from the vial into a sterile syringe. Discard any unused portion of product remaining in the 2 mL vial. Inject into a single 250 mL bag of 0.9% Sodium Chloride Injection, USP or 0.45% Sodium Chloride Injection, USP for intravenous infusion. Do not mix or dilute with other drugs. - Invert the infusion bag containing the dilute KRYSTEXXA solution a number of times to ensure thorough mixing. Do not shake. - KRYSTEXXA diluted in infusion bags is stable for 4 hours at 2° to 8°C (36° to 46°F) and at room temperature (20° to 25°C, 68° to 77°F). However it is recommended that diluted solutions be stored under refrigeration, not frozen, protected from light, and used within 4 hours of dilution. - Before administration, allow the diluted solution of KRYSTEXXA to reach room temperature. KRYSTEXXA in a vial or in an intravenous infusion fluid should never be subjected to artificial heating (e.g., hot water, microwave). # Overdosage ## Acute Overdose - No reports of overdosage with KRYSTEXXA have been reported. The maximum dose that has been administered as a single intravenous dose is 12 mg as uricase protein. - Patients suspected of receiving an overdose should be monitored, and general supportive measures should be initiated as no specific antidote has been identified. ## Chronic Overdose There is limited information regarding Chronic Overdose of Pegloticase in the drug label. # Pharmacology ## Mechanism of Action - KRYSTEXXA is a uric acid specific enzyme which is a recombinant uricase and achieves its therapeutic effect by catalyzing the oxidation of uric acid to allantoin, thereby lowering serum uric acid. Allantoin is an inert and water soluble purine metabolite. It is readily eliminated, primarily by renal excretion. ## Structure - KRYSTEXXA (pegloticase) is a uric acid specific enzyme which is a PEGylated product that consists of recombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of Escherichia coli. Uricase is covalently conjugated to monomethoxypoly(ethylene glycol) [mPEG] (10 kDa molecular weight). The cDNA coding for uricase is based on mammalian sequences. Each uricase subunit has a molecular weight of approximately 34 kDa per subunit. The average molecular weight of pegloticase (tetrameric enzyme conjugated to mPEG) is approximately 540 kDa. - KRYSTEXXA is intended for intravenous infusion. - KRYSTEXXA is a sterile, clear, colorless solution containing 8 mg/mL pegloticase in phosphate-buffered saline. - KRYSTEXXA (pegloticase) concentrations are expressed as concentrations of uricase protein. Each mL of KRYSTEXXA contains 8 mg of uricase protein (conjugated to 24 mg of 10 kDa mPEG), 2.18 mg Disodium Hydrogen Phosphate Dihydrate (Na2HPO4•2H2O), 8.77 mg Sodium Chloride (NaCl), 0.43 mg Sodium Dihydrogen Phosphate Dihydrate (NaH2PO4•2H2O), and Water for Injection to deliver 8 mg of pegloticase (as uricase protein). ## Pharmacodynamics - Approximately 24 hours following the first dose of KRYSTEXXA, mean plasma uric acid levels for subjects in the KRYSTEXXA groups were 0.7 mg/dL for the KRYSTEXXA 8 mg every 2 weeks group. In comparison, the mean plasma uric acid level for the placebo group was 8.2 mg/dL. - In a single-dose, dose-ranging trial, following 1-hour intravenous infusions of 0.5, 1, 2, 4, 8 or 12 mg of pegloticase in 24 patients with symptomatic gout (n=4 subjects/dose group), plasma uric acid decreased with increasing pegloticase dose or concentrations. The duration of suppression of plasma uric acid appeared to be positively associated with pegloticase dose. Sustained decrease in plasma uric acid below the solubility concentration of 6 mg/dL for more than 300 hours was observed with doses of 8 mg and 12 mg. ## Pharmacokinetics - Pegloticase levels were determined in serum based on measurements of uricase enzyme activity. - Following single intravenous infusions of 0.5 mg to 12 mg pegloticase in 23 patients with symptomatic gout, maximum serum concentrations of pegloticase increased in proportion to the dose administered. - The population pharmacokinetic analysis showed that age, sex, weight, and creatinine clearance did not influence the pharmacokinetics of pegloticase. Significant covariates included in the model for determining clearance and volume of distribution were found to be body surface area and anti-pegloticase antibodies. - The pharmacokinetics of pegloticase has not been studied in children and adolescents. - No formal studies were conducted to examine the effects of either renal or hepatic impairment on pegloticase pharmacokinetics. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term animal studies have not been performed to evaluate the carcinogenic potential of pegloticase. - The genotoxic potential of pegloticase has not been evaluated. - Fertility studies in animals have not been performed. - Animal Toxicology and/or Pharmacology - In a 12-week intravenous repeat-dose study in dogs, there was a dose-dependent increase in vacuolated macrophages in the spleen. The presence of vacuolated macrophages likely reflects accumulated removal of injected pegloticase (foreign) material from the circulation. There was no evidence of degeneration, inflammation, or necrosis associated with the vacuoles findings, however there was evidence of decreased functional response to liposaccharides. - In a 39-week, repeat dose dog study, there was a dose dependent increase in vacuolated cells in several organs, including the spleen, adrenal gland, liver, heart, duodenum and jejunum. In the spleen, liver, duodenum and jejunum, these vacuoles were within macrophages and most likely represented phagocytic removal of pegloticase from the circulation. However, the vacuolated cells in the heart and adrenal gland did not stain as macrophages. In the aortic outflow tract of the heart, vacuoles were in the cytoplasm of endothelial cells in the intimal lining of the aorta. In the adrenal gland, vacuoles were located within cortical cells in the zona reticularis and zona fasciculata. The clinical significance of these findings and the functional consequences are unknown. # Clinical Studies - The efficacy of KRYSTEXXA was studied in adult patients with chronic gout refractory to conventional therapy in two replicate, multicenter, randomized, double-blind, placebo-controlled studies of six months duration: Trial 1 and Trial 2. Patients were randomized to receive KRYSTEXXA 8 mg every 2 weeks or every 4 weeks or placebo in a 2:2:1 ratio. Studies were stratified for the presence of tophi. Seventy-one percent (71%) of patients had baseline tophi. All patients were prophylaxed with an oral antihistamine, intravenous corticosteroid and acetaminophen. Patients also received prophylaxis for gout flares with non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine, or both, beginning at least one week before KRYSTEXXA treatment unless medically contraindicated or not tolerated. Patients who completed the randomized clinical trials were eligible to enroll in a 2-year open label extension study. - Entry criteria for patients to be eligible for the trials were: baseline serum uric acid (SUA) of at least 8 mg/dL; had symptomatic gout with at least 3 gout flares in the previous 18 months or at least 1 gout tophus or gouty arthritis; and had a self-reported medical contraindication to allopurinol or medical history of failure to normalize uric acid (to less than 6 mg/dL) with at least 3 months of allopurinol treatment at the maximum medically appropriate dose. - The mean age of study subjects was 55 years (23-89); 82% were male, mean body mass index (BMI) was 33 kg/m2, mean duration of gout was 15 years, and mean baseline SUA was 10 mg/dL. - To assess the efficacy of KRYSTEXXA in lowering uric acid, the primary endpoint in both trials was the proportion of patients who achieved plasma uric acid (PUA) less than 6 mg/dL for at least 80% of the time during Month 3 and Month 6. As shown in Table 2, a greater proportion of patients treated with KRYSTEXXA every 2 weeks achieved urate lowering to below 6 mg/dL than patients receiving placebo. Although the 4 week regimen also demonstrated efficacy for the primary endpoint, this regimen was associated with increased frequency of anaphylaxis and infusion reactions and less efficacy with respect to tophi. - The effect of treatment on tophi was a secondary efficacy endpoint and was assessed using standardized digital photography, image analysis, and a Central Reader blinded to treatment assignment. Approximately 70% of patients had tophi at baseline. A pooled analysis of data from Trial 1 and Trial 2 was performed as pre-specified in the protocols. At Month 6, the percentage of patients who achieved a complete response (defined as 100% resolution of at least one target tophus, no new tophi appear and no single tophus showing progression) was 45%, 26%, and 8%, with KRYSTEXXA 8 mg every 2 weeks, KRYSTEXXA 8 mg every 4 weeks, and placebo, respectively. The difference between KRYSTEXXA and placebo was statistically significant for the every 2 week dosing regimen, but not for the every 4 week dosing regimen. # How Supplied - KRYSTEXXA is supplied as a clear, colorless, sterile solution in phosphate buffered saline intended for intravenous infusion after dilution. KRYSTEXXA is supplied in a single-use 2 mL glass vial with a Teflon® coated (latex-free) rubber injection stopper to deliver KRYSTEXXA as 8 mg of uricase protein in 1 mL volume. - Storage and Handling - Before the preparation for use, KRYSTEXXA must be stored in the carton and maintained at all times under refrigeration between 2° to 8°C (36° to 46°F). Protect from light. Do not shake or freeze. - Do not use beyond the expiration date stamped. ## Storage There is limited information regarding Pegloticase Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - General Information - Provide and instruct patients to read the accompanying Medication Guide before starting treatment and before each subsequent treatment. - Anaphylaxis and Infusion Reactions - Anaphylaxis and infusion reactions can occur at any infusion while on therapy. Counsel patients on the importance of adhering to any prescribed medications to help prevent or lessen the severity of these reactions. - Educate patients on the signs and symptoms of anaphylaxis, including wheezing, peri-oral or lingual edema, hemodynamic instability, and rash or urticaria. - Educate patients on the most common signs and symptoms of an infusion reaction, including urticaria (skin rash), erythema (redness of the skin), dyspnea (difficulty breathing), flushing, chest discomfort, chest pain, and rash. - Advise patients to seek medical care immediately if they experience any symptoms of an allergic reaction during or at any time after the infusion of KRYSTEXXA. - Advise patients to discontinue any oral urate-lowering agents before starting on KRYSTEXXA and not to take any oral urate-lowering agents while on KRYSTEXXA. - Glucose-6-phosphate dehydrogenase (G6PD) Deficiency - Inform patients not to take KRYSTEXXA if they have a condition known as G6PD deficiency. Explain to patients that G6PD deficiency is more frequently found in individuals of African or Mediterranean ancestry and that they may be tested to determine if they have G6PD deficiency, unless already known. - Gout Flares - Explain to patients that gout flares may initially increase when starting treatment with KRYSTEXXA, and that medications to help reduce flares may need to be taken regularly for the first few months after KRYSTEXXA is started. Advise patients that they should not stop KRYSTEXXA therapy if they have a flare. # Precautions with Alcohol - Alcohol-Pegloticase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - KRYSTEXXA®[1] # Look-Alike Drug Names There is limited information regarding Pegloticase Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Pegloticase
27161e8919047189b5bb912c6c9de7a1654c2208	wikidoc	Pegvisomant	Pegvisomant # 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 Pegvisomant is a growth hormone receptor antagonist that is FDA approved for the treatment of acromegaly in patients who have had an inadequate response to surgery or radiation therapy, or for whom these therapies are not appropriate. Common adverse reactions include infection, pain, nausea, diarrhea, abnormal liver tests, flu syndrome, injection site reaction. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended loading dose of SOMAVERT is 40 mg given subcutaneously, under healthcare provider supervision. Provide proper training in subcutaneous injection technique to patients or their caregivers so they can receive once daily subcutaneous injections. On the next day following the loading dose, instruct patients or their caregivers to begin daily subcutaneous injections of 10 mg of SOMAVERT. - Titrate the dosage to normalize serum IGF-I concentrations (serum IGF-I concentrations should be measured every four to six weeks). The dosage should not be based on growth hormone (GH) concentrations or signs and symptoms of acromegaly. It is unknown whether patients who remain symptomatic while achieving normalized IGF-I concentrations would benefit from increased SOMAVERT dosage. - Increase the dosage by 5 mg increments every 4–6 weeks if IGF-I concentrations are elevated. - Decrease the dosage by 5 mg decrements every 4–6 weeks if IGF-I concentrations are below the normal range. - IGF-I levels should also be monitored when a Somavert dose given in multiple injections is converted to a single daily injection. - The recommended dosage range is between 10 to 30 mg given subcutaneously once daily and the maximum daily dosage is 30 mg given subcutaneously once daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pegvisomant in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegvisomant in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Pegvisomant in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pegvisomant in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegvisomant in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Hypoglycemia associated with GH lowering in patients with Diabetes Mellitus - GH opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity; thus, glucose tolerance may improve in some patients treated with SOMAVERT. Patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary to avoid hypoglycemia in patients with diabetes mellitus. - Liver Test Elevations - Baseline serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), and alkaline phosphatase (ALP) levels should be obtained prior to initiating therapy with SOMAVERT. Table 1 lists recommendations regarding initiation of treatment with SOMAVERT, based on the results of these liver tests (LTs). - Asymptomatic, transient elevations in transaminases up to 15 times ULN have been observed in < 2% of subjects among two open-label trials (with a total of 147 patients). These reports were not associated with an increase in bilirubin. Transaminase elevations normalized with time, most often after suspending treatment (SOMAVERT should be used in accordance with the information presented in Table 2 with respect to liver test abnormalities while on Somavert treatment). - If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction while receiving SOMAVERT, the following patient management is recommended (Table 2). - Cross-Reactivity with GH Assays - SOMAVERT has significant structural similarity to growth hormone (GH) which causes it to cross-react in commercially available GH assays. Since serum concentrations of therapeutically effective doses of SOMAVERT are generally 100 to 1000 times higher than the actual serum GH concentrations seen in patients with acromegaly, measurements of serum GH concentrations will appear falsely elevated. - Lipohypertrophy - There have been cases of lipohypertrophy in patients treated with SOMAVERT. In a double-blind, 12-week, placebo-controlled study, there was one case (1.3%) of injection site lipohypertrophy reported in a subject receiving 10 mg/day. The subject recovered while on treatment. Among two open-label trials (with a total of 147 patients), there were two subjects, both receiving 10 mg/day, who developed lipohypertrophy. One case recovered while on treatment, and one case resulted in a discontinuation of treatment. Injection sites should be rotated daily to help prevent lipohypertrophy (different area than the last injection). - Systemic Hypersensitivity - In subjects with systemic hypersensitivity reactions, caution and close monitoring should be exercised when re-initiating Somavert therapy. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. - In a 12-week randomized, placebo-controlled, double-blind, fixed-dose study of SOMAVERT in subjects with acromegaly, 32 subjects received placebo and 80 subjects received SOMAVERT once daily. A total of 108 subjects (30 placebo, 78 Somavert) completed 12 weeks of study treatment. . - Overall, eight patients with acromegaly (5.3%) withdrew from pre-marketing clinical studies because of adverse events, including two patients with marked transaminase elevations, one patient with lipohypertrophy at the injection sites, and one patient with substantial weight gain. Most adverse events did not appear to be dose-dependent. Table 3 shows the incidence of adverse events that were reported in at least two patients treated with SOMAVERT and at frequencies greater than placebo during the 12-week, placebo-controlled study. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of SOMAVERT. 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. - Systemic hypersensitivity reactions including anaphylactic reactions, laryngospasm, angioedema, generalized skin reactions (rash, erythema, pruritus, urticaria) have been reported in post-marketing use. Some patients required hospitalization. Symptoms did not re-occur in all patients after re-challenge. - Registry of Patients with Acromegaly Treated with SOMAVERT - ACROSTUDY is an international observational registry that captures long term safety data in patients with acromegaly treated with SOMAVERT, as used in clinical practice. Treatment dose and schedule were at the discretion of each treating physician. Although safety monitoring as per the recommended schedule was mandatory, not all assessments were performed at all time points for every patient. Because of this, comparison of rates of adverse events to those in the original clinical trial is not appropriate. In an interim report, there were 1288 patients enrolled (mean duration of treatment 3.7 years). - At the start of SOMAVERT treatment 648 patients were on SOMAVERT monotherapy for acromegaly. Of the 454 patients who had a normal AST and ALT at baseline, 4 patients had elevated tests >3 times ULN, two of whom had elevated tests >5 times ULN. - Lipohypertrophy was reported in 6 (0.5%) patients. - MRIs were compared to any previous ones, and a change in tumor volume was reported as significant locally only if the diameter increased by more than 3 mm for microadenomas or volume increased by more than 20% for macroadenomas. All MRI changes considered significant at the local reading were reanalyzed centrally. Of the 747 patients who had a MRI reported at baseline and at least once during follow up in the study, 51 (7%) were reported to have an increase by local MRI. Of these, 16 patients (2%) had confirmation of this increase, 6 patients had a decrease, 12 had "no change"; there was 1 with insufficient data and 16 patients did not have a central MRI reading. # Drug Interactions - Insulin and/or Oral hypoglycemic Agents - After initiation of SOMAVERT, patients with acromegaly and diabetes mellitus treated with insulin and/or oral hypoglycemic agents may require dose reductions of insulin and/or oral hypoglycemic agents. - Opioids - In clinical studies, patients taking opioids often needed higher SOMAVERT doses to normalize IGF-I concentrations compared with patients not receiving opioids. The mechanism of this interaction is not known. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Early embryonic development and teratology studies were conducted in pregnant rabbits with pegvisomant at subcutaneous doses of 1, 3, and 10 mg/kg/day. There was no evidence of teratogenic effects associated with pegvisomant treatment during organogenesis. At the 10-mg/kg/day dose (10 times the maximum human therapeutic dose based on body surface area), a reproducible, slight increase in post-implantation loss was observed in both studies. Because animal reproduction studies are not always predictive of human responses, SOMAVERT 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 Pegvisomant in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Pegvisomant during labor and delivery. ### Nursing Mothers - It is not known whether pegvisomant is excreted in human milk. Because many drugs are excreted in milk, caution should be exercised when SOMAVERT is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of SOMAVERT in pediatric patients have not been established. ### Geriatic Use - Clinical studies of SOMAVERT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from 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 Pegvisomant with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pegvisomant with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Pegvisomant in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Pegvisomant in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pegvisomant in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pegvisomant in patients who are immunocompromised. # Administration and Monitoring ### Administration - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Pegvisomant in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Pegvisomant in the drug label. # Overdosage ## Acute Overdose - In one reported incident of acute overdose with SOMAVERT during pre-marketing clinical studies, a patient self-administered 80 mg/day (2.7 times the maximum recommended maintenance dosage) for seven days. The patient experienced a slight increase in fatigue, had no other complaints, and demonstrated no significant clinical laboratory abnormalities. - In cases of overdose, administration of SOMAVERT should be discontinued and not resumed until IGF-I levels return to within or above the normal range. ## Chronic Overdose There is limited information regarding Chronic Overdose of Pegvisomant in the drug label. # Pharmacology ## Mechanism of Action - Pegvisomant selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction. - Inhibition of GH action results in decreased serum concentrations of IGF-I, as well as other GH-responsive serum proteins such as free IGF-I, the acid-labile subunit of IGF-I (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3). ## Structure - SOMAVERT contains pegvisomant, an analog of human growth hormone (GH) that has been structurally altered to act as a GH receptor antagonist. - Pegvisomant is a protein of recombinant DNA origin containing 191 amino acid residues to which several polyethylene glycol (PEG) polymers are covalently bound (predominantly 4 to 6 PEG/protein molecule). The molecular weight of the protein of pegvisomant is 21,998 Daltons. The molecular weight of the PEG portion of pegvisomant is approximately 5000 Daltons. The predominant molecular weights of pegvisomant are thus approximately 42,000, 47,000, and 52,000 Daltons. The schematic shows the amino acid sequence of the pegvisomant protein (PEG polymers are shown attached to the 5 most probable attachment sites). Pegvisomant is synthesized by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist. Biological potency is determined using a cell proliferation bioassay. Binding of Somavert to the GH receptor results in disruption of the proper binding of the second GH receptor with inhibition of functional receptor dimerization and subsequent intracellular signaling. - SOMAVERT for injection is supplied as a sterile, white lyophilized powder intended for subcutaneous injection after reconstitution with 1 mL of Sterile Water for Injection. SOMAVERT is available in single-dose sterile vials containing 10, 15, 20, 25 or 30 mg of pegvisomant protein (approximately 10, 15, 20, 25 and 30 U activity, respectively). Each vial 10, 15 and 20 also contains 1.36 mg of glycine, 36.0 mg of mannitol, 1.04 mg of sodium phosphate dibasic anhydrous, and 0.36 mg of sodium phosphate monobasic monohydrate. Each 25 mg vial also contains 1.7 mg of glycine, 46.1 mg of mannitol, 1.3 mg of sodium phosphate dibasic anhydrous, and 0.5 mg of sodium phosphate monobasic monohydrate. Each 30 mg vial also contains 2.1 mg of glycine, 56.5 mg of mannitol, 1.6 mg of sodium phosphate dibasic anhydrous, and 0.6 mg of sodium phosphate monobasic monohydrate. - SOMAVERT is supplied in packages that include a vial containing diluent. Sterile Water for Injection, USP, is a sterile, nonpyrogenic preparation of water for injection that contains no bacteriostat, antimicrobial agent, or added buffer, and is supplied in single-dose containers to be used as a diluent. ## Pharmacodynamics - Pegvisomant binds selectively to the GH receptor, and does not cross-react with 19 other cytokine receptors tested, including prolactin. Pegvisomant leads to decreased serum concentrations of IGF-I, free IGF-I, ALS, and IGFBP-3. ## Pharmacokinetics - Absorption: Following subcutaneous administration, peak serum pegvisomant concentrations are not generally attained until 33 to 77 hours after administration. The mean extent of absorption of a 20-mg subcutaneous dose was 57%, relative to a 10-mg intravenous dose. - Distribution: The mean apparent volume of distribution of pegvisomant is 7 L (12% coefficient of variation), suggesting that pegvisomant does not distribute extensively into tissues. After a single subcutaneous administration, exposure (Cmax, AUC) to pegvisomant increases disproportionately with increasing dose. Mean ± SEM serum pegvisomant concentrations after 12 weeks of therapy with daily doses of 10, 15, and 20 mg were 6600 ± 1330; 16,000 ± 2200; and 27,000 ± 3100 ng/mL, respectively. - The relative bioavailability of 1 × 30 mg pegvisomant was compared to 2 × 15 mg pegvisomant in a single dose study. The AUCinf and Cmax of pegvisomant when administered as one injection of 30 mg strength was approximately 6% and 4% greater, respectively, as compared to when administered as two injections of 15 mg strengths. - Metabolism and Elimination: The pegvisomant molecule contains covalently bound polyethylene glycol polymers in order to reduce the clearance rate. Clearance of pegvisomant following multiple doses is lower than seen following a single dose. The mean total body systemic clearance of pegvisomant following multiple doses is estimated to range between 36 to 28 mL/h for subcutaneous doses ranging from 10 to 20 mg/day, respectively. Clearance of pegvisomant was found to increase with body weight. Pegvisomant is eliminated from serum with a mean half-life estimates ranging from 60 to 138 hours following either single or multiple doses. Less than 1% of administered drug is recovered in the urine over 96 hours. The elimination route of pegvisomant has not been studied in humans. - Drug Interaction Studies - In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known. - Specific Populations - No pharmacokinetic studies have been conducted in patients with renal impairment, patients with hepatic impairment, geriatric patients, or pediatric patients and the effects of race on the pharmacokinetics of pegvisomant has not been studied. No gender effect on the pharmacokinetics of pegvisomant was found in a population pharmacokinetic analysis. ## Nonclinical Toxicology - Carcinogenesis - Pegvisomant was administered subcutaneously to rats daily for 2 years at doses of 2, 8 and 20 mg/kg (about 2, 10 and 25-fold a single 20 mg dose in humans on an AUC basis). Long term treatment with pegvisomant at 8 and 20 mg/kg caused an increase in malignant fibrous histiocytoma at injection sites in males. Injection site tumors were not seen in female rats at the same doses. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections. - Mutagenesis - Pegvisomant did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration). - Impairment of Fertility - Pegvisomant was found to have no effect on fertility or reproductive performance of female rabbits at subcutaneous doses up to 10 mg/kg/day (10-fold the recommended human dose on a body surface area basis). # Clinical Studies - A total of one hundred twelve patients (63 men and 49 women) with acromegaly participated in a 12-week, randomized, double-blind, multi-center study comparing placebo and SOMAVERT. The mean ±SD age was 48±14 years, and the mean duration of acromegaly was 8±8 years. Ninety three had undergone previous pituitary surgery, of which 57 had also been treated with conventional radiation therapy. Six patients had undergone irradiation without surgery, nine had received only drug therapy, and four had received no previous therapy. At study start, the mean ± SD time since the subjects' last surgery and/or irradiation therapy, respectively, was 6.8 ± 0.93 years (n=63) and 5.6 ± 0.57 years (n=93). - Subjects were qualified for enrollment if their serum IGF-I, drawn after the required drug washout period, was ≥1.3 times the upper limit of the age-adjusted normal range. They were randomly assigned at the baseline visit to one of four treatment groups: placebo (n=32), 10 mg/day (n=26), 15 mg/day (n= 26), or 20 mg/day (n=28) of SOMAVERT subcutaneouslyIGF-I. The primary efficacy endpoint was IGF-Ipercent change in IGF-I concentrations from baseline to week 12. The three groups that received SOMAVERT showed statistically. - There were also reductions in serum levels of free IGF-I, IGFBP-3, and ALS compared with placebo at all post-baseline visits (Figure 1). - After 12 weeks of treatment, the following percentages of patients had normalized IGF-1 (Figure 2): - Table 5 shows the effect of treatment with SOMAVERT on ring size (standard jeweler's sizes converted to a numeric score ranging from 1 to 63), and on signs and symptoms of acromegaly. Each individual score for a sign or symptom of acromegaly (for soft-tissue swelling, arthralgia, headache, perspiration and fatigue) was based on a nine-point ordinal rating scale (0 = absent and 8 = severe and incapacitating), and the total score for signs or symptoms of acromegaly was derived from the sum of the individual scores. Mean baseline scores were as follows: ring size = 47.1; total signs and symptoms = 15.2; soft tissue swelling = 2.5; arthralgia = 3.2; headache = 2.4; perspiration = 3.3; and fatigue = 3.7. - Serum growth hormone (GH) concentrations, as measured by research assays using antibodies that do not cross-react with pegvisomant, rose within two weeks of beginning treatment with SOMAVERT. The largest increase in GH concentration was seen in patients treated with doses of SOMAVERT 20 mg/day. This effect is presumably the result of diminished inhibition of GH secretion as IGF-I levels fall. As shown in Figure 3, when patients with acromegaly were given a loading dose of SOMAVERT followed by a fixed daily dose, the rise in GH was inversely proportional to the fall in IGF-I and generally stabilized by week 2. Serum GH concentrations remained stable in patients treated with SOMAVERT for the average of 43 weeks (range, 0–82 weeks). - In the open-label extension to the clinical study, 109 subjects (including 6 new patients) with mean treatment exposure of 42.6 weeks (range 1 day – 82 weeks), 93 (85.3%) subjects had an adverse event, 16 (14.7%) had an SAE, and 4 (3.7%) discontinued due to an AE (headaches, elevated liver function tests, pancreatic cancer, and weight gain). A total of 100 (92.6%) of the 108 subjects with available IGF-I data had a normal IGF-I concentration at any visit during the study. # How Supplied - SOMAVERT (pegvisomant) is supplied in the following strengths and package configurations: - Each package of SOMAVERT also includes a single-dose vial containing Sterile Water for Injection, USP. - Storage - Prior to reconstitution, SOMAVERT should be stored in a refrigerator at 2 to 8°C (36 to 46°F). Do not freeze. ## Storage There is limited information regarding Pegvisomant Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients (and/or their caregivers) of the following information to aid in the safe and effective use of SOMAVERT: - Not to use SOMAVERT if they are allergic to SOMAVERT or anything in it. - They will need blood testing to check IGF-I levels and liver tests before and during treatment with SOMAVERT and that the dose of SOMAVERT may be changed based on the results of these tests - SOMAVERT has not been studied in pregnant women and instruct them to notify their healthcare provider as soon as they are aware that they are pregnant. - It is not known whether SOMAVERT is excreted in human milk and instruct them to notify their healthcare provider if they plan to do so. - Advise patients (and/or their caregivers) of the following adverse reactions: - The most common reported adverse reactions are injection site reaction, elevations of liver tests, pain, nausea, and diarrhea. - If they have liver test elevations they may need to have more frequent liver tests and/or discontinue SOMAVERT. Instruct patients to immediately discontinue therapy and contact their physician if they become jaundiced. - GH-secreting tumors may enlarge in people with acromegaly and that these tumors need to be watched carefully and monitored by MRI imaging. - Thickening under the skin may occur at the injection site that could lead to lumps and that switching sites may prevent or lessen this. - If they have diabetes mellitus, they may require careful monitoring and dose reductions of insulin and/or oral hypoglycemic agents while on SOMAVERT. - If they take opioids, they may need higher SOMAVERT doses to achieve appropriate IGF-I suppression. - Advise patients that SOMAVERT is supplied as lyophilized powder in different strengths of 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg in a sterile glass vial within a package also containing a single-dose flip top vial of sterile water (diluent) for injection. Advise patients that the stoppers on both vials are not made with natural rubber latex. Advise patients to follow the directions for reconstitution provided with each package including shaking may cause denaturation (destruction) of the active ingredient (therefore do not shake). - Advise patients that the package of SOMAVERT should be stored in a refrigerator 2 to 8°C (36 to 46°F) prior to use. It should NOT BE FROZEN. # Precautions with Alcohol - Alcohol-Pegvisomant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SOMAVERT® # Look-Alike Drug Names There is limited information regarding Pegvisomant Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Pegvisomant 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 Pegvisomant is a growth hormone receptor antagonist that is FDA approved for the treatment of acromegaly in patients who have had an inadequate response to surgery or radiation therapy, or for whom these therapies are not appropriate. Common adverse reactions include infection, pain, nausea, diarrhea, abnormal liver tests, flu syndrome, injection site reaction. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended loading dose of SOMAVERT is 40 mg given subcutaneously, under healthcare provider supervision. Provide proper training in subcutaneous injection technique to patients or their caregivers so they can receive once daily subcutaneous injections. On the next day following the loading dose, instruct patients or their caregivers to begin daily subcutaneous injections of 10 mg of SOMAVERT. - Titrate the dosage to normalize serum IGF-I concentrations (serum IGF-I concentrations should be measured every four to six weeks). The dosage should not be based on growth hormone (GH) concentrations or signs and symptoms of acromegaly. It is unknown whether patients who remain symptomatic while achieving normalized IGF-I concentrations would benefit from increased SOMAVERT dosage. - Increase the dosage by 5 mg increments every 4–6 weeks if IGF-I concentrations are elevated. - Decrease the dosage by 5 mg decrements every 4–6 weeks if IGF-I concentrations are below the normal range. - IGF-I levels should also be monitored when a Somavert dose given in multiple injections is converted to a single daily injection. - The recommended dosage range is between 10 to 30 mg given subcutaneously once daily and the maximum daily dosage is 30 mg given subcutaneously once daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pegvisomant in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegvisomant in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Pegvisomant in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pegvisomant in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pegvisomant in pediatric patients. # Contraindications - None. # Warnings ### Precautions - Hypoglycemia associated with GH lowering in patients with Diabetes Mellitus - GH opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity; thus, glucose tolerance may improve in some patients treated with SOMAVERT. Patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary to avoid hypoglycemia in patients with diabetes mellitus. - Liver Test Elevations - Baseline serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), and alkaline phosphatase (ALP) levels should be obtained prior to initiating therapy with SOMAVERT. Table 1 lists recommendations regarding initiation of treatment with SOMAVERT, based on the results of these liver tests (LTs). - Asymptomatic, transient elevations in transaminases up to 15 times ULN have been observed in < 2% of subjects among two open-label trials (with a total of 147 patients). These reports were not associated with an increase in bilirubin. Transaminase elevations normalized with time, most often after suspending treatment (SOMAVERT should be used in accordance with the information presented in Table 2 with respect to liver test abnormalities while on Somavert treatment). - If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction while receiving SOMAVERT, the following patient management is recommended (Table 2). - Cross-Reactivity with GH Assays - SOMAVERT has significant structural similarity to growth hormone (GH) which causes it to cross-react in commercially available GH assays. Since serum concentrations of therapeutically effective doses of SOMAVERT are generally 100 to 1000 times higher than the actual serum GH concentrations seen in patients with acromegaly, measurements of serum GH concentrations will appear falsely elevated. - Lipohypertrophy - There have been cases of lipohypertrophy in patients treated with SOMAVERT. In a double-blind, 12-week, placebo-controlled study, there was one case (1.3%) of injection site lipohypertrophy reported in a subject receiving 10 mg/day. The subject recovered while on treatment. Among two open-label trials (with a total of 147 patients), there were two subjects, both receiving 10 mg/day, who developed lipohypertrophy. One case recovered while on treatment, and one case resulted in a discontinuation of treatment. Injection sites should be rotated daily to help prevent lipohypertrophy (different area than the last injection). - Systemic Hypersensitivity - In subjects with systemic hypersensitivity reactions, caution and close monitoring should be exercised when re-initiating Somavert therapy. # Adverse Reactions ## Clinical Trials Experience - Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. - In a 12-week randomized, placebo-controlled, double-blind, fixed-dose study of SOMAVERT in subjects with acromegaly, 32 subjects received placebo and 80 subjects received SOMAVERT once daily. A total of 108 subjects (30 placebo, 78 Somavert) completed 12 weeks of study treatment. . - Overall, eight patients with acromegaly (5.3%) withdrew from pre-marketing clinical studies because of adverse events, including two patients with marked transaminase elevations, one patient with lipohypertrophy at the injection sites, and one patient with substantial weight gain. Most adverse events did not appear to be dose-dependent. Table 3 shows the incidence of adverse events that were reported in at least two patients treated with SOMAVERT and at frequencies greater than placebo during the 12-week, placebo-controlled study. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of SOMAVERT. 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. - Systemic hypersensitivity reactions including anaphylactic reactions, laryngospasm, angioedema, generalized skin reactions (rash, erythema, pruritus, urticaria) have been reported in post-marketing use. Some patients required hospitalization. Symptoms did not re-occur in all patients after re-challenge. - Registry of Patients with Acromegaly Treated with SOMAVERT - ACROSTUDY is an international observational registry that captures long term safety data in patients with acromegaly treated with SOMAVERT, as used in clinical practice. Treatment dose and schedule were at the discretion of each treating physician. Although safety monitoring as per the recommended schedule was mandatory, not all assessments were performed at all time points for every patient. Because of this, comparison of rates of adverse events to those in the original clinical trial is not appropriate. In an interim report, there were 1288 patients enrolled (mean duration of treatment 3.7 years). - At the start of SOMAVERT treatment 648 patients were on SOMAVERT monotherapy for acromegaly. Of the 454 patients who had a normal AST and ALT at baseline, 4 patients had elevated tests >3 times ULN, two of whom had elevated tests >5 times ULN. - Lipohypertrophy was reported in 6 (0.5%) patients. - MRIs were compared to any previous ones, and a change in tumor volume was reported as significant locally only if the diameter increased by more than 3 mm for microadenomas or volume increased by more than 20% for macroadenomas. All MRI changes considered significant at the local reading were reanalyzed centrally. Of the 747 patients who had a MRI reported at baseline and at least once during follow up in the study, 51 (7%) were reported to have an increase by local MRI. Of these, 16 patients (2%) had confirmation of this increase, 6 patients had a decrease, 12 had "no change"; there was 1 with insufficient data and 16 patients did not have a central MRI reading. # Drug Interactions - Insulin and/or Oral hypoglycemic Agents - After initiation of SOMAVERT, patients with acromegaly and diabetes mellitus treated with insulin and/or oral hypoglycemic agents may require dose reductions of insulin and/or oral hypoglycemic agents. - Opioids - In clinical studies, patients taking opioids often needed higher SOMAVERT doses to normalize IGF-I concentrations compared with patients not receiving opioids. The mechanism of this interaction is not known. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Early embryonic development and teratology studies were conducted in pregnant rabbits with pegvisomant at subcutaneous doses of 1, 3, and 10 mg/kg/day. There was no evidence of teratogenic effects associated with pegvisomant treatment during organogenesis. At the 10-mg/kg/day dose (10 times the maximum human therapeutic dose based on body surface area), a reproducible, slight increase in post-implantation loss was observed in both studies. Because animal reproduction studies are not always predictive of human responses, SOMAVERT 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 Pegvisomant in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Pegvisomant during labor and delivery. ### Nursing Mothers - It is not known whether pegvisomant is excreted in human milk. Because many drugs are excreted in milk, caution should be exercised when SOMAVERT is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of SOMAVERT in pediatric patients have not been established. ### Geriatic Use - Clinical studies of SOMAVERT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from 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 Pegvisomant with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pegvisomant with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Pegvisomant in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Pegvisomant in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pegvisomant in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pegvisomant in patients who are immunocompromised. # Administration and Monitoring ### Administration - Subcutaneous ### Monitoring There is limited information regarding Monitoring of Pegvisomant in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Pegvisomant in the drug label. # Overdosage ## Acute Overdose - In one reported incident of acute overdose with SOMAVERT during pre-marketing clinical studies, a patient self-administered 80 mg/day (2.7 times the maximum recommended maintenance dosage) for seven days. The patient experienced a slight increase in fatigue, had no other complaints, and demonstrated no significant clinical laboratory abnormalities. - In cases of overdose, administration of SOMAVERT should be discontinued and not resumed until IGF-I levels return to within or above the normal range. ## Chronic Overdose There is limited information regarding Chronic Overdose of Pegvisomant in the drug label. # Pharmacology ## Mechanism of Action - Pegvisomant selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction. - Inhibition of GH action results in decreased serum concentrations of IGF-I, as well as other GH-responsive serum proteins such as free IGF-I, the acid-labile subunit of IGF-I (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3). ## Structure - SOMAVERT contains pegvisomant, an analog of human growth hormone (GH) that has been structurally altered to act as a GH receptor antagonist. - Pegvisomant is a protein of recombinant DNA origin containing 191 amino acid residues to which several polyethylene glycol (PEG) polymers are covalently bound (predominantly 4 to 6 PEG/protein molecule). The molecular weight of the protein of pegvisomant is 21,998 Daltons. The molecular weight of the PEG portion of pegvisomant is approximately 5000 Daltons. The predominant molecular weights of pegvisomant are thus approximately 42,000, 47,000, and 52,000 Daltons. The schematic shows the amino acid sequence of the pegvisomant protein (PEG polymers are shown attached to the 5 most probable attachment sites). Pegvisomant is synthesized by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist. Biological potency is determined using a cell proliferation bioassay. Binding of Somavert to the GH receptor results in disruption of the proper binding of the second GH receptor with inhibition of functional receptor dimerization and subsequent intracellular signaling. - SOMAVERT for injection is supplied as a sterile, white lyophilized powder intended for subcutaneous injection after reconstitution with 1 mL of Sterile Water for Injection. SOMAVERT is available in single-dose sterile vials containing 10, 15, 20, 25 or 30 mg of pegvisomant protein (approximately 10, 15, 20, 25 and 30 U activity, respectively). Each vial 10, 15 and 20 also contains 1.36 mg of glycine, 36.0 mg of mannitol, 1.04 mg of sodium phosphate dibasic anhydrous, and 0.36 mg of sodium phosphate monobasic monohydrate. Each 25 mg vial also contains 1.7 mg of glycine, 46.1 mg of mannitol, 1.3 mg of sodium phosphate dibasic anhydrous, and 0.5 mg of sodium phosphate monobasic monohydrate. Each 30 mg vial also contains 2.1 mg of glycine, 56.5 mg of mannitol, 1.6 mg of sodium phosphate dibasic anhydrous, and 0.6 mg of sodium phosphate monobasic monohydrate. - SOMAVERT is supplied in packages that include a vial containing diluent. Sterile Water for Injection, USP, is a sterile, nonpyrogenic preparation of water for injection that contains no bacteriostat, antimicrobial agent, or added buffer, and is supplied in single-dose containers to be used as a diluent. ## Pharmacodynamics - Pegvisomant binds selectively to the GH receptor, and does not cross-react with 19 other cytokine receptors tested, including prolactin. Pegvisomant leads to decreased serum concentrations of IGF-I, free IGF-I, ALS, and IGFBP-3. ## Pharmacokinetics - Absorption: Following subcutaneous administration, peak serum pegvisomant concentrations are not generally attained until 33 to 77 hours after administration. The mean extent of absorption of a 20-mg subcutaneous dose was 57%, relative to a 10-mg intravenous dose. - Distribution: The mean apparent volume of distribution of pegvisomant is 7 L (12% coefficient of variation), suggesting that pegvisomant does not distribute extensively into tissues. After a single subcutaneous administration, exposure (Cmax, AUC) to pegvisomant increases disproportionately with increasing dose. Mean ± SEM serum pegvisomant concentrations after 12 weeks of therapy with daily doses of 10, 15, and 20 mg were 6600 ± 1330; 16,000 ± 2200; and 27,000 ± 3100 ng/mL, respectively. - The relative bioavailability of 1 × 30 mg pegvisomant was compared to 2 × 15 mg pegvisomant in a single dose study. The AUCinf and Cmax of pegvisomant when administered as one injection of 30 mg strength was approximately 6% and 4% greater, respectively, as compared to when administered as two injections of 15 mg strengths. - Metabolism and Elimination: The pegvisomant molecule contains covalently bound polyethylene glycol polymers in order to reduce the clearance rate. Clearance of pegvisomant following multiple doses is lower than seen following a single dose. The mean total body systemic clearance of pegvisomant following multiple doses is estimated to range between 36 to 28 mL/h for subcutaneous doses ranging from 10 to 20 mg/day, respectively. Clearance of pegvisomant was found to increase with body weight. Pegvisomant is eliminated from serum with a mean half-life estimates ranging from 60 to 138 hours following either single or multiple doses. Less than 1% of administered drug is recovered in the urine over 96 hours. The elimination route of pegvisomant has not been studied in humans. - Drug Interaction Studies - In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known. - Specific Populations - No pharmacokinetic studies have been conducted in patients with renal impairment, patients with hepatic impairment, geriatric patients, or pediatric patients and the effects of race on the pharmacokinetics of pegvisomant has not been studied. No gender effect on the pharmacokinetics of pegvisomant was found in a population pharmacokinetic analysis. ## Nonclinical Toxicology - Carcinogenesis - Pegvisomant was administered subcutaneously to rats daily for 2 years at doses of 2, 8 and 20 mg/kg (about 2, 10 and 25-fold a single 20 mg dose in humans on an AUC basis). Long term treatment with pegvisomant at 8 and 20 mg/kg caused an increase in malignant fibrous histiocytoma at injection sites in males. Injection site tumors were not seen in female rats at the same doses. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections. - Mutagenesis - Pegvisomant did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration). - Impairment of Fertility - Pegvisomant was found to have no effect on fertility or reproductive performance of female rabbits at subcutaneous doses up to 10 mg/kg/day (10-fold the recommended human dose on a body surface area basis). # Clinical Studies - A total of one hundred twelve patients (63 men and 49 women) with acromegaly participated in a 12-week, randomized, double-blind, multi-center study comparing placebo and SOMAVERT. The mean ±SD age was 48±14 years, and the mean duration of acromegaly was 8±8 years. Ninety three had undergone previous pituitary surgery, of which 57 had also been treated with conventional radiation therapy. Six patients had undergone irradiation without surgery, nine had received only drug therapy, and four had received no previous therapy. At study start, the mean ± SD time since the subjects' last surgery and/or irradiation therapy, respectively, was 6.8 ± 0.93 years (n=63) and 5.6 ± 0.57 years (n=93). - Subjects were qualified for enrollment if their serum IGF-I, drawn after the required drug washout period, was ≥1.3 times the upper limit of the age-adjusted normal range. They were randomly assigned at the baseline visit to one of four treatment groups: placebo (n=32), 10 mg/day (n=26), 15 mg/day (n= 26), or 20 mg/day (n=28) of SOMAVERT subcutaneouslyIGF-I. The primary efficacy endpoint was IGF-Ipercent change in IGF-I concentrations from baseline to week 12. The three groups that received SOMAVERT showed statistically. - There were also reductions in serum levels of free IGF-I, IGFBP-3, and ALS compared with placebo at all post-baseline visits (Figure 1). - After 12 weeks of treatment, the following percentages of patients had normalized IGF-1 (Figure 2): - Table 5 shows the effect of treatment with SOMAVERT on ring size (standard jeweler's sizes converted to a numeric score ranging from 1 to 63), and on signs and symptoms of acromegaly. Each individual score for a sign or symptom of acromegaly (for soft-tissue swelling, arthralgia, headache, perspiration and fatigue) was based on a nine-point ordinal rating scale (0 = absent and 8 = severe and incapacitating), and the total score for signs or symptoms of acromegaly was derived from the sum of the individual scores. Mean baseline scores were as follows: ring size = 47.1; total signs and symptoms = 15.2; soft tissue swelling = 2.5; arthralgia = 3.2; headache = 2.4; perspiration = 3.3; and fatigue = 3.7. - Serum growth hormone (GH) concentrations, as measured by research assays using antibodies that do not cross-react with pegvisomant, rose within two weeks of beginning treatment with SOMAVERT. The largest increase in GH concentration was seen in patients treated with doses of SOMAVERT 20 mg/day. This effect is presumably the result of diminished inhibition of GH secretion as IGF-I levels fall. As shown in Figure 3, when patients with acromegaly were given a loading dose of SOMAVERT followed by a fixed daily dose, the rise in GH was inversely proportional to the fall in IGF-I and generally stabilized by week 2. Serum GH concentrations remained stable in patients treated with SOMAVERT for the average of 43 weeks (range, 0–82 weeks). - In the open-label extension to the clinical study, 109 subjects (including 6 new patients) with mean treatment exposure of 42.6 weeks (range 1 day – 82 weeks), 93 (85.3%) subjects had an adverse event, 16 (14.7%) had an SAE, and 4 (3.7%) discontinued due to an AE (headaches, elevated liver function tests, pancreatic cancer, and weight gain). A total of 100 (92.6%) of the 108 subjects with available IGF-I data had a normal IGF-I concentration at any visit during the study. # How Supplied - SOMAVERT (pegvisomant) is supplied in the following strengths and package configurations: - Each package of SOMAVERT also includes a single-dose vial containing Sterile Water for Injection, USP. - Storage - Prior to reconstitution, SOMAVERT should be stored in a refrigerator at 2 to 8°C (36 to 46°F). Do not freeze. ## Storage There is limited information regarding Pegvisomant Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients (and/or their caregivers) of the following information to aid in the safe and effective use of SOMAVERT: - Not to use SOMAVERT if they are allergic to SOMAVERT or anything in it. - They will need blood testing to check IGF-I levels and liver tests before and during treatment with SOMAVERT and that the dose of SOMAVERT may be changed based on the results of these tests - SOMAVERT has not been studied in pregnant women and instruct them to notify their healthcare provider as soon as they are aware that they are pregnant. - It is not known whether SOMAVERT is excreted in human milk and instruct them to notify their healthcare provider if they plan to do so. - Advise patients (and/or their caregivers) of the following adverse reactions: - The most common reported adverse reactions are injection site reaction, elevations of liver tests, pain, nausea, and diarrhea. - If they have liver test elevations they may need to have more frequent liver tests and/or discontinue SOMAVERT. Instruct patients to immediately discontinue therapy and contact their physician if they become jaundiced. - GH-secreting tumors may enlarge in people with acromegaly and that these tumors need to be watched carefully and monitored by MRI imaging. - Thickening under the skin may occur at the injection site that could lead to lumps and that switching sites may prevent or lessen this. - If they have diabetes mellitus, they may require careful monitoring and dose reductions of insulin and/or oral hypoglycemic agents while on SOMAVERT. - If they take opioids, they may need higher SOMAVERT doses to achieve appropriate IGF-I suppression. - Advise patients that SOMAVERT is supplied as lyophilized powder in different strengths of 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg in a sterile glass vial within a package also containing a single-dose flip top vial of sterile water (diluent) for injection. Advise patients that the stoppers on both vials are not made with natural rubber latex. Advise patients to follow the directions for reconstitution provided with each package including shaking may cause denaturation (destruction) of the active ingredient (therefore do not shake). - Advise patients that the package of SOMAVERT should be stored in a refrigerator 2 to 8°C (36 to 46°F) prior to use. It should NOT BE FROZEN. # Precautions with Alcohol - Alcohol-Pegvisomant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SOMAVERT®[1] # Look-Alike Drug Names There is limited information regarding Pegvisomant Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Pegvisomant
1c30841667dd8a55b3703e8d10b0370f0be0b3f8	wikidoc	Penciclovir	Penciclovir # 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 Penciclovir is an antiviral cream that is FDA approved for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age or older. Common adverse reactions include rash,applications site reaction,hypesthesia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Penciclovir is a nucleoside analog HSV DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age or older. # Dosage - Penciclovir should be applied every 2 hours during waking hours for a period of 4 days. Treatment should be started as early as possible (i.e., during the prodrome or when lesions appear). # DOSAGE FORMS & STRENGTHS - Each gram of penciclovir contains 10 mg of penciclovir in a cream base, which is equivalent to 1% (w/w). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Penciclovir in adult patients. ### Non–Guideline-Supported Use # Indications - Indicated for the treatment of Herpes simplex. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Indications Penciclovir is a nucleoside analog HSV DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in children 12 years of age or older. # Dosage - Penciclovir should be applied every 2 hours during waking hours for a period of 4 days. Treatment should be started as early as possible (i.e., during the prodrome or when lesions appear). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Penciclovir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Penciclovir in pediatric patients. # Contraindications - penciclovir is contraindicated in patients with known hypersensitivity to the product or any of its components. # Warnings - Only for topical use of herpes labialis on the lips and face . - Penciclovir should only be used on herpes labialis on the lips and face. Because no data are available, application to human mucous membranes is not recommended. Particular care should be taken to avoid application in or near the eyes since it may cause irritation. Lesions that do not improve or that worsen on therapy should be evaluated for secondary bacterial infection. The effect of penciclovir has not been established in immunocompromised patients. # Adverse Reactions ## Clinical Trials Experience - One or more local skin reactions were reported by 3% of the patients treated with penciclovir and 4% of placebo-treated patients. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - In two double-blind, placebo-controlled trials, 1516 patients were treated with penciclovir (penciclovir cream) and 1541 with placebo. One or more local adverse reactions were reported by 3% of the patients treated with penciclovir and 4% of placebo-treated patients. The rates of reported local adverse reactions are shown in Table 1. - Two studies, enrolling 108 healthy subjects, were conducted to evaluate the dermal tolerance of 5% penciclovir cream (a 5-fold higher concentration than the commercial formulation) compared to vehicle using repeated occluded patch testing methodology. The 5% penciclovir cream induced mild erythema in approximately one-half of the subjects exposed, an irritancy profile similar to the vehicle control in terms of severity and proportion of subjects with a response. No evidence of sensitization was observed. - The following adverse reactions have been identified during post-approval use of penciclovir. 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. ## Postmarketing Experience - The following events have been identified from worldwide post-marketing use of penciclovir in treatment of recurrent herpes labialis (cold sores) in adults. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to penciclovir. - General: Headache, oral/pharyngeal edema, parosmia. - Skin: Aggravated condition, decreased therapeutic response, local edema, pain, paresthesia, pruritus, skin discoloration, and urticaria. # Drug Interactions - No drug interaction studies have been performed with DENAVIR. Due to minimal systemic absorption of DENAVIR, systemic drug interactions are unlikely. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category B Category B - There are no adequate and well-controlled studies in pregnant women. Animal Data - No adverse effects on the course and outcome of pregnancy or on fetal development were noted in rats and rabbits following the intravenous administration of penciclovir at doses of 80 and 60 mg/kg/day, respectively (estimated human equivalent doses of 13 and 18 mg/kg/day for the rat and rabbit, respectively, based on body surface area conversion; the body surface area doses being 260 and 355x the maximum recommended dose following topical application of the penciclovir cream). Because animal reproduction studies are not always predictive of human response, penciclovir should be used during pregnancy only if clearly needed. - There is no information on whether penciclovir is excreted in human milk after topical administration. However, following oral administration of famciclovir (the oral prodrug of penciclovir) to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. Therefore, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. - There are no data on the safety of penciclovir in newborns. - An open-label, uncontrolled trial with penciclovir cream 1% was conducted in 102 patients, ages 12-17 years, with recurrent herpes labialis. The frequency of adverse events was generally similar to the frequency previously reported for adult patients. Safety and effectiveness in pediatric patients less than 12 years of age have not been established. - In 74 patients ≥ 65 years of age, the adverse events profile was comparable to that observed in younger patients. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Penciclovir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Penciclovir during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Penciclovir with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Penciclovir with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Penciclovir with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Penciclovir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Penciclovir with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Penciclovir in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Penciclovir in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Penciclovir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Penciclovir in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Penciclovir in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Penciclovir in the drug label. # Overdosage - Since penciclovir is poorly absorbed following oral administration, adverse reactions related to penciclovir ingestion are unlikely. There is no information on overdose. # Pharmacology ## Mechanism of Action - The antiviral compound penciclovir has inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). In cells infected with HSV-1 or HSV-2, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1 and 20 hours in HSV-2 infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown. ## Structure - DENAVIR (penciclovir) cream 1% contains penciclovir, an antiviral agent active against herpes viruses. DENAVIR is available for topical administration as a 1% white cream. Each gram of DENAVIR contains 10 mg of penciclovir and the following inactive ingredients: cetostearyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water and white petrolatum. Figure 1: Structural Formula of Penciclovir Penciclovir is a white to pale yellow solid. At 20°C it has a solubility of 0.2 mg/mL in methanol, 1.3 mg/mL in propylene glycol, and 1.7 mg/mL in water. In aqueous buffer (pH 2) the solubility is 10.0 mg/mL. Penciclovir is not hygroscopic. Its partition coefficient in n-octanol/water at pH 7.5 is 0.024 (logP = -1.62). Chemically, penciclovir is known as 9- guanine. Its molecular formula is C10H15N5O3; its molecular weight is 253.26. It is a synthetic acyclic guanine derivative and has the following structure: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Penciclovir in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Penciclovir in the drug label. ## Nonclinical Toxicology - In clinical trials, systemic drug exposure following topical administration of penciclovir cream was negligible, as the penciclovir content of all plasma and urine samples was below the limit of assay detection (0.1 mcg/mL and 10 mcg/mL, respectively). However, for the purpose of inter-species dose comparisons presented in the following sections, an assumption of 100% absorption of penciclovir from the topically applied product has been used. Based on the use of the maximal recommended topical dose of penciclovir of 0.05 mg/kg/day and an assumption of 100% absorption, the maximum theoretical plasma AUC0-24 hrs for penciclovir is approximately 0.129 mcg.hr/mL. Carcinogenesis: Two-year carcinogenicity studies were conducted with famciclovir (the oral prodrug of penciclovir) in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in female rats of the strain used) was seen in female rats receiving 600 mg/kg/day (approximately 395x the maximum theoretical human exposure to penciclovir following application of the topical product, based on area under the plasma concentration curve comparisons ). No increases in tumor incidence were seen among male rats treated at doses up to 240 mg/kg/day (approximately 190x the maximum theoretical human AUC for penciclovir), or in male and female mice at doses up to 600 mg/kg/day (approximately 100x the maximum theoretical human AUC for penciclovir). Mutagenesis: When tested in vitro, penciclovir did not cause an increase in gene mutation in the Ames assay using multiple strains of S. typhimurium or E. coli (at up to 20,000 mcg/plate), nor did it cause an increase in unscheduled DNA repair in mammalian HeLa S3 cells (at up to 5,000 mcg/mL). However, an increase in clastogenic responses was seen with penciclovir in the L5178Y mouse lymphoma cell assay (at doses ≥1000 mcg/mL) and, in human lymphocytes incubated in vitro at doses ≥250 mcg/mL. When tested in vivo, penciclovir caused an increase in micronuclei in mouse bone marrow following the intravenous administration of doses ≥500 mg/kg (≥810x the maximum human dose, based on body surface area conversion). Impairment of Fertility: Testicular toxicity was observed in multiple animal species (rats and dogs) following repeated intravenous administration of penciclovir (160 mg/kg/day and 100 mg/kg/day, respectively, approximately 1155 and 3255x the maximum theoretical human AUC). Testicular changes seen in both species included atrophy of the seminiferous tubules and reductions in epididymal sperm counts and/or an increased incidence of sperm with abnormal morphology or reduced motility. Adverse testicular effects were related to an increasing dose or duration of exposure to penciclovir. No adverse testicular or reproductive effects (fertility and reproductive function) were observed in rats after 10 to 13 weeks dosing at 80 mg/kg/day, or testicular effects in dogs after 13 weeks dosing at 30 mg/kg/day (575 and 845x the maximum theoretical human AUC, respectively). Intravenously administered penciclovir had no effect on fertility or reproductive performance in female rats at doses of up to 80 mg/kg/day (260x the maximum human dose ). There was no evidence of any clinically significant effects on sperm count, motility or morphology in 2 placebo-controlled clinical trials of Famvir® (famciclovir , 250 mg b.i.d.; n=66) in immunocompetent men with recurrent genital herpes, when dosing and follow-up were maintained for 18 and 8 weeks, respectively (approximately 2 and 1 spermatogenic cycles in the human). # Clinical Studies - DENAVIR was studied in two double-blind, placebo (vehicle)-controlled trials for the treatment of recurrent herpes labialis in which otherwise healthy adults were randomized to either DENAVIR or placebo. Therapy was to be initiated by the subjects within 1 hour of noticing signs or symptoms and continued for 4 days, with application of study medication every 2 hours while awake. In both studies, the mean duration of lesions was approximately one-half-day shorter in the subjects treated with DENAVIR (N=1,516) as compared to subjects treated with placebo (N=1,541) (approximately 4.5 days versus 5 days, respectively). The mean duration of lesion pain was also approximately one half-day shorter in the DENAVIR group compared to the placebo group. # How Supplied There is limited information regarding Penciclovir How Supplied in the drug label. ## Storage There is limited information regarding Penciclovir Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - DENAVIR is a prescription topical cream for the treatment of cold sores (recurrent herpes labialis) that occur on the face and lips. It is not a cure for cold sores and not all patients respond to it. Do not use if you are allergic to DENAVIR (penciclovir) or any of the ingredients in DENAVIR. Before you use DENAVIR, tell your doctor if you are pregnant, planning to become pregnant, or are breast-feeding. - Wash your hands. Your face should be clean and dry. Apply a layer of DENAVIR to cover only the cold sore area or the area of tingling (or other symptoms) before the cold sore appears. Rub in the cream until it disappears. Apply the cream every 2 hours during waking hours for 4 days. Treatment should be started at the earliest sign of a cold sore (i.e. tingling, redness, itching, or bump). Wash your hands with soap and water after using DENAVIR. Store DENAVIR at room temperature between 68°F to 77°F (20ºC to 25ºC). Keep out of reach of children. - DENAVIR was well tolerated in clinical studies in patients with cold sores. Common skin-related side effects that occurred when DENAVIR was applied are application site reactions, local anesthesia, and rash. Taste perversion was also reported. # Precautions with Alcohol - Alcohol-Penciclovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DENAVIR # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Penciclovir 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 Penciclovir is an antiviral cream that is FDA approved for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age or older. Common adverse reactions include rash,applications site reaction,hypesthesia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Penciclovir is a nucleoside analog HSV DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age or older. # Dosage - Penciclovir should be applied every 2 hours during waking hours for a period of 4 days. Treatment should be started as early as possible (i.e., during the prodrome or when lesions appear). # DOSAGE FORMS & STRENGTHS - Each gram of penciclovir contains 10 mg of penciclovir in a cream base, which is equivalent to 1% (w/w). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Penciclovir in adult patients. ### Non–Guideline-Supported Use # Indications - Indicated for the treatment of Herpes simplex. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) # Indications Penciclovir is a nucleoside analog HSV DNA polymerase inhibitor indicated for the treatment of recurrent herpes labialis (cold sores) in children 12 years of age or older. # Dosage - Penciclovir should be applied every 2 hours during waking hours for a period of 4 days. Treatment should be started as early as possible (i.e., during the prodrome or when lesions appear). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Penciclovir in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Penciclovir in pediatric patients. # Contraindications - penciclovir is contraindicated in patients with known hypersensitivity to the product or any of its components. # Warnings - Only for topical use of herpes labialis on the lips and face . - Penciclovir should only be used on herpes labialis on the lips and face. Because no data are available, application to human mucous membranes is not recommended. Particular care should be taken to avoid application in or near the eyes since it may cause irritation. Lesions that do not improve or that worsen on therapy should be evaluated for secondary bacterial infection. The effect of penciclovir has not been established in immunocompromised patients. # Adverse Reactions ## Clinical Trials Experience - One or more local skin reactions were reported by 3% of the patients treated with penciclovir and 4% of placebo-treated patients. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. - In two double-blind, placebo-controlled trials, 1516 patients were treated with penciclovir (penciclovir cream) and 1541 with placebo. One or more local adverse reactions were reported by 3% of the patients treated with penciclovir and 4% of placebo-treated patients. The rates of reported local adverse reactions are shown in Table 1. - Two studies, enrolling 108 healthy subjects, were conducted to evaluate the dermal tolerance of 5% penciclovir cream (a 5-fold higher concentration than the commercial formulation) compared to vehicle using repeated occluded patch testing methodology. The 5% penciclovir cream induced mild erythema in approximately one-half of the subjects exposed, an irritancy profile similar to the vehicle control in terms of severity and proportion of subjects with a response. No evidence of sensitization was observed. - The following adverse reactions have been identified during post-approval use of penciclovir. 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. ## Postmarketing Experience - The following events have been identified from worldwide post-marketing use of penciclovir in treatment of recurrent herpes labialis (cold sores) in adults. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to penciclovir. - General: Headache, oral/pharyngeal edema, parosmia. - Skin: Aggravated condition, decreased therapeutic response, local edema, pain, paresthesia, pruritus, skin discoloration, and urticaria. # Drug Interactions - No drug interaction studies have been performed with DENAVIR. Due to minimal systemic absorption of DENAVIR, systemic drug interactions are unlikely. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category B Category B - There are no adequate and well-controlled studies in pregnant women. Animal Data - No adverse effects on the course and outcome of pregnancy or on fetal development were noted in rats and rabbits following the intravenous administration of penciclovir at doses of 80 and 60 mg/kg/day, respectively (estimated human equivalent doses of 13 and 18 mg/kg/day for the rat and rabbit, respectively, based on body surface area conversion; the body surface area doses being 260 and 355x the maximum recommended dose following topical application of the penciclovir cream). Because animal reproduction studies are not always predictive of human response, penciclovir should be used during pregnancy only if clearly needed. - There is no information on whether penciclovir is excreted in human milk after topical administration. However, following oral administration of famciclovir (the oral prodrug of penciclovir) to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. Therefore, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. - There are no data on the safety of penciclovir in newborns. - An open-label, uncontrolled trial with penciclovir cream 1% was conducted in 102 patients, ages 12-17 years, with recurrent herpes labialis. The frequency of adverse events was generally similar to the frequency previously reported for adult patients. Safety and effectiveness in pediatric patients less than 12 years of age have not been established. - In 74 patients ≥ 65 years of age, the adverse events profile was comparable to that observed in younger patients. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Penciclovir in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Penciclovir during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Penciclovir with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Penciclovir with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Penciclovir with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Penciclovir with respect to specific gender populations. ### Race There is no FDA guidance on the use of Penciclovir with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Penciclovir in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Penciclovir in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Penciclovir in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Penciclovir in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Penciclovir in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Penciclovir in the drug label. # Overdosage - Since penciclovir is poorly absorbed following oral administration, adverse reactions related to penciclovir ingestion are unlikely. There is no information on overdose. # Pharmacology ## Mechanism of Action - The antiviral compound penciclovir has inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). In cells infected with HSV-1 or HSV-2, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1 and 20 hours in HSV-2 infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown. ## Structure - DENAVIR (penciclovir) cream 1% contains penciclovir, an antiviral agent active against herpes viruses. DENAVIR is available for topical administration as a 1% white cream. Each gram of DENAVIR contains 10 mg of penciclovir and the following inactive ingredients: cetostearyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water and white petrolatum. Figure 1: Structural Formula of Penciclovir Penciclovir is a white to pale yellow solid. At 20°C it has a solubility of 0.2 mg/mL in methanol, 1.3 mg/mL in propylene glycol, and 1.7 mg/mL in water. In aqueous buffer (pH 2) the solubility is 10.0 mg/mL. Penciclovir is not hygroscopic. Its partition coefficient in n-octanol/water at pH 7.5 is 0.024 (logP = -1.62). Chemically, penciclovir is known as 9-[4-hydroxy-3-(hydroxymethyl)butyl] guanine. Its molecular formula is C10H15N5O3; its molecular weight is 253.26. It is a synthetic acyclic guanine derivative and has the following structure: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Penciclovir in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Penciclovir in the drug label. ## Nonclinical Toxicology - In clinical trials, systemic drug exposure following topical administration of penciclovir cream was negligible, as the penciclovir content of all plasma and urine samples was below the limit of assay detection (0.1 mcg/mL and 10 mcg/mL, respectively). However, for the purpose of inter-species dose comparisons presented in the following sections, an assumption of 100% absorption of penciclovir from the topically applied product has been used. Based on the use of the maximal recommended topical dose of penciclovir of 0.05 mg/kg/day and an assumption of 100% absorption, the maximum theoretical plasma AUC0-24 hrs for penciclovir is approximately 0.129 mcg.hr/mL. Carcinogenesis: Two-year carcinogenicity studies were conducted with famciclovir (the oral prodrug of penciclovir) in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in female rats of the strain used) was seen in female rats receiving 600 mg/kg/day (approximately 395x the maximum theoretical human exposure to penciclovir following application of the topical product, based on area under the plasma concentration curve comparisons [24 hr. AUC]). No increases in tumor incidence were seen among male rats treated at doses up to 240 mg/kg/day (approximately 190x the maximum theoretical human AUC for penciclovir), or in male and female mice at doses up to 600 mg/kg/day (approximately 100x the maximum theoretical human AUC for penciclovir). Mutagenesis: When tested in vitro, penciclovir did not cause an increase in gene mutation in the Ames assay using multiple strains of S. typhimurium or E. coli (at up to 20,000 mcg/plate), nor did it cause an increase in unscheduled DNA repair in mammalian HeLa S3 cells (at up to 5,000 mcg/mL). However, an increase in clastogenic responses was seen with penciclovir in the L5178Y mouse lymphoma cell assay (at doses ≥1000 mcg/mL) and, in human lymphocytes incubated in vitro at doses ≥250 mcg/mL. When tested in vivo, penciclovir caused an increase in micronuclei in mouse bone marrow following the intravenous administration of doses ≥500 mg/kg (≥810x the maximum human dose, based on body surface area conversion). Impairment of Fertility: Testicular toxicity was observed in multiple animal species (rats and dogs) following repeated intravenous administration of penciclovir (160 mg/kg/day and 100 mg/kg/day, respectively, approximately 1155 and 3255x the maximum theoretical human AUC). Testicular changes seen in both species included atrophy of the seminiferous tubules and reductions in epididymal sperm counts and/or an increased incidence of sperm with abnormal morphology or reduced motility. Adverse testicular effects were related to an increasing dose or duration of exposure to penciclovir. No adverse testicular or reproductive effects (fertility and reproductive function) were observed in rats after 10 to 13 weeks dosing at 80 mg/kg/day, or testicular effects in dogs after 13 weeks dosing at 30 mg/kg/day (575 and 845x the maximum theoretical human AUC, respectively). Intravenously administered penciclovir had no effect on fertility or reproductive performance in female rats at doses of up to 80 mg/kg/day (260x the maximum human dose [BSA]). There was no evidence of any clinically significant effects on sperm count, motility or morphology in 2 placebo-controlled clinical trials of Famvir® (famciclovir [the oral prodrug of penciclovir], 250 mg b.i.d.; n=66) in immunocompetent men with recurrent genital herpes, when dosing and follow-up were maintained for 18 and 8 weeks, respectively (approximately 2 and 1 spermatogenic cycles in the human). # Clinical Studies - DENAVIR was studied in two double-blind, placebo (vehicle)-controlled trials for the treatment of recurrent herpes labialis in which otherwise healthy adults were randomized to either DENAVIR or placebo. Therapy was to be initiated by the subjects within 1 hour of noticing signs or symptoms and continued for 4 days, with application of study medication every 2 hours while awake. In both studies, the mean duration of lesions was approximately one-half-day shorter in the subjects treated with DENAVIR (N=1,516) as compared to subjects treated with placebo (N=1,541) (approximately 4.5 days versus 5 days, respectively). The mean duration of lesion pain was also approximately one half-day shorter in the DENAVIR group compared to the placebo group. # How Supplied There is limited information regarding Penciclovir How Supplied in the drug label. ## Storage There is limited information regarding Penciclovir Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - DENAVIR is a prescription topical cream for the treatment of cold sores (recurrent herpes labialis) that occur on the face and lips. It is not a cure for cold sores and not all patients respond to it. Do not use if you are allergic to DENAVIR (penciclovir) or any of the ingredients in DENAVIR. Before you use DENAVIR, tell your doctor if you are pregnant, planning to become pregnant, or are breast-feeding. - Wash your hands. Your face should be clean and dry. Apply a layer of DENAVIR to cover only the cold sore area or the area of tingling (or other symptoms) before the cold sore appears. Rub in the cream until it disappears. Apply the cream every 2 hours during waking hours for 4 days. Treatment should be started at the earliest sign of a cold sore (i.e. tingling, redness, itching, or bump). Wash your hands with soap and water after using DENAVIR. Store DENAVIR at room temperature between 68°F to 77°F (20ºC to 25ºC). Keep out of reach of children. - DENAVIR was well tolerated in clinical studies in patients with cold sores. Common skin-related side effects that occurred when DENAVIR was applied are application site reactions, local anesthesia, and rash. Taste perversion was also reported. # Precautions with Alcohol - Alcohol-Penciclovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DENAVIR # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Penciclovir
30da5979035c9381e170c94c942dd72c67719ee2	wikidoc	Penicillium	Penicillium Penicillium is a genus of ascomyceteous fungi that includes: - Penicillium bilaiae, which is an agricultural inoculant. - Penicillium camemberti, which is used in the production of Camembert and Brie cheeses. - Penicillium candida, which is used in making Brie and Camembert. - Penicillium glaucum, which is used in making Gorgonzola cheese. - Penicillium marneffei, a thermally dimorphic species endemic in Southeast Asia, which presents a threat of systemic infection to AIDS patients. - Penicillium chrysogenum (previously known as Penicillium notatum), which produces the antibiotic penicillin. - Penicillium purpurogenum - Penicillium roqueforti, which is used in making Roquefort, Danish Blue cheese and also recently Gorgonzola. - Penicillium stoloniferum - Penicillium viridicatum produces ochratoxin - Penicillium verrucosum produces ochratoxin A bg:Хлебен мухъл ca:Penicillium de:Penicillium it:Penicillium nl:Penicillium simple:Penicillium	Penicillium Penicillium is a genus of ascomyceteous fungi that includes: - Penicillium bilaiae, which is an agricultural inoculant. - Penicillium camemberti, which is used in the production of Camembert and Brie cheeses. - Penicillium candida, which is used in making Brie and Camembert. - Penicillium glaucum, which is used in making Gorgonzola cheese. - Penicillium marneffei, a thermally dimorphic species endemic in Southeast Asia, which presents a threat of systemic infection to AIDS patients. - Penicillium chrysogenum (previously known as Penicillium notatum), which produces the antibiotic penicillin. - Penicillium purpurogenum - Penicillium roqueforti, which is used in making Roquefort, Danish Blue cheese and also recently Gorgonzola. - Penicillium stoloniferum - Penicillium viridicatum produces ochratoxin - Penicillium verrucosum produces ochratoxin A bg:Хлебен мухъл ca:Penicillium de:Penicillium it:Penicillium nl:Penicillium simple:Penicillium Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Penicillium
fd029175413dbabec2dc8bcc7fabbc3adf24b4a4	wikidoc	Penta Water	Penta Water Penta® Water (sometimes called AquaRx™ Water) is a commercially sold brand of bottled water that is claimed by its manufacturer to be structurally different from 'normal' water. It is advertised as the 'ultimate bottled water' on Penta's official website. It is manufactured and distributed by sister companies Bio Hydration Research Lab and AquaPhotonics. Penta's name derives from its association with five-molecule clusters of water. In particular, Bio Hydration Research Labs states that their 'Penta process' of subjecting water to high energy sound waves, creating sonoluminescence, reduces the average size of the water clusters present in liquid water. This supposedly makes it easier for water molecules to pass through cell membranes. It is further claimed that water so treated improves the 'survivability' of cells. In 2003, Penta became the best selling bottled water in American health food stores. The various claims made by Penta are classed as pseudoscience by scientists , as they have never been scientifically established. Penta has commissioned studies which appear to validate a few of their claims, but none of these studies was published in mainstream peer-reviewed scientific literature. These studies also suffer from major experimental design flaws. Penta is a registered trademark of Aquaphotonics, Inc. In physical chemistry, the commonly used (non-trademarked) term for a cluster of five water molecules is the water pentamer. # Claims made by Penta This is a list of past specific claims for Penta found on websites once maintained and owned by Penta/Bio Hydration Research Labs/Aquaphotonics and targeting the U.S. market. Current claims are solely for "higher purity". - Penta Water contains water clusters of fewer molecules than normal water. - Penta Water has a 30% reduction in cluster size. * - Penta Water enters cells 14% faster than normal water. * - Cells cultured in Penta Water survive 266% longer than in normal water. - Cells cultured in Penta Water have a 3× decrease in acidity compared to cells cultured in distilled water. - Athletic performance measurably improves after consumption of Penta Water. - Penta Water has a higher boiling point than normal water and this is not due to dissolved impurities. * - Penta is easier to drink than normal water. - Penta aids in weight loss. * - Penta is the purest bottled water on the market. - In vitro, Penta dissolves kidney stones faster than lab water. - DNA mutation is 271% greater in distilled water than in Penta Water.* - Penta is 16.7× faster water. * - "..healthier skin, hair, and joints; stronger immune system; faster recovery from surgery or physical activity; and reduced hypertension and cholesterol." Bill Holloway, Penta CEO. - Increased energy and mental alertness. - Helps houseplants grow. * - Penta has helped clear up skin problems. * - Protein crystals grown in Penta have a different structure. - Featured testimonial on Penta website claims Penta can help with fibromyalgia, lupus, arthritis, or chronic fatigue syndrome. - Featured testimonial on Penta website claims Penta can help with diabetes. - Penta acts like an energy drink. * - It has helped to reduce the side effects of chemotherapy treatment for cancer. * - Adding Penta to Pap smear test samples increases the accuracy of cervical cancer screenings. - Scavenges free radicals. - Enhances absorption of moisturiser cream onto skin. * All of the entries marked by an asterisk (*) were found on the UK Penta web pages which have now been taken offline due to Penta being forced to cease trading in Britain. Many of these specific claims are criticized on a skeptic's website . The claims have also been discussed in a commentary by James Randi and in Ben Goldacre's Bad Science column in The Guardian (for which, it is claimed, he received hate mail). # Reliability of claims The Penta Water website claims that a paper has appeared in a peer-reviewed journal validating one of their claims that Penta Water contains smaller clusters (30% smaller) than 'normal' bulk liquid water: Study of cluster molecular structures in various types of liquid water by using spontaneous Raman Spectroscopy, A. F. Bunkin, A. A. Nyrmatov, and S. M. Pershin, Physics of Vibrations, Volume 10 Number 2, 2002. Physics of Vibrations changed its name to Physics of Wave Phenomena in 2003 and is a Russian physics journal published by Allerton Press . The paper in question discusses differences in the Raman Spectra between Penta water and normal lab water. There is no discussion of any possible health benefits. At the time of writing (March 2005), there are no peer-reviewed papers in the scientific literature showing any health benefits of Penta water. In fact, the Penta Water web site makes several claims from studies that "are pending publication". Other such claims, from other "pending publications" have disappeared from their site. The claim that smaller water clusters are present in Penta Water appears to mean that there are fewer molecules in each cluster, not that the actual physical size of a particular molecule is smaller. No explanation has been given for a proposed mechanism that creates these smaller clusters. Apart from the aforementioned interpretation of Raman Spectra results, there is no published evidence showing a reduction in the average number of monomers per cluster. In any case, claims for smaller clusters seem to be irrelevant to Penta's claim for 'better hydration', because water molecules only enter through aquaporin cell-membrane channels one at a time. This point was made by Oxford University professor Robert Williams in an article by Mark Henderson in The Times on 7th February 2004) There has been no replication of these results or further evidence published in peer-reviewed scientific journals to support the claims of Penta/Bio Hydration Research Labs. Also, there is no known mechanism by which normal liquid water can be 'restructured'. Penta Water appears therefore to be pseudoscience. If Penta's claims were found to be true, then noted skeptic James Randi has stated that they would be eligible for the Randi Prize of one million dollars for "anyone who is able to show evidence of any paranormal, supernatural, or occult power or event under test conditions agreed to by both parties". In July 2001, Penta agreed to submit to the Randi Prize, but later withdrew. In April 2005, Mark Fairhead, director of Penta UK wrote that they were considering re-applying. In addition to the Randi Prize, published evidence in peer reviewed mainstream scientific journals would make it likely that Penta would win the Nobel Prize for being able to demonstrate the restructuring of water and its improved health benefits. An oft-used criticism of skeptics' literature such as Randi's website is that the skeptics are apparently dismissing a subject without personally carrying out scientific tests to see if the claims are true. However, the onus of proof is generally agreed to be upon the people or company making extraordinary claims and not the skeptics to try and duplicate every experiment. In general, skeptics such as Randi tend to point out where the claims disagree with well-known mainstream scientific principles and this does not by itself require any further testing on the part of the skeptic. In 2001 , the James Randi Educational Foundation offered to arrange for independent tests of Penta's claims with protocols to be agreed upon by the foundation and Penta. It is a matter of record that Penta have yet to accept the challenge. # Mainstream science It is important to note that the study of water clusters is real science. There is much spectroscopic evidence to show beyond the doubt of most physical chemists that water clusters exist under appropriate (gas-phase) conditions (see for example , ). Furthermore, there are many scientific papers published in major peer-reviewed journals, hypothesizing that bulk-liquid water can be thought of as conglomerates of macroscopic numbers of 'flickering' water clusters. However, there is not evidence yet of 'restructuring' on time-scales greater than tiny fractions of a second. On the Penta Water links page was included a link to a Cambridge University science group under the heading of "partnerships". In fact, this is false and the Cambridge science group has no association with Penta . There was also a similar link to Johns Hopkins University. Again, there is no evidence of a partnership between Penta and Johns Hopkins. (Note, as of March 23rd 2005 these links have been removed from their website, though it is still possible to view an archived copy of the links page.) Up until Penta UK ceased trading, the now offline British Penta webpages continued to link to a Cambridge water-cluster science page even though the page in question carries the clear and prominent disclaimer: "PLEASE NOTE THAT LINKS FROM ANY COMMERCIAL ORGANISATIONS TO THIS SITE ARE ENTIRELY UNAUTHORISED AND UNWELCOME. THE MAINTAINERS OF THIS SITE HAVE NO CONNECTIONS WITH ANY SUCH COMPANIES OR THEIR PRODUCTS." Penta sister company AquaPhotonics claimed in a May 2005 Press release that Dr. Nikolai Tankovich, CEO of AquaPhotonics, had "joined the Scientific Advisory Board of Procter & Gamble". A reader of the James Randi webpage attempted to verify the accuracy of the press release with Procter & Gamble. A Procter & Gamble spokesperson replied: "We are unaware of any advisory board Dr. Nikolai Tankovich is on with P&G" A few days later the press release was removed by AquaPhotonics from their news page. . Penta has provided £15,000 in research funding to the British Brunel University in 2003 for a research study The ergogenic effects of Penta Water . Dr. Andy Sparks and Prof. Don MacLaren from the Research Institute for Sport and Exercise Sciences in Liverpool John Moores University have also carried out research for Penta. (Their unpublished paper, Simulated soccer study is available from the AquaPhotonics website. ) # Response to criticism In response to critical articles written by the British Guardian journalist, Ben Goldacre, in his Bad Science column, a Penta employee sent Goldacre the text message: An apology, on behalf of Penta, from publicist Max Clifford followed. Goldacre contacted the British police in response to the threat. In correspondence with James Randi , Penta CEO Bill Holloway wrote the following in response to Randi's request for Penta to follow their agreed upon protocol for application of the Randi Prize The (now defunct) official British Penta website had a page devoted to critical articles in the press in which they nominated newspapers and other news organizations for their 'Dunce Awards'. On this page, they respond to criticism with the following: On this page Penta also states At the time of writing (2005) these studies have not been published in peer reviewed journals, though the British Penta website did post quotes from researchers in two British sports research groups indicating that the studies were successful at demonstrating a performance improvement for athletes using Penta . Details of these studies were scheduled to appear at the end of February 2005, but as of June 2006, they still have yet to appear. # No longer sold in the United Kingdom In March 2005 the British Advertising Standards Authority (ASA) ruled on the accuracy of a Penta Water leaflet. The complaint was upheld. Among their findings the ASA wrote that As a result of these findings, the ASA ruled that The ASA is a regulatory authority set up as an independent body by the British advertising industry. It does not have any statutory power, but it is usually able to enforce correct observance of advertising codes in Britain. Penta has now been forced to cease trading in the United Kingdom. It was reported in a commentary by James Randi that The British Penta distributors have also apparently closed their Team Penta website, though they have left the message that The Guardian's Bad Science column has also covered this event . # Criticism of specific claims ## Boiling point It is often mentioned that Penta has a higher boiling point than liquid water. This claim appears to be based on a research report paid for by Penta on Measurements of the Boiling Temperature of Penta ® Water. In the study, which was not double blinded, the researchers found a 0.043 °C increase in the boiling temperature of the Penta Water samples (relative to deionized water) and wrote In this study, neither water was found to have exactly the expected boiling point of 100 °C, which the researchers attributed to a probable error in the calibration of the thermometer. Thus, the experiment was only able to measure the relative boiling points of the two waters. The study was further discussed in an article in The Guardian Bad Science column . One specific criticism of the experiment was that the quoted boiling temperature of the Penta sample appeared - contrary to thermodynamics - to be greater than that of the water jacket heating it. Another was that the thermometer resolution was very likely insufficient to resolve the claimed 0.043 °C temperature difference, but this point has been disputed. According to its makers , the Hart 1504 used has an accuracy of ±0.003 °C (at 0-25 °C); the accuracy of ±0.02 °C. quoted by The Guardian may refer to the Hart 1502 or may be using the charted accuracy at 100°C as listed on the chart here. Note that similar claims of a raised boiling point have also been made for the now discredited polywater, which was investigated in the 1960s and was also proposed to be a new structure of water. In the case of polywater, the elevated boiling point was eventually shown to be a result of dissolved impurities. ## Structure The consensus in mainstream science (arrived at through numerous experiments and accumulated knowledge) is that water does not have a structural memory of the sort claimed by Penta or in homeopathy. Even if smaller-than-average clusters are being formed by sound waves in the so-called "Penta-process", these structures would almost instantly disappear once the waves are stopped . It is worth noting that the picture of five water molecules on every Penta Water bottle label does not represent a low-energy structure of the water pentamer since none of the waters are forming hydrogen bonds. If molecules were placed in this geometry they would quickly repel each-other (whilst quickly reorienting) due to the mutual electrostatic repulsion of the negatively charged oxygens. However this structure might occur around a positively charged ion such as Na+. The accepted lowest energy global minimum structure for five water molecules is shown in the accompanying figure. Note that this structure contains five hydrogen bonds (dashed red lines), whilst the Pentamer logo on the Penta bottle contains no hydrogen bonds. Supporters of Penta have claimed that the structure depicted on the Penta water labels should be regarded as only a convenient logo and not a scientific claim. If this distinction exists, it is not made clear on the label. However, there are many examples of non-scientific depictions of molecules on the labels of a variety of household products. ## Hydration It is difficult to determine whether Penta is consistently claiming that their product offers improved hydration. In the past, the official Penta website made specific claims on its What makes Penta unique? page, section heading Proven More Effective Hydration, that the altered structure speeded cell hydration via aquaporin transport. For instance, the page for Jun 04 2003 features a diagram showing stylised pentamers entering a cell and states Currently on the same page, this is apparently contradicted by the text Confusingly, the (now defunct) equivalent page of the British Penta website features the diagram and the earlier more explicit claims It is unclear as to why water more easily penetrating cell membranes is nessesarily a good thing. Cells maintain themselves in a careful homeostasis. Water that behaved in the way claimed of penta-water would probably be poisonous, rather than healthful. # Peer-reviewed papers quoted by Penta ## Raman spectroscopy This subsection concerns the (published and peer-reviewed) paper. In this paper the authors examine a peak in the Raman spectrum at a wavelength around 650 nm for various liquid water samples. The samples include several types of distilled water and Penta Water. The authors claim that the relative position and width of the peak for Penta compared to other waters is evidence for Penta being a new structure of water. Graphs of the results can be found at a Bio Hydration Research Labs website . From these, it is seen that the difference between the two distilled water samples Distilled 1 and Distilled 2 is similar in size to the difference between either and the Penta sample. The authors do not provide an explanation as to why only the Penta to Distilled 1 /Distilled 2 difference is evidence for a new structure of water, whilst the difference between the distilled waters is presumably due to impurities. However, supporters of Penta argue that data showing peaks for Penta samples at >658.8 nm, compared to the other samples are below 658.4 nm is a significant and meaningful difference. The authors also find that the effective cluster temperature of the Penta water samples are 12 °C higher than the control samples. In other words, they observe that the Penta water samples behave similarly to normal water that is heated by an extra 12 degrees (though the actual measurable temperature of the water remains the same). This appears to be inconsistent with the claimed higher boiling point of Penta Water. (If normal water boils at 100 °C, then one might expect Penta water to boil at 88 °C due to its claimed effective higher temperature.) These were not double blind measurements. The Penta water samples were provided by Bio Hydration Research Labs. Supporters of Penta point out that the vast majority of sample analysis experiments are not performed double-blinded. However, it should be noted that double-blinded experiments are generally to be preferred in cases where the differences between samples is small, and in the cases where any difference between samples is likely to prove highly controversial. This paper is available from the AquaPhotonics website. ## COM crystals This subsection concerns the (published and peer-reviewed) paper In this paper, the authors find that calcium oxalate crystals (which can form kidney stones) dissolve 3X faster in samples of Penta compared to the rate in distilled water. The rate in Penta water is found to be 0.47 nanometers per second, which is roughly 0.04 mm per day. It would take approximately 4 months at this rate to dissolve a 10 mm stone. These were not double blind measurements. # Associated organizations - Bio Hydration Research Labs manufactures Penta water. They are located in Carlsbad California. The CEO is Bill Holloway. G. R. Holloway, wife of Bill Holloway is the President and co-founder. Their son, Michael Holloway is also a co-founder and sits on the board of directors. Others on the board include Dr Nikolai I. Tankovich and David Cheatham. - AquaPhotonics is a biotechnology company in Carlsbad California that makes extensive use of Penta in their products and appears to be a sister company to Bio Hydration Research Labs. Dr Nikolai I. Tankovich is the CEO and David Cheatham is the president. Bill Holloway, G. R. Holloway and Tommy Thompson (who was the Secretary for Health and Human Services for President George W. Bush) sit on the board of directors. - Diamics is a company dealing in medical diagnostics technology that has distribution rights for AquaRX (or Penta) water in diagnostic markets, claiming that its properties give cell samples "longer shelf life, better maintenance of cellular structure and improved performance in molecular assays". # Positive reviews Penta Water has received much positive publicity in the press and has received positive reviews from health-oriented websites (e.g. ). There are also numerous testimonials from the public and endorsements from celebrities (e.g. Sting and Farrah Fawcett ) who have stated that they have enjoyed or benefitted from drinking Penta Water (though there is no independent verification of these endorsements). The official Penta site also carries many testimonials from successful sports-people including Olympic contestants and medalists. Testimonials such as the above are known by scientists as anecdotal evidence. Mainstream science generally places little weight on anecdotal evidence because it is known that people can be (unintentionally) unreliable witnesses of subtle phenomena, such as health improvements after taking a proposed cure. Furthermore, Penta's stated promotional system ("Initially a trial sample of Penta will be sent to select teams or sports people. Following a successful trial a special rate is offered.") could be interpreted as targeting athletes who are already successful or improving. Penta is a sponsor of the National Fibromyalgia Association (U.S.) website and is endorsed by them for being the "purest known bottled water on the market" . Donald MacLaren, in the physiology department of Liverpool John Moores University in Britain is doing research for Penta and was quoted on their now defunct website as stating These studies have yet to be published in a peer-reviewed academic journal. Jorge Cruise, author of The 3-Hour Diet has recommended Penta water as "one of the keys to weight loss" , even though there have been no peer-reviewed studies in any academic journal that show this.	Penta Water Penta® Water (sometimes called AquaRx™ Water) is a commercially sold brand of bottled water that is claimed by its manufacturer to be structurally different from 'normal' water. It is advertised as the 'ultimate bottled water' on Penta's official website.[1] It is manufactured and distributed by sister companies Bio Hydration Research Lab and AquaPhotonics. Penta's name derives from its association with five-molecule clusters of water. In particular, Bio Hydration Research Labs states that their 'Penta process' of subjecting water to high energy sound waves, creating sonoluminescence, reduces the average size of the water clusters present in liquid water.[2][3] This supposedly makes it easier for water molecules to pass through cell membranes. It is further claimed that water so treated improves the 'survivability' of cells. In 2003, Penta became the best selling bottled water in American health food stores.[4] The various claims made by Penta are classed as pseudoscience by scientists [5], as they have never been scientifically established. Penta has commissioned studies which appear to validate a few of their claims, but none of these studies was published in mainstream peer-reviewed scientific literature. These studies also suffer from major experimental design flaws. Penta is a registered trademark of Aquaphotonics, Inc. In physical chemistry, the commonly used (non-trademarked) term for a cluster of five water molecules is the water pentamer. # Claims made by Penta This is a list of past specific claims for Penta found on websites once maintained and owned by Penta/Bio Hydration Research Labs/Aquaphotonics and targeting the U.S. market. Current claims are solely for "higher purity". - Penta Water contains water clusters of fewer molecules than normal water. [6] - Penta Water has a 30% reduction in cluster size. * - Penta Water enters cells 14% faster than normal water. * - Cells cultured in Penta Water survive 266% longer than in normal water. [6] - Cells cultured in Penta Water have a 3× decrease in acidity compared to cells cultured in distilled water.[7] - Athletic performance measurably improves after consumption of Penta Water. [6] - Penta Water has a higher boiling point than normal water and this is not due to dissolved impurities. * - Penta is easier to drink than normal water. [6] - Penta aids in weight loss. * - Penta is the purest bottled water on the market.[8] - In vitro, Penta dissolves kidney stones faster than lab water.[8] - DNA mutation is 271% greater in distilled water than in Penta Water.[7]* - Penta is 16.7× faster water. * - "..healthier skin, hair, and joints; stronger immune system; faster recovery from surgery or physical activity; and reduced hypertension and cholesterol." Bill Holloway, Penta CEO.[9] - Increased energy and mental alertness.[9] - Helps houseplants grow. * - Penta has helped clear up skin problems. * - Protein crystals grown in Penta have a different structure.[10] - Featured testimonial on Penta website claims Penta can help with fibromyalgia, lupus, arthritis, or chronic fatigue syndrome.[11] - Featured testimonial on Penta website claims Penta can help with diabetes.[12] - Penta acts like an energy drink. * - It has helped to reduce the side effects of chemotherapy treatment for cancer. * - Adding Penta to Pap smear test samples increases the accuracy of cervical cancer screenings.[13] - Scavenges free radicals.[14] - Enhances absorption of moisturiser cream onto skin. * All of the entries marked by an asterisk (*) were found on the UK Penta web pages which have now been taken offline due to Penta being forced to cease trading in Britain. Many of these specific claims are criticized on a skeptic's website [1]. The claims have also been discussed in a commentary by James Randi [2] and in Ben Goldacre's Bad Science column in The Guardian (for which, it is claimed, he received hate mail). # Reliability of claims The Penta Water website claims [7] that a paper has appeared in a peer-reviewed journal validating one of their claims that Penta Water contains smaller clusters (30% smaller) than 'normal' bulk liquid water: Study of cluster molecular structures in various types of liquid water by using spontaneous Raman Spectroscopy, A. F. Bunkin, A. A. Nyrmatov, and S. M. Pershin, Physics of Vibrations, Volume 10 Number 2, 2002. Physics of Vibrations changed its name to Physics of Wave Phenomena in 2003 and is a Russian physics journal published by Allerton Press [3]. The paper in question discusses differences in the Raman Spectra between Penta water and normal lab water. There is no discussion of any possible health benefits. At the time of writing (March 2005), there are no peer-reviewed papers in the scientific literature showing any health benefits of Penta water. In fact, the Penta Water web site makes several claims from studies that "are pending publication". Other such claims, from other "pending publications" have disappeared from their site. The claim that smaller water clusters are present in Penta Water appears to mean that there are fewer molecules in each cluster, not that the actual physical size of a particular molecule is smaller. No explanation has been given for a proposed mechanism that creates these smaller clusters. Apart from the aforementioned interpretation of Raman Spectra results, there is no published evidence showing a reduction in the average number of monomers per cluster. In any case, claims for smaller clusters seem to be irrelevant to Penta's claim for 'better hydration', because water molecules only enter through aquaporin cell-membrane channels one at a time. This point was made by Oxford University professor Robert Williams in an article by Mark Henderson in The Times on 7th February 2004) There has been no replication of these results or further evidence published in peer-reviewed scientific journals to support the claims of Penta/Bio Hydration Research Labs. Also, there is no known mechanism by which normal liquid water can be 'restructured'. Penta Water appears therefore to be pseudoscience. If Penta's claims were found to be true, then noted skeptic James Randi has stated [4] that they would be eligible for the Randi Prize of one million dollars for "anyone who is able to show evidence of any paranormal, supernatural, or occult power or event under test conditions agreed to by both parties". In July 2001, Penta agreed to submit to the Randi Prize, but later withdrew. In April 2005, Mark Fairhead, director of Penta UK wrote that they were considering re-applying. In addition to the Randi Prize, published evidence in peer reviewed mainstream scientific journals would make it likely that Penta would win the Nobel Prize for being able to demonstrate the restructuring of water and its improved health benefits. An oft-used criticism of skeptics' literature such as Randi's website is that the skeptics are apparently dismissing a subject without personally carrying out scientific tests to see if the claims are true. However, the onus of proof is generally agreed to be upon the people or company making extraordinary claims and not the skeptics to try and duplicate every experiment. In general, skeptics such as Randi tend to point out where the claims disagree with well-known mainstream scientific principles and this does not by itself require any further testing on the part of the skeptic. In 2001 [6], the James Randi Educational Foundation offered to arrange for independent tests of Penta's claims with protocols to be agreed upon by the foundation and Penta. It is a matter of record that Penta have yet to accept the challenge. # Mainstream science It is important to note that the study of water clusters is real science. There is much spectroscopic evidence to show beyond the doubt of most physical chemists that water clusters exist under appropriate (gas-phase) conditions (see for example [7], [8]). Furthermore, there are many scientific papers published in major peer-reviewed journals, hypothesizing that bulk-liquid water can be thought of as conglomerates of macroscopic numbers of 'flickering' water clusters. However, there is not evidence yet of 'restructuring' on time-scales greater than tiny fractions of a second. On the Penta Water links page [9] was included a link to a Cambridge University science group under the heading of "partnerships". In fact, this is false and the Cambridge science group has no association with Penta [10]. There was also a similar link to Johns Hopkins University. Again, there is no evidence of a partnership between Penta and Johns Hopkins. (Note, as of March 23rd 2005 these links have been removed from their website, though it is still possible to view an archived copy of the links page.) Up until Penta UK ceased trading, the now offline British Penta webpages [11] continued to link to a Cambridge water-cluster science page even though the page in question carries the clear and prominent disclaimer: "PLEASE NOTE THAT LINKS FROM ANY COMMERCIAL ORGANISATIONS TO THIS SITE ARE ENTIRELY UNAUTHORISED AND UNWELCOME. THE MAINTAINERS OF THIS SITE HAVE NO CONNECTIONS WITH ANY SUCH COMPANIES OR THEIR PRODUCTS." [12] Penta sister company AquaPhotonics claimed in a May 2005 Press release that Dr. Nikolai Tankovich, CEO of AquaPhotonics, had "joined the Scientific Advisory Board of Procter & Gamble". A reader of the James Randi webpage attempted to verify the accuracy of the press release with Procter & Gamble. A Procter & Gamble spokesperson replied: "We are unaware of any advisory board Dr. Nikolai Tankovich is on with P&G" [13] A few days later the press release was removed by AquaPhotonics from their news page. [14]. Penta has provided £15,000 in research funding to the British Brunel University in 2003 for a research study The ergogenic effects of Penta Water [15]. Dr. Andy Sparks and Prof. Don MacLaren from the Research Institute for Sport and Exercise Sciences in Liverpool John Moores University have also carried out research for Penta. (Their unpublished paper, Simulated soccer study is available from the AquaPhotonics website. [16]) # Response to criticism In response to critical articles written by the British Guardian journalist, Ben Goldacre, in his Bad Science column, a Penta employee sent Goldacre the text message: An apology, on behalf of Penta, from publicist Max Clifford followed. Goldacre contacted the British police in response to the threat. In correspondence with James Randi [18], Penta CEO Bill Holloway wrote the following in response to Randi's request for Penta to follow their agreed upon protocol for application of the Randi Prize The (now defunct) official British Penta website [19] had a page devoted to critical articles in the press in which they nominated newspapers and other news organizations for their 'Dunce Awards'. On this page, they respond to criticism with the following: On this page Penta also states At the time of writing (2005) these studies have not been published in peer reviewed journals, though the British Penta website did post quotes from researchers in two British sports research groups indicating that the studies were successful at demonstrating a performance improvement for athletes using Penta [20]. Details of these studies were scheduled to appear at the end of February 2005, but as of June 2006, they still have yet to appear. # No longer sold in the United Kingdom In March 2005 the British Advertising Standards Authority (ASA) ruled [21] on the accuracy of a Penta Water leaflet. The complaint was upheld. Among their findings the ASA wrote that As a result of these findings, the ASA ruled that The ASA is a regulatory authority set up as an independent body by the British advertising industry. It does not have any statutory power, but it is usually able to enforce correct observance of advertising codes in Britain. Penta has now been forced to cease trading in the United Kingdom. It was reported in a commentary by James Randi that The British Penta distributors have also apparently closed their Team Penta website, though they have left the message that The Guardian's Bad Science column has also covered this event [24]. # Criticism of specific claims ## Boiling point It is often mentioned that Penta has a higher boiling point than liquid water. This claim appears to be based on a research report paid for by Penta on Measurements of the Boiling Temperature of Penta ® Water. In the study, which was not double blinded, the researchers found a 0.043 °C increase in the boiling temperature of the Penta Water samples (relative to deionized water) and wrote In this study, neither water was found to have exactly the expected boiling point of 100 °C, which the researchers attributed to a probable error in the calibration of the thermometer. Thus, the experiment was only able to measure the relative boiling points of the two waters. The study was further discussed in an article in The Guardian Bad Science column [25]. One specific criticism of the experiment was that the quoted boiling temperature of the Penta sample appeared - contrary to thermodynamics - to be greater than that of the water jacket heating it. Another was that the thermometer resolution was very likely insufficient to resolve the claimed 0.043 °C temperature difference, but this point has been disputed. According to its makers [26], the Hart 1504 used has an accuracy of ±0.003 °C (at 0-25 °C); the accuracy of ±0.02 °C. quoted by The Guardian may refer to the Hart 1502 or may be using the charted accuracy at 100°C as listed on the chart here. Note that similar claims of a raised boiling point have also been made for the now discredited polywater, which was investigated in the 1960s and was also proposed to be a new structure of water. In the case of polywater, the elevated boiling point was eventually shown to be a result of dissolved impurities. ## Structure The consensus in mainstream science (arrived at through numerous experiments and accumulated knowledge) is that water does not have a structural memory of the sort claimed by Penta or in homeopathy. Even if smaller-than-average clusters are being formed by sound waves in the so-called "Penta-process", these structures would almost instantly disappear once the waves are stopped [27]. It is worth noting that the picture of five water molecules on every Penta Water bottle label does not represent a low-energy structure of the water pentamer since none of the waters are forming hydrogen bonds. If molecules were placed in this geometry they would quickly repel each-other (whilst quickly reorienting) due to the mutual electrostatic repulsion of the negatively charged oxygens. However this structure might occur around a positively charged ion such as Na+. The accepted [28] lowest energy global minimum structure for five water molecules is shown in the accompanying figure. Note that this structure contains five hydrogen bonds (dashed red lines), whilst the Pentamer logo on the Penta bottle contains no hydrogen bonds. Supporters of Penta have claimed that the structure depicted on the Penta water labels should be regarded as only a convenient logo and not a scientific claim. If this distinction exists, it is not made clear on the label. However, there are many examples of non-scientific depictions of molecules on the labels of a variety of household products. ## Hydration It is difficult to determine whether Penta is consistently claiming that their product offers improved hydration. In the past, the official Penta website made specific claims on its What makes Penta unique? page, section heading Proven More Effective Hydration, that the altered structure speeded cell hydration via aquaporin transport. For instance, the page for Jun 04 2003 [29] features a diagram showing stylised pentamers entering a cell and states Currently on the same page, this is apparently contradicted by the text Confusingly, the (now defunct) equivalent page of the British Penta website features the diagram and the earlier more explicit claims It is unclear as to why water more easily penetrating cell membranes is nessesarily a good thing. Cells maintain themselves in a careful homeostasis. Water that behaved in the way claimed of penta-water would probably be poisonous, rather than healthful. # Peer-reviewed papers quoted by Penta ## Raman spectroscopy This subsection concerns the (published and peer-reviewed) paper. In this paper the authors examine a peak in the Raman spectrum at a wavelength around 650 nm for various liquid water samples. The samples include several types of distilled water and Penta Water. The authors claim that the relative position and width of the peak for Penta compared to other waters is evidence for Penta being a new structure of water. Graphs of the results can be found at a Bio Hydration Research Labs website [30]. From these, it is seen that the difference between the two distilled water samples Distilled 1 and Distilled 2 is similar in size to the difference between either and the Penta sample. The authors do not provide an explanation as to why only the Penta to Distilled 1 /Distilled 2 difference is evidence for a new structure of water, whilst the difference between the distilled waters is presumably due to impurities. However, supporters of Penta argue that data showing peaks for Penta samples at >658.8 nm, compared to the other samples are below 658.4 nm is a significant and meaningful difference. The authors also find that the effective cluster temperature of the Penta water samples are 12 °C higher than the control samples. In other words, they observe that the Penta water samples behave similarly to normal water that is heated by an extra 12 degrees (though the actual measurable temperature of the water remains the same). This appears to be inconsistent with the claimed higher boiling point of Penta Water. (If normal water boils at 100 °C, then one might expect Penta water to boil at 88 °C due to its claimed effective higher temperature.) These were not double blind measurements. The Penta water samples were provided by Bio Hydration Research Labs. Supporters of Penta point out that the vast majority of sample analysis experiments are not performed double-blinded. However, it should be noted that double-blinded experiments are generally to be preferred in cases where the differences between samples is small, and in the cases where any difference between samples is likely to prove highly controversial. This paper is available from the AquaPhotonics website. [31] ## COM crystals This subsection concerns the (published and peer-reviewed) paper In this paper, the authors find that calcium oxalate crystals (which can form kidney stones) dissolve 3X faster in samples of Penta compared to the rate in distilled water. The rate in Penta water is found to be 0.47 nanometers per second, which is roughly 0.04 mm per day. It would take approximately 4 months at this rate to dissolve a 10 mm stone. These were not double blind measurements. # Associated organizations - Bio Hydration Research Labs manufactures Penta water. They are located in Carlsbad California. The CEO is Bill Holloway. G. R. Holloway, wife of Bill Holloway is the President and co-founder. Their son, Michael Holloway is also a co-founder and sits on the board of directors. Others on the board include Dr Nikolai I. Tankovich and David Cheatham. [32] - AquaPhotonics is a biotechnology company in Carlsbad California that makes extensive use of Penta in their products and appears to be a sister company to Bio Hydration Research Labs. Dr Nikolai I. Tankovich is the CEO and David Cheatham is the president. Bill Holloway, G. R. Holloway and Tommy Thompson (who was the Secretary for Health and Human Services for President George W. Bush) sit on the board of directors. - Diamics is a company dealing in medical diagnostics technology that has distribution rights for AquaRX (or Penta) water in diagnostic markets, claiming that its properties give cell samples "longer shelf life, better maintenance of cellular structure and improved performance in molecular assays". [33] # Positive reviews Penta Water has received much positive publicity in the press and has received positive reviews from health-oriented websites (e.g. [34]). There are also numerous testimonials from the public and endorsements from celebrities (e.g. Sting and Farrah Fawcett ) who have stated [35] that they have enjoyed or benefitted from drinking Penta Water (though there is no independent verification of these endorsements). The official Penta site also carries many testimonials from successful sports-people [36] including Olympic contestants and medalists. Testimonials such as the above are known by scientists as anecdotal evidence. Mainstream science generally places little weight on anecdotal evidence because it is known that people can be (unintentionally) unreliable witnesses of subtle phenomena, such as health improvements after taking a proposed cure. Furthermore, Penta's stated promotional system ("Initially a trial sample of Penta will be sent to select teams or sports people. Following a successful trial a special rate is offered.") could be interpreted as targeting athletes who are already successful or improving. Penta is a sponsor of the National Fibromyalgia Association (U.S.) website and is endorsed by them for being the "purest known bottled water on the market" [37]. Donald MacLaren, in the physiology department of Liverpool John Moores University in Britain is doing research for Penta and was quoted on their now defunct website as stating These studies have yet to be published in a peer-reviewed academic journal. Jorge Cruise, author of The 3-Hour Diet has recommended Penta water as "one of the keys to weight loss" [38], even though there have been no peer-reviewed studies in any academic journal that show this.	https://www.wikidoc.org/index.php/Penta_Water
ff63b882af4349eb592c9867b04c00bafdfbd783	wikidoc	Pentaborane	Pentaborane Pentaborane, also called pentaboron nonahydride, stable pentaborane, or pentaborane(9) (to distinguish it from B5H11), is a chemical compound considered in the 1950s as a good prospect for a rocket or jet fuel by both the U.S. and Russian armed services, a so-called "exotic fuel". Its chemical structure is that of five atoms of boron compounded with nine atoms of hydrogen (B5H9); it is one of the boranes. Because simple boron compounds burn with a characteristic green flame, the nickname for this fuel in the U.S. industry was "Green Dragon". Pentaborane is a colorless mobile liquid with a strong pungent odor (resembling garlic, acetylene, or sour milk). Above 30 °C it can form explosive concentration of vapors with air. Its vapors are heavier than air. It is pyrophoric - can ignite spontaneously in contact with air, when even slightly impure. It can also readily form shock sensitive explosive compounds, and reacts violently with some fire suppressants, notably with halocarbons and water. Above 150 °C, it decomposes, producing hydrogen; when it occurs in a closed container, the consequent rise of pressure may be dangerous. It is highly toxic on inhalation, ingestion, and skin absorption; it is damaging to eyes and skin, can damage liver and kidneys, and can attack the nervous system; symptoms of lower-level exposure may occur with up to 48 hours delay. Its acute chemical toxicity is comparable to some nerve agents. It is much more stable in presence of water than diborane. It is highly soluble in hydrocarbons, benzene, and cyclohexane, and in greases including those used in lab equipment. Evaporation from skin may cause frostbites. In storage, it decomposes negligibly, yielding small amount of hydrogen and solid residue. It is manufactured by pyrolysis of diborane. In the USA, pentaborane was produced by Callery Chemical Company; in 1985, Callery repurchased some of the reserve fuel and processed it to elementary boron. # Fuel use Because hydrogen makes the most energetic fuel with either oxygen or fluorine as oxidizer, but can only be liquefied at very low temperatures and is still cumbersome to work with due to its lack of density even in liquid form, compounds are sought to put the most hydrogen in the least volume and with the lightest non-hydrogen component. Pentaborane surpasses its equivalent carbon compounds because their self-linking element, carbon, weighs two unified atomic mass units more than an atom of boron, and some boranes contain more hydrogen than the carbon equivalent. The ease of breaking the chemical bonds of the compound is also taken into consideration. Interest in this substance began as a possible fuel for high-speed jets. The propellant mix that would produce the greatest specific impulse for a rocket motor is sometimes given as oxygen difluoride and pentaborane. During the early years of the space race and the missile gap, American rocket engineers thought they could more cheaply produce a rocket that would compete with the Soviets by using an existing first stage and putting an upper stage with an engine that produces thrust at a very high specific impulse atop it. So projects were begun to investigate this fuel. Problems with this fuel include its toxicity and its characteristic of bursting into flame on contact with the air; furthermore, its exhaust would also be toxic. Long after the chemical was considered unworkable, the total United States stock of the chemical, 1900 pounds, was destroyed in the year 2000, when a safe and inexpensive means for doing so was discovered - hydrolysis with steam, yielding hydrogen and a boric acid solution. The system was nicknamed "Dragon Slayer". Pentaborane was also investigated to be used as a bipropellant with nitrogen tetroxide. In the Soviet Union, Valentin Glushko used it for the experimental RD-270M rocket engine, under development between 1962-1970. Other borane-derived fuels were eg. propyl pentaborane (BEF-2) and ethyl decaborane (REF-3). Diborane and decaborane and their derivates were also investigated. In chemistry, pentaborane is used for synthesis of polyboron cages.	Pentaborane Template:Chembox new Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Pentaborane, also called pentaboron nonahydride, stable pentaborane, or pentaborane(9) (to distinguish it from B5H11), is a chemical compound considered in the 1950s as a good prospect for a rocket or jet fuel by both the U.S. and Russian armed services, a so-called "exotic fuel". Its chemical structure is that of five atoms of boron compounded with nine atoms of hydrogen (B5H9); it is one of the boranes. Because simple boron compounds burn with a characteristic green flame, the nickname for this fuel in the U.S. industry was "Green Dragon". Pentaborane is a colorless mobile liquid with a strong pungent odor (resembling garlic, acetylene, or sour milk). Above 30 °C it can form explosive concentration of vapors with air. Its vapors are heavier than air. It is pyrophoric - can ignite spontaneously in contact with air, when even slightly impure. It can also readily form shock sensitive explosive compounds, and reacts violently with some fire suppressants, notably with halocarbons and water. Above 150 °C, it decomposes, producing hydrogen; when it occurs in a closed container, the consequent rise of pressure may be dangerous. It is highly toxic on inhalation, ingestion, and skin absorption; it is damaging to eyes and skin, can damage liver and kidneys, and can attack the nervous system; symptoms of lower-level exposure may occur with up to 48 hours delay. Its acute chemical toxicity is comparable to some nerve agents. It is much more stable in presence of water than diborane. It is highly soluble in hydrocarbons, benzene, and cyclohexane, and in greases including those used in lab equipment. Evaporation from skin may cause frostbites. In storage, it decomposes negligibly, yielding small amount of hydrogen and solid residue. It is manufactured by pyrolysis of diborane. In the USA, pentaborane was produced by Callery Chemical Company; in 1985, Callery repurchased some of the reserve fuel and processed it to elementary boron. # Fuel use Because hydrogen makes the most energetic fuel with either oxygen or fluorine as oxidizer, but can only be liquefied at very low temperatures and is still cumbersome to work with due to its lack of density even in liquid form, compounds are sought to put the most hydrogen in the least volume and with the lightest non-hydrogen component. Pentaborane surpasses its equivalent carbon compounds because their self-linking element, carbon, weighs two unified atomic mass units more than an atom of boron, and some boranes contain more hydrogen than the carbon equivalent. The ease of breaking the chemical bonds of the compound is also taken into consideration. Interest in this substance began as a possible fuel for high-speed jets. The propellant mix that would produce the greatest specific impulse for a rocket motor is sometimes given as oxygen difluoride and pentaborane. During the early years of the space race and the missile gap, American rocket engineers thought they could more cheaply produce a rocket that would compete with the Soviets by using an existing first stage and putting an upper stage with an engine that produces thrust at a very high specific impulse atop it. So projects were begun to investigate this fuel. Problems with this fuel include its toxicity and its characteristic of bursting into flame on contact with the air; furthermore, its exhaust would also be toxic. Long after the chemical was considered unworkable, the total United States stock of the chemical, 1900 pounds, was destroyed in the year 2000, when a safe and inexpensive means for doing so was discovered - hydrolysis with steam, yielding hydrogen and a boric acid solution. The system was nicknamed "Dragon Slayer".[1] Pentaborane was also investigated to be used as a bipropellant with nitrogen tetroxide.[2] In the Soviet Union, Valentin Glushko used it for the experimental RD-270M rocket engine, under development between 1962-1970.[3] Other borane-derived fuels were eg. propyl pentaborane (BEF-2) and ethyl decaborane (REF-3).[4] Diborane and decaborane and their derivates were also investigated. In chemistry, pentaborane is used for synthesis of polyboron cages.	https://www.wikidoc.org/index.php/Pentaborane
00a0459d516ce808444929913cbc0ae98f570bdf	wikidoc	Pentastarch	Pentastarch Pentastarch is a synthetic derivative of starch, which has five hydroxyethyl groups. It is sold under the name Pentaspan and used for fluid resuscitation. It is considered a plasma expander because it remains primarily intravascular after infusion. # Choice of resuscitation fluid The choice of fluid (normal saline vs. Ringer's lactate vs. pentaspan) is controversial. Physiologically, fluid with pentaspan stays primarily in the blood plasma. This is different than normal saline, which shifts quickly into the intracellular compartment. Advocates of pentaspan use believe that: - the primary deficit in fluid resuscitation is intravascular volume loss and - use of normal saline may lead to pulmonary edema, particularily in older patients. # Normal saline versus pentastarch ## Casualty Pentastarch in the emergency setting does not give a survival advantage; however, significantly less volume is required for resuscitation. ## Cardiac surgery A study is currently being done to compare normal saline with pentastarch following cardiac surgery. # Cost Pentastarch is more expensive than normal saline, but less expensive than albumin.	Pentastarch Template:Mergeto Pentastarch is a synthetic derivative of starch, which has five hydroxyethyl groups. It is sold under the name Pentaspan and used for fluid resuscitation. It is considered a plasma expander because it remains primarily intravascular after infusion. # Choice of resuscitation fluid The choice of fluid (normal saline vs. Ringer's lactate vs. pentaspan) is controversial.[1] Physiologically, fluid with pentaspan stays primarily in the blood plasma. This is different than normal saline, which shifts quickly into the intracellular compartment. Advocates of pentaspan use believe that: - the primary deficit in fluid resuscitation is intravascular volume loss[1] and - use of normal saline may lead to pulmonary edema, particularily in older patients.[1] # Normal saline versus pentastarch ## Casualty Pentastarch in the emergency setting does not give a survival advantage; however, significantly less volume is required for resuscitation.[2] ## Cardiac surgery A study is currently being done to compare normal saline with pentastarch following cardiac surgery.[3] # Cost Pentastarch is more expensive than normal saline, but less expensive than albumin.	https://www.wikidoc.org/index.php/Pentastarch
2c47c748d18097742d00c9d53fd7c97caf9b31f1	wikidoc	Pentazocine	Pentazocine # 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 Pentazocine is an analgesic opioid that is FDA approved for the {{{indicationType}}} of anesthesia; adjunct, labor pain, pain (moderate to severe). Common adverse reactions include gastrointestinal: nausea, vomiting, neurologic: dizziness, lightheadedness, psychiatric: euphoria. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Anesthesia; Adjunct: 30 mg IV, IM or SC every 3 to 4 hr as needed, max 360 mg/day; doses above 30 mg IV or 60 mg IM, SC are not recommended. - Labor pain: a single 30 mg/dose IM (most common); or 20 mg/dose IV for 2-3 doses at 2-3-hr intervals, as needed, after contractions have become regular. - Pain (moderate to severe): 30 mg IV, IM or SC every 3-4 hr as needed, max 360 mg/day; doses above 30 mg IV or 60 mg IM, SC are not recommended. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Pentazocine in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Pentazocine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in children less than 12 yr of age not established. - Anesthesia; adjunct: single 0.5 mg/kg IM dose ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Pentazocine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Pentazocine in pediatric patients. # Contraindications - Pentazocine should not be administered to patients who are hypersensitive to it. # Warnings - Special care should be exercised in prescribing pentazocine for emotionally unstable patients and for those with a history of drug misuse. Such patients should be closely supervised when greater than 4 or 5 days of therapy is contemplated. There have been instances of psychological and physical dependence on pentazocine in patients with such a history and, rarely, in patients without such a history. Extended use of parenteral pentazocine may lead to physical or psychological dependence in some patients. When pentazocine is abruptly discontinued, withdrawal symptoms such as abdominal cramps, elevated temperature, rhinorrhea, restlessness, anxiety, and lacrimation may occur. However, even when these have occurred, discontinuance has been accomplished with minimal difficulty. In the rare patient in whom more than minor difficulty has been encountered, reinstitution of parenteral pentazocine with gradual withdrawal has ameliorated the patient’s symptoms. Substituting methadone or other narcotics for pentazocine in the treatment of the pentazocine abstinence syndrome should be avoided. There have been rare reports of possible abstinence syndromes in newborns after prolonged use of pentazocine during pregnancy. - In prescribing parenteral pentazocine for chronic use, particularly if the drug is to be self-administered, the physician should take precautions to avoid increases in dose and frequency of injection by the patient. - Just as with all medication, the oral form of pentazocine is preferable for chronic administration. - Tissue Damage at Injection Sites: Severe sclerosis of the skin, subcutaneous tissues, and underlying muscle have occurred at the injection sites of patients who have received multiple doses of pentazocine lactate. Constant rotation of injection sites is, therefore, essential. In addition, animal studies have demonstrated that pentazocine is tolerated less well subcutaneously than intramuscularly. (See Dosage and Administration.) - As in the case of other potent analgesics, the potential of pentazocine injection for elevating cerebrospinal fluid pressure may be attributed to CO2 retention due to the respiratory depressant effects of the drug. These effects may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial pressure. Furthermore, pentazocine can produce effects which may obscure the clinical course of patients with head injuries. In such patients, pentazocine must be used with extreme caution and only if its use is deemed essential. - Patients receiving therapeutic doses of pentazocine have experienced hallucinations (usually visual), disorientation, and confusion which have cleared spontaneously within a period of hours. The mechanism of this reaction is not known. Such patients should be closely observed and vital signs checked. If the drug is reinstituted, it should be done with caution since these acute CNS manifestations may recur. - Due to the potential for increased CNS depressant effects, alcohol should be used with caution in patients who are currently receiving pentazocine. - Since sedation, dizziness, and occasional euphoria have been noted, ambulatory patients should be warned not to operate machinery, drive cars, or unnecessarily expose themselves to hazards. - Caution should be exercised in the intravenous use of pentazocine for patients with acute myocardial infarction accompanied by hypertension or left ventricular failure. Data suggest that intravenous administration of pentazocine increases systemic and pulmonary arterial pressure and systemic vascular resistance in patients with acute myocardial infarction. - Acetone 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, is contained in multiple-dose vials. 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. - The ampuls in the Uni-Amp™ Pak do not contain acetone sodium bisulfite. # Adverse Reactions ## Clinical Trials Experience - The most commonly occurring reactions are: nausea, dizziness or lightheadedness, vomiting, euphoria. - Soft tissue induration, nodules, and cutaneous depression can occur at injection sites. Ulceration (sloughing) and severe sclerosis of the skin and subcutaneous tissues (and, rarely, underlying muscle) have been reported after multiple doses. Other reported dermatologic reactions include diaphoresis, sting on injection, flushed skin including plethora, dermatitis including pruritus. - Infrequently occurring reactions are—respiratory: respiratory depression, dyspnea, transient apnea in a small number of newborn infants whose mothers received pentazocine during labor; cardiovascular: circulatory depression, shock, hypertension; CNS effects: dizziness, lightheadedness, hallucinations, sedation, euphoria, headache, confusion, disorientation; infrequently weakness, disturbed dreams, insomnia, syncope, visual blurring and focusing difficulty, depression; and rarely tremor, irritability, excitement, tinnitus; gastrointestinal: constipation, dry mouth; other: urinary retention, headache, paresthesia, alterations in rate or strength of uterine contractions during labor. - Rarely reported reactions include—neuromuscular and psychiatric: muscle tremor, insomnia, disorientation, hallucinations; gastrointestinal: taste alteration, diarrhea and cramps; ophthalmic: blurred vision, nystagmus, diplopia, miosis; hematologic: depression of white blood cells (especially granulocytes), which is usually reversible, moderate transient eosinophilia; other: tachycardia, weakness or faintness, chills; allergic reactions including edema of the face, toxic epidermal necrolysis. (See Acute CNS Manifestations and Drug Dependence under Warnings.) ## Postmarketing Experience There is limited information regarding Pentazocine Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Pentazocine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Safe use of pentazocine during pregnancy (other than labor) has not been established. Animal reproduction studies have not demonstrated teratogenic or embryotoxic effects. However, pentazocine should be administered to pregnant patients (other than labor) only when, in the judgment of the physician, the potential benefits outweigh the possible hazards. Patients receiving pentazocine during labor have experienced no adverse effects other than those that occur with commonly used analgesics. pentazocine should be used with caution in women delivering premature infants. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pentazocine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Pentazocine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Pentazocine in women who are nursing. ### Pediatric Use - The safety and efficacy of pentazocine as preoperative or preanesthetic medication have been established in pediatric patients 1 to 16 years of age. Use of pentazocine in these age groups is supported by evidence from adequate and controlled studies in adults with additional data from published controlled trials in pediatric patients. The safety and efficacy of pentazocine as a premedication for sedation have not been established in pediatric patients less than one year old. Information on the safety profile of pentazocine as a postoperative analgesic in children less than 16 years is limited. ### Geriatic Use - Elderly patients may be more sensitive to the analgesic effects of pentazocine than younger patients. (See Dosage and Administration.) - Clinical data indicate that differences in various pharmacokinetic parameters of pentazocine may exist between elderly and younger patients. (See Clinical Pharmacology.) - Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of pentazocine and observed closely. - 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 Pentazocine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pentazocine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Pentazocine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Pentazocine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pentazocine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pentazocine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Pentazocine Administration in the drug label. ### Monitoring There is limited information regarding Pentazocine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Pentazocine and IV administrations. # Overdosage - Clinical experience with pentazocine overdosage has been insufficient to define the signs of this condition. - Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to pentazocine, parenteral naloxone is a specific and effective antagonist. # Pharmacology ## Mechanism of Action There is limited information regarding Pentazocine Mechanism of Action in the drug label. ## Structure - Pentazocine injection, Pentazocine Injection, USP, is a member of the benzazocine series (also known as the benzomorphan series). Chemically, pentazocine lactate is 1, 2, 3, 4, 5, 6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol lactate, a white, crystalline substance soluble in acidic aqueous solutions. ## Pharmacodynamics - Pentazocine is a potent analgesic and 30 mg is usually as effective an analgesic as morphine 10 mg or meperidine 75 mg to 100 mg; however, a few studies suggest the Pentazocine to morphine ratio may range from 20 mg to 40 mg Pentazocine to 10 mg morphine. The duration of analgesia may sometimes be less than that of morphine. Analgesia usually occurs within 15 to 20 minutes after intramuscular or subcutaneous injection and within 2 to 3 minutes after intravenous injection. Pentazocine weakly antagonizes the analgesic effects of morphine, meperidine, and phenazocine; in addition, it produces incomplete reversal of cardiovascular, respiratory, and behavioral depression induced by morphine and meperidine. Pentazocine has about 1/50 the antagonistic activity of nalorphine. It also has sedative activity. ## Pharmacokinetics - Clinical data indicate that differences in various pharmacokinetic parameters may be observed with increasing age. In one study, elderly patients exhibited a longer mean elimination half-life, a lower mean total plasma clearance, and a larger mean area under the concentration-time curve than younger patients. ## Nonclinical Toxicology There is limited information regarding Pentazocine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Pentazocine Clinical Studies in the drug label. # How Supplied - The pH of Pentazocine solutions is adjusted between 4 and 5 with lactic acid or sodium hydroxide. The air in the ampuls and vials has been displaced by nitrogen gas. ## 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 Pentazocine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Pentazocine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Pentazocine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Pentazocine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Pentazocine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Pentazocine is an analgesic opioid that is FDA approved for the {{{indicationType}}} of anesthesia; adjunct, labor pain, pain (moderate to severe). Common adverse reactions include gastrointestinal: nausea, vomiting, neurologic: dizziness, lightheadedness, psychiatric: euphoria. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Anesthesia; Adjunct: 30 mg IV, IM or SC every 3 to 4 hr as needed, max 360 mg/day; doses above 30 mg IV or 60 mg IM, SC are not recommended. - Labor pain: a single 30 mg/dose IM (most common); or 20 mg/dose IV for 2-3 doses at 2-3-hr intervals, as needed, after contractions have become regular. - Pain (moderate to severe): 30 mg IV, IM or SC every 3-4 hr as needed, max 360 mg/day; doses above 30 mg IV or 60 mg IM, SC are not recommended. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Pentazocine in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Pentazocine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness in children less than 12 yr of age not established. - Anesthesia; adjunct: single 0.5 mg/kg IM dose ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Pentazocine in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Pentazocine in pediatric patients. # Contraindications - Pentazocine should not be administered to patients who are hypersensitive to it. # Warnings - Special care should be exercised in prescribing pentazocine for emotionally unstable patients and for those with a history of drug misuse. Such patients should be closely supervised when greater than 4 or 5 days of therapy is contemplated. There have been instances of psychological and physical dependence on pentazocine in patients with such a history and, rarely, in patients without such a history. Extended use of parenteral pentazocine may lead to physical or psychological dependence in some patients. When pentazocine is abruptly discontinued, withdrawal symptoms such as abdominal cramps, elevated temperature, rhinorrhea, restlessness, anxiety, and lacrimation may occur. However, even when these have occurred, discontinuance has been accomplished with minimal difficulty. In the rare patient in whom more than minor difficulty has been encountered, reinstitution of parenteral pentazocine with gradual withdrawal has ameliorated the patient’s symptoms. Substituting methadone or other narcotics for pentazocine in the treatment of the pentazocine abstinence syndrome should be avoided. There have been rare reports of possible abstinence syndromes in newborns after prolonged use of pentazocine during pregnancy. - In prescribing parenteral pentazocine for chronic use, particularly if the drug is to be self-administered, the physician should take precautions to avoid increases in dose and frequency of injection by the patient. - Just as with all medication, the oral form of pentazocine is preferable for chronic administration. - Tissue Damage at Injection Sites: Severe sclerosis of the skin, subcutaneous tissues, and underlying muscle have occurred at the injection sites of patients who have received multiple doses of pentazocine lactate. Constant rotation of injection sites is, therefore, essential. In addition, animal studies have demonstrated that pentazocine is tolerated less well subcutaneously than intramuscularly. (See Dosage and Administration.) - As in the case of other potent analgesics, the potential of pentazocine injection for elevating cerebrospinal fluid pressure may be attributed to CO2 retention due to the respiratory depressant effects of the drug. These effects may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a preexisting increase in intracranial pressure. Furthermore, pentazocine can produce effects which may obscure the clinical course of patients with head injuries. In such patients, pentazocine must be used with extreme caution and only if its use is deemed essential. - Patients receiving therapeutic doses of pentazocine have experienced hallucinations (usually visual), disorientation, and confusion which have cleared spontaneously within a period of hours. The mechanism of this reaction is not known. Such patients should be closely observed and vital signs checked. If the drug is reinstituted, it should be done with caution since these acute CNS manifestations may recur. - Due to the potential for increased CNS depressant effects, alcohol should be used with caution in patients who are currently receiving pentazocine. - Since sedation, dizziness, and occasional euphoria have been noted, ambulatory patients should be warned not to operate machinery, drive cars, or unnecessarily expose themselves to hazards. - Caution should be exercised in the intravenous use of pentazocine for patients with acute myocardial infarction accompanied by hypertension or left ventricular failure. Data suggest that intravenous administration of pentazocine increases systemic and pulmonary arterial pressure and systemic vascular resistance in patients with acute myocardial infarction. - Acetone 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, is contained in multiple-dose vials. 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. - The ampuls in the Uni-Amp™ Pak do not contain acetone sodium bisulfite. # Adverse Reactions ## Clinical Trials Experience - The most commonly occurring reactions are: nausea, dizziness or lightheadedness, vomiting, euphoria. - Soft tissue induration, nodules, and cutaneous depression can occur at injection sites. Ulceration (sloughing) and severe sclerosis of the skin and subcutaneous tissues (and, rarely, underlying muscle) have been reported after multiple doses. Other reported dermatologic reactions include diaphoresis, sting on injection, flushed skin including plethora, dermatitis including pruritus. - Infrequently occurring reactions are—respiratory: respiratory depression, dyspnea, transient apnea in a small number of newborn infants whose mothers received pentazocine during labor; cardiovascular: circulatory depression, shock, hypertension; CNS effects: dizziness, lightheadedness, hallucinations, sedation, euphoria, headache, confusion, disorientation; infrequently weakness, disturbed dreams, insomnia, syncope, visual blurring and focusing difficulty, depression; and rarely tremor, irritability, excitement, tinnitus; gastrointestinal: constipation, dry mouth; other: urinary retention, headache, paresthesia, alterations in rate or strength of uterine contractions during labor. - Rarely reported reactions include—neuromuscular and psychiatric: muscle tremor, insomnia, disorientation, hallucinations; gastrointestinal: taste alteration, diarrhea and cramps; ophthalmic: blurred vision, nystagmus, diplopia, miosis; hematologic: depression of white blood cells (especially granulocytes), which is usually reversible, moderate transient eosinophilia; other: tachycardia, weakness or faintness, chills; allergic reactions including edema of the face, toxic epidermal necrolysis. (See Acute CNS Manifestations and Drug Dependence under Warnings.) ## Postmarketing Experience There is limited information regarding Pentazocine Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Pentazocine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Safe use of pentazocine during pregnancy (other than labor) has not been established. Animal reproduction studies have not demonstrated teratogenic or embryotoxic effects. However, pentazocine should be administered to pregnant patients (other than labor) only when, in the judgment of the physician, the potential benefits outweigh the possible hazards. Patients receiving pentazocine during labor have experienced no adverse effects other than those that occur with commonly used analgesics. pentazocine should be used with caution in women delivering premature infants. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pentazocine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Pentazocine during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Pentazocine in women who are nursing. ### Pediatric Use - The safety and efficacy of pentazocine as preoperative or preanesthetic medication have been established in pediatric patients 1 to 16 years of age. Use of pentazocine in these age groups is supported by evidence from adequate and controlled studies in adults with additional data from published controlled trials in pediatric patients. The safety and efficacy of pentazocine as a premedication for sedation have not been established in pediatric patients less than one year old. Information on the safety profile of pentazocine as a postoperative analgesic in children less than 16 years is limited. ### Geriatic Use - Elderly patients may be more sensitive to the analgesic effects of pentazocine than younger patients. (See Dosage and Administration.) - Clinical data indicate that differences in various pharmacokinetic parameters of pentazocine may exist between elderly and younger patients. (See Clinical Pharmacology.) - Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of pentazocine and observed closely. - 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 Pentazocine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Pentazocine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Pentazocine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Pentazocine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Pentazocine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Pentazocine in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Pentazocine Administration in the drug label. ### Monitoring There is limited information regarding Pentazocine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Pentazocine and IV administrations. # Overdosage - Clinical experience with pentazocine overdosage has been insufficient to define the signs of this condition. - Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to pentazocine, parenteral naloxone is a specific and effective antagonist. # Pharmacology ## Mechanism of Action There is limited information regarding Pentazocine Mechanism of Action in the drug label. ## Structure - Pentazocine injection, Pentazocine Injection, USP, is a member of the benzazocine series (also known as the benzomorphan series). Chemically, pentazocine lactate is 1, 2, 3, 4, 5, 6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol lactate, a white, crystalline substance soluble in acidic aqueous solutions. ## Pharmacodynamics - Pentazocine is a potent analgesic and 30 mg is usually as effective an analgesic as morphine 10 mg or meperidine 75 mg to 100 mg; however, a few studies suggest the Pentazocine to morphine ratio may range from 20 mg to 40 mg Pentazocine to 10 mg morphine. The duration of analgesia may sometimes be less than that of morphine. Analgesia usually occurs within 15 to 20 minutes after intramuscular or subcutaneous injection and within 2 to 3 minutes after intravenous injection. Pentazocine weakly antagonizes the analgesic effects of morphine, meperidine, and phenazocine; in addition, it produces incomplete reversal of cardiovascular, respiratory, and behavioral depression induced by morphine and meperidine. Pentazocine has about 1/50 the antagonistic activity of nalorphine. It also has sedative activity. ## Pharmacokinetics - Clinical data indicate that differences in various pharmacokinetic parameters may be observed with increasing age. In one study, elderly patients exhibited a longer mean elimination half-life, a lower mean total plasma clearance, and a larger mean area under the concentration-time curve than younger patients. ## Nonclinical Toxicology There is limited information regarding Pentazocine Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Pentazocine Clinical Studies in the drug label. # How Supplied - The pH of Pentazocine solutions is adjusted between 4 and 5 with lactic acid or sodium hydroxide. The air in the ampuls and vials has been displaced by nitrogen gas. ## Storage - Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Pentazocine Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Pentazocine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names There is limited information regarding Pentazocine Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Pentazocine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Pentazocine
ea8e6d532269db3344de63acb01c8276c122aaf8	wikidoc	Perchlorate	Perchlorate Perchlorates are the salts derived from perchloric acid (HClO4). They occur both naturally and through manufacturing. They have been used as a medicine for more than 50 years to treat thyroid gland disorders. They are also used as an oxidizer in rocket fuel and can be found in airbags, fireworks, and Chilean fertilizers. Both potassium perchlorate (KClO4) and ammonium perchlorate (NH4ClO4) are used extensively within the pyrotechnics industry, whereas ammonium perchlorate is a component of solid rocket fuel. Lithium perchlorate, which decomposes exothermically to give oxygen, is used in oxygen "candles" on spacecraft, submarines and in other esoteric situations where a reliable backup or supplementary oxygen supply is needed. Most perchlorate salts are soluble in water. # Scientific definition The perchlorate ion is ClO4−, and it has a molecular mass of 99.45 a.u. A perchlorate (compound) is a compound containing this group, with chlorine in oxidation state +7. # Strength of oxidation The perchlorate ion is the weakest oxidizer of the generalized chlorates. Lower oxidation numbers are progressively stronger oxidizers, and less stable. Perchlorate has the highest redox potential, but is a closed shell species, and as such, is sluggish to oxidize other species. # Stability Most perchlorates, especially salts of electropositive metals such as sodium perchlorate or potassium perchlorate, are slow to react unless heated, the perchlorate ion being largely inert and not oxidizing at lower temperatures. This property is useful in many applications, such as flares, where the device should not explode, or even catch fire spontaneously. Mixtures of perchlorates with organic compounds are more reactive; although generally they do not catch fire or explode unless heated, there are a number of exceptions. # Environmental presence Low levels of perchlorate have been detected in both drinking water and groundwater in 35 states in the US according to the Environmental Protection Agency. In 2004, the chemical was also found in cow's milk in the area with an average level of 1.3 parts per billion ("ppb" or µg/L), which may have entered the cows through feeding on crops that had exposure to water containing perchlorates. According to the Impact Area Groundwater Study Program , the chemical has been detected as high as 5 µg/L in Massachusetts, well over the state regulation of 1 µg/L. In some places it is being detected because of contamination from industrial sites that use or manufacture perchlorate. In other places, there is no clear source of perchlorate. In those areas it may be naturally occurring or could be present because of the use of Chilean fertilizers, which were imported to the U.S. by the hundreds of tons in the early 19th century. One recent area of research has even suggested that perchlorate can be created when lightning strikes a body of water, and perchlorates are created as a byproduct of chlorine generators used in swimming pool chlorination systems. As of April 2007, the EPA has not yet determined whether perchlorate is present at sufficient levels in the environment to require a nationwide regulation on how much should be allowed in drinking water. In 2005, U.S. EPA issued a recommended Drinking Water Equivalent Level (DWEL) for perchlorate of 24.5 µg/L. In early 2006, EPA issued a “Cleanup Guidance” for this same amount. Both the DWEL and the Cleanup Guidance were based on a thorough review of the existing research by the National Academy of Science (NAS). This followed numerous other studies, including one which suggested human breast milk had an average of 10.5 µg/L of perchlorate. Both the Pentagon and some environmental groups have voiced questions about the NAS report, but no credible science has emerged to challenge the NAS findings. # Health effects A study involving healthy adult volunteers determined that at levels above 0.007 milligrams per kilogram per day (mg/kg-d), perchlorate can temporarily and reversibly inhibit the thyroid gland’s ability to absorb iodine from the bloodstream ("iodide uptake inhibition", thus perchlorate is a known goitrogen). The EPA converted this dose into a "drinking water equivalent level" of 245 ppb by assuming a person weighs 70 kilograms (154 pounds) and consumes 2 liters (68 ounces) of drinking water per day over a lifetime. While the thyroid uses iodine to produce hormones, NAS says this process of iodide uptake inhibition is not an "adverse," or harmful, effect. There has been some speculation that exposure to extremely high doses of perchlorate, for several months or years could lead to hypothyroidism, but NAS found that iodide uptake inhibition was the only consistently documented health effect of perchlorate in humans. Furthermore, a 2006 CDC study found this to only be true in women, and because the study was not properly controlled for autoimmune thyroid disease (which causes identical effects on iodine uptake and which is much more common in women), improved analysis may show that the effect is extremely small or even nonexistent. The NAS also found that perchlorate only affects the thyroid gland. There is no evidence that it causes brain damage, birth defects or cancer in humans. It is also not stored in the body, it is not metabolized, and any effects of perchlorate on the thyroid gland are fully reversible once exposure stops. There has been some concern on perchlorates effects on fetuses, newborns and children, but several peer-reviewed studies on children and newborns also provide reason to believe that low levels of perchlorate do not pose a threat to these populations. On October 1, 2004, the American Thyroid Association (ATA) reported that perchlorate may not be as harmful to newborns, pregnant women and other adults as previously thought. The EPA and NAS divided the No Observed Effect Level (NOEL) for perchlorate of 0.007 mg/kg-d by the standard intraspecies uncertainty factor of 10 to derive a “reference dose” of 0.0007 mg/kg-d, and declared this would be protective of even the most sensitive subpopulations. Usually an additional 10-fold interspecies uncertainty factor is also used in the calculation of reference doses, but since the perchlorate NOEL was derived from a human study, rather than an animal study, this additional uncertainty factor was not used. Using the 70 kg body weight and 2 liter/day assumptions used above, this dose is converted to 25 ppb in drinking water. For that reason, most media reports call this the "safe" level of exposure. The NAS report also stated additional research would be helpful, but emphasized that the existing database on perchlorate was sufficient to make its reference dose recommendation and ensure it would be protective for everyone. Recent research, however, has shown inhibition of iodide uptake in the thyroids of women at much lower levels, levels attainable from normally contaminated water and milk. # Types of perchlorates - Ammonium perchlorate, NH4ClO4 - Caesium perchlorate, CsClO4 - Lithium perchlorate, LiClO4 - Magnesium perchlorate, Mg(ClO4)2 - Perchloric acid, HClO4 - Potassium perchlorate, KClO4 - Rubidium perchlorate, RbClO4 - Silver perchlorate, AgClO4 - Sodium perchlorate, NaClO4	Perchlorate Perchlorates are the salts derived from perchloric acid (HClO4). They occur both naturally and through manufacturing. They have been used as a medicine for more than 50 years to treat thyroid gland disorders. They are also used as an oxidizer in rocket fuel and can be found in airbags, fireworks, and Chilean fertilizers. Both potassium perchlorate (KClO4) and ammonium perchlorate (NH4ClO4) are used extensively within the pyrotechnics industry, whereas ammonium perchlorate is a component of solid rocket fuel. Lithium perchlorate, which decomposes exothermically to give oxygen, is used in oxygen "candles" on spacecraft, submarines and in other esoteric situations where a reliable backup or supplementary oxygen supply is needed. Most perchlorate salts are soluble in water. # Scientific definition The perchlorate ion is ClO4−, and it has a molecular mass of 99.45 a.u. A perchlorate (compound) is a compound containing this group, with chlorine in oxidation state +7. # Strength of oxidation The perchlorate ion is the weakest oxidizer of the generalized chlorates. Lower oxidation numbers are progressively stronger oxidizers, and less stable. Perchlorate has the highest redox potential, but is a closed shell species, and as such, is sluggish to oxidize other species. # Stability Most perchlorates, especially salts of electropositive metals such as sodium perchlorate or potassium perchlorate, are slow to react unless heated, the perchlorate ion being largely inert and not oxidizing at lower temperatures. This property is useful in many applications, such as flares, where the device should not explode, or even catch fire spontaneously. Mixtures of perchlorates with organic compounds are more reactive; although generally they do not catch fire or explode unless heated, there are a number of exceptions. # Environmental presence Low levels of perchlorate have been detected in both drinking water and groundwater in 35 states in the US according to the Environmental Protection Agency. In 2004, the chemical was also found in cow's milk in the area with an average level of 1.3 parts per billion ("ppb" or µg/L), which may have entered the cows through feeding on crops that had exposure to water containing perchlorates.[1] According to the Impact Area Groundwater Study Program [1], the chemical has been detected as high as 5 µg/L in Massachusetts, well over the state regulation of 1 µg/L. In some places it is being detected because of contamination from industrial sites that use or manufacture perchlorate. In other places, there is no clear source of perchlorate. In those areas it may be naturally occurring or could be present because of the use of Chilean fertilizers, which were imported to the U.S. by the hundreds of tons in the early 19th century. One recent area of research has even suggested that perchlorate can be created when lightning strikes a body of water, and perchlorates are created as a byproduct of chlorine generators used in swimming pool chlorination systems. As of April 2007, the EPA has not yet determined whether perchlorate is present at sufficient levels in the environment to require a nationwide regulation on how much should be allowed in drinking water.[2] In 2005, U.S. EPA issued a recommended Drinking Water Equivalent Level (DWEL) for perchlorate of 24.5 µg/L. In early 2006, EPA issued a “Cleanup Guidance” for this same amount. Both the DWEL and the Cleanup Guidance were based on a thorough review of the existing research by the National Academy of Science (NAS). This followed numerous other studies, including one which suggested human breast milk had an average of 10.5 µg/L of perchlorate.[3] Both the Pentagon and some environmental groups have voiced questions about the NAS report, but no credible science has emerged to challenge the NAS findings. # Health effects A study involving healthy adult volunteers determined that at levels above 0.007 milligrams per kilogram per day (mg/kg-d), perchlorate can temporarily and reversibly inhibit the thyroid gland’s ability to absorb iodine from the bloodstream ("iodide uptake inhibition", thus perchlorate is a known goitrogen).[4] The EPA converted this dose into a "drinking water equivalent level" of 245 ppb by assuming a person weighs 70 kilograms (154 pounds) and consumes 2 liters (68 ounces) of drinking water per day over a lifetime.[5] While the thyroid uses iodine to produce hormones, NAS says this process of iodide uptake inhibition is not an "adverse," or harmful, effect. There has been some speculation that exposure to extremely high doses of perchlorate, for several months or years could lead to hypothyroidism, but NAS found that iodide uptake inhibition was the only consistently documented health effect of perchlorate in humans.[citation needed] Furthermore, a 2006 CDC study found this to only be true in women, and because the study was not properly controlled for autoimmune thyroid disease (which causes identical effects on iodine uptake and which is much more common in women), improved analysis may show that the effect is extremely small or even nonexistent.[citation needed] The NAS also found that perchlorate only affects the thyroid gland. There is no evidence that it causes brain damage, birth defects or cancer in humans.[citation needed] It is also not stored in the body, it is not metabolized, and any effects of perchlorate on the thyroid gland are fully reversible once exposure stops. There has been some concern on perchlorates effects on fetuses, newborns and children, but several peer-reviewed studies on children and newborns also provide reason to believe that low levels of perchlorate do not pose a threat to these populations. On October 1, 2004, the American Thyroid Association (ATA) reported that perchlorate may not be as harmful to newborns, pregnant women and other adults as previously thought.[6] The EPA and NAS divided the No Observed Effect Level (NOEL) for perchlorate of 0.007 mg/kg-d by the standard intraspecies uncertainty factor of 10 to derive a “reference dose” of 0.0007 mg/kg-d, and declared this would be protective of even the most sensitive subpopulations. Usually an additional 10-fold interspecies uncertainty factor is also used in the calculation of reference doses, but since the perchlorate NOEL was derived from a human study, rather than an animal study, this additional uncertainty factor was not used. Using the 70 kg body weight and 2 liter/day assumptions used above, this dose is converted to 25 ppb in drinking water. For that reason, most media reports call this the "safe" level of exposure. The NAS report also stated additional research would be helpful, but emphasized that the existing database on perchlorate was sufficient to make its reference dose recommendation and ensure it would be protective for everyone. Recent research, however, has shown inhibition of iodide uptake in the thyroids of women at much lower levels, levels attainable from normally contaminated water and milk.[7] # Types of perchlorates - Ammonium perchlorate, NH4ClO4 - Caesium perchlorate, CsClO4 - Lithium perchlorate, LiClO4 - Magnesium perchlorate, Mg(ClO4)2 - Perchloric acid, HClO4 - Potassium perchlorate, KClO4 - Rubidium perchlorate, RbClO4 - Silver perchlorate, AgClO4 - Sodium perchlorate, NaClO4	https://www.wikidoc.org/index.php/Perchlorate
7197985d54cabe8a383c91af2dab200eaea7f524	wikidoc	Perhexiline	Perhexiline # Overview Perhexiline is a prophylactic antianginal agent used primarily in Australia and New Zealand. Perhexiline is thought to act by inhibiting mitochondrial carnitine palmitoyltransferase-1 this shifts myocardial metabolism from fatty acid to glucose utilisation which results in increased ATP production for the same O2 consumption and consequently increases myocardial efficiency. Its clinical use has been limited by its narrow therapeutic index and high inter- and intra-individual pharmacokinetic variability. It was outlawed in many countries due to its adverse effects on poor metabolisers (PM). The product has been reintroduced for patients who have contraindications, or have not responded to, other treatments for angina. # Perhexiline Metabolism The major route of perhexiline metabolism in humans is hydroxylation by microsomal CYP2D6. The two main metabolites of perhexiline are the cis and trans isomers of hydroxyperhexiline. CYP2D6 accounts for only a small percentage of total hepatic CYP450s but it is one of the main pathways for phase one metabolism of xenobiotics. The limited availability of CYP2D6 means perhexiline metabolism is a saturable process. # Poor Metabolisers It is estimated that 7–10% of Caucasians are CYP2D6 PMs. Most PMs have an autosomal recessive polymorphism in the CYP2D6 locus which results in the severely compromised metabolism of at least 25 drugs. It is believed the there are hundreds of potential polymorphism which will result in a PM, some result in functionally deficient CYP2D6, while others cause the absence of CYP2D6. # The Hydroxyperhexiline:Perhexiline Ratio Cis-hydroxyperhexiline is the primary determinant of perhexiline clearance and there is relatively little interindividual variability in the clearance of Cis-hydroxyperhexiline; therefore, the Cis-hydroxyperhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline. There is a segment of the population with very low hydroxyperhexiline/perhexiline ratios, this subpopulation contains those patients with the PM phenotype. It has been suggested that those with ratios ≤0.3 should be considered PMs; thus, providing a simple method for identifying PMs. # Perhexiline Toxicity The adverse effects of perhexiline have been seen in more than 60% of recipients in some clinical trials. The most commonly reported adverse effects include headache, dizziness, nausea and vomiting. Plasma perhexiline concentrations as low as 0.6mg/L> are known to cause nausea and dizziness; however, perhexiline is also known to cause hepatotoxicity and peripheral neuropathy at plasma concentrations >0.6mg/L. The symptoms of peripheral neuropathy include weakness or sensory loss and pain in the arms, hand, legs, and feet. Histological investigations indicate the development of phospholipoidosis, with scaly inclusions in hepatocytes, Schwann cells and other tissues which could point to the cause of peripheral neuropathy. The peripheral neuropathy is often but not always permanent. The risk of perhexiline toxicity is reduced by therapeutic drug monitoring (TDM). The simplest way to rectify the problem of perhexiline toxicity is to stop administering the drug and allowing the plasma concentration to fall; once the concentration has reached the desired level resume the treatment at a lower dose. Most PMs should receive doses of no more than 50mg/week of perhexiline.	Perhexiline Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Perhexiline is a prophylactic antianginal agent used primarily in Australia and New Zealand. Perhexiline is thought to act by inhibiting mitochondrial carnitine palmitoyltransferase-1 this shifts myocardial metabolism from fatty acid to glucose utilisation which results in increased ATP production for the same O2 consumption and consequently increases myocardial efficiency. Its clinical use has been limited by its narrow therapeutic index and high inter- and intra-individual pharmacokinetic variability. It was outlawed in many countries due to its adverse effects on poor metabolisers (PM). The product has been reintroduced for patients who have contraindications, or have not responded to, other treatments for angina. # Perhexiline Metabolism The major route of perhexiline metabolism in humans is hydroxylation by microsomal CYP2D6.[1] The two main metabolites of perhexiline are the cis and trans isomers of hydroxyperhexiline.[1] CYP2D6 accounts for only a small percentage of total hepatic CYP450s but it is one of the main pathways for phase one metabolism of xenobiotics.[2] The limited availability of CYP2D6 means perhexiline metabolism is a saturable process.[3] # Poor Metabolisers It is estimated that 7–10% of Caucasians are CYP2D6 PMs.[4] Most PMs have an autosomal recessive polymorphism in the CYP2D6 locus which results in the severely compromised metabolism of at least 25 drugs.[5] It is believed the there are hundreds of potential polymorphism which will result in a PM, some result in functionally deficient CYP2D6, while others cause the absence of CYP2D6.[6][7] # The Hydroxyperhexiline:Perhexiline Ratio Cis-hydroxyperhexiline is the primary determinant of perhexiline clearance and there is relatively little interindividual variability in the clearance of Cis-hydroxyperhexiline;[8] therefore, the Cis-hydroxyperhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline.[8] There is a segment of the population with very low hydroxyperhexiline/perhexiline ratios, this subpopulation contains those patients with the PM phenotype.[8] It has been suggested that those with ratios ≤0.3 should be considered PMs; thus, providing a simple method for identifying PMs. # Perhexiline Toxicity The adverse effects of perhexiline have been seen in more than 60% of recipients in some clinical trials. The most commonly reported adverse effects include headache, dizziness, nausea and vomiting. Plasma perhexiline concentrations as low as 0.6mg/L> are known to cause nausea and dizziness; however, perhexiline is also known to cause hepatotoxicity and peripheral neuropathy at plasma concentrations >0.6mg/L.[9][10] The symptoms of peripheral neuropathy include weakness or sensory loss and pain in the arms, hand, legs, and feet. Histological investigations indicate the development of phospholipoidosis, with scaly inclusions in hepatocytes, Schwann cells and other tissues which could point to the cause of peripheral neuropathy.[11] The peripheral neuropathy is often but not always permanent.[10] The risk of perhexiline toxicity is reduced by therapeutic drug monitoring (TDM).[12] The simplest way to rectify the problem of perhexiline toxicity is to stop administering the drug and allowing the plasma concentration to fall;[9] once the concentration has reached the desired level resume the treatment at a lower dose. Most PMs should receive doses of no more than 50mg/week of perhexiline.[8]	https://www.wikidoc.org/index.php/Perhexiline
d296e540a96b53feae28013c018cb0947fa1a767	wikidoc	Periciazine	Periciazine # Overview Periciazine (INN), also known as pericyazine (BAN) or propericiazine, is a drug that belongs to the phenothiazine class of typical antipsychotics. Pericyazine is not approved for sale in the United States. It is commonly sold in Canada under the tradename Neuleptil and in United Kingdom and Australia under the tradename Neulactil. # Medical Uses The primary uses of pericyazine include in the short-term treatment of severe anxiety or tension and in the maintenance treatment of psychotic disorders such as schizophrenia. Periciazine has also been studied in the treatment of opioid dependence. # Adverse effects Pericyazine is a rather sedating and anticholinergic antipsychotic, and despite being classed with the typical antipsychotics, its risk of extrapyramidal side effects is comparatively low. It has a relatively high risk of causing hyperprolactinaemia and a moderate risk of causing weight gain and orthostatic hypotension.	Periciazine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Periciazine (INN), also known as pericyazine (BAN) or propericiazine, is a drug that belongs to the phenothiazine class of typical antipsychotics. Pericyazine is not approved for sale in the United States. It is commonly sold in Canada under the tradename Neuleptil and in United Kingdom and Australia under the tradename Neulactil.[2] # Medical Uses The primary uses of pericyazine include in the short-term treatment of severe anxiety or tension and in the maintenance treatment of psychotic disorders such as schizophrenia.[1] Periciazine has also been studied in the treatment of opioid dependence.[3] # Adverse effects Pericyazine is a rather sedating and anticholinergic antipsychotic, and despite being classed with the typical antipsychotics, its risk of extrapyramidal side effects is comparatively low.[4] It has a relatively high risk of causing hyperprolactinaemia and a moderate risk of causing weight gain and orthostatic hypotension.[4]	https://www.wikidoc.org/index.php/Periciazine
741cddd942017e533eb959e892d6e0a4d60c2f9a	wikidoc	Perilipin-2	Perilipin-2 Adipose differentiation-related protein, also known as perilipin 2 , ADRP or adipophilin, is a protein which belongs from PAT family of cytoplasmic lipid droplet(CLD) binding protein. In humans it is encoded by the ADFP gene. This protein surrounds the lipid droplet along with phospholipids and are involved in assisting the storage of neutral lipids within the lipid droplets. # Discovery The adipose differentiation related protein (ADRP) was first characterized as an mRNA molecule that express early in adipocyte differentiation. The full length cDNA was cloned by rapid amplification of cDNA ends method and sequence analysis results in a protein with 425 amino acids that is unique and similar sequences had not previously been reported. # Gene location In human, the gene for adipose differentiation related protein is located at short p arm of chromosome 9 at region 22 band 1 from base pair 19108391 to 19127606 (GRCh38.p7) (map). # Protein structure The proposed models for adipose differentiation related protein (perilipin 2) is maintained by the protein model portal. It is based on homology modelling and no models were found with greater than 90 percent homology. Perlipin2 has three different functional domains . 1-115 amino acid sequences at N-terminal is highly similar with other perlipin family proteins and is required for stabilization of lipid droplets, 103-215 mid- region is needed for binding at lipid droplets while the C-terminal sequence from 220-437 forms four helix bundle. # Function Perlipin 2 was thought to be expressed only in adipose tissues previously. However, later on it was found to be expressed in all types of cells including many non-adipose tissues. The function of perlipin 2 involves the formation of lipid droplets, formation of fatty liver by increasing uptake of fatty acids etc. Decreased expression of perlipin 2 decreases the fatty liver while increase expression of perlipin is associated with several metabolic diseases like type 2 diabetes, insulin resistance, heart diseases. Moreover, its expression was also found to be linked with other age related diseases. This protein is associated with the globule surface membrane material and is major constituent of the globule surface. Increase in mRNA levels is one of the earliest indications of adipocyte differentiation. Pre-adipocytes are undifferentiated fibroblasts that can be stimulated to form adipocytes. Recent studies shed light into potential molecular mechanisms in the fate determination of pre-adipocytes although the exact lineage of adipocyte is still unclear. # Mutation In humans, a substitution mutation at the C-terminal region of perlipin 2 was shown to affect both the structure and function of the protein. At 251 position , serine residue was substituted by proline which results in the disruption of predicted alpha helical structure of the protein as well as reduction in the plasma triglycerides and lipolysis. Thus, mutation in perlipin 2 may influence the development of different metabolic diseases in human. # In vitro and animal studies ## Metabolic disorders and liver diseases Conditions like obesity, type 2 diabetes are related with metabolic disorders. It involves increase accumulation of lipid due to impaired fatty acid metabolism. Alcoholic liver diseases and non-alcoholic fatty liver disease are two types of conditions associated with lipid accumulation at liver. Obesity is related with increase accumulation of lipid droplets in non-adipose tissues causing lipotoxicity. The expression of perlipin 2 at normal level appears necessary to induce obesity in mouse model. Increased activity of perlipin 2 increases the resistance to insulin thereby promoting type 2 diabetes. ## Cardiovascular diseases Age related diseases like atherosclerosis, hypertension accounts many deaths in elderly people. Accumulation of lipid droplets induce the modification of macrophages to foam cells. Lysis of foam cells resulted in Atherosclerotic plaques and such plaques rupture and blocked the thrombotic vessel. Perlipin 2 protein around the macrophages and foam cells was found to play important role in formation of atheroma. Downregulation of perlipin 2 inhibits the lipid droplet accumulation and decreases the likelihood to convert macrophages to foam cells. ## Cancer Another factor which increases the risk for cancer is aging process. Analysis of body fluids like urine and blood from circulation from different types of cancer for example colorectal cancer, Burkitt cancer, lung adenocarcinoma showed increase level of Perlipin 2. Perlipin 2 can also serve as a biomarker for early detection of some type of cancer.	Perilipin-2 Adipose differentiation-related protein, also known as perilipin 2 , ADRP or adipophilin, is a protein which belongs from PAT family of cytoplasmic lipid droplet(CLD) binding protein.[1] In humans it is encoded by the ADFP gene.[2] This protein surrounds the lipid droplet along with phospholipids and are involved in assisting the storage of neutral lipids within the lipid droplets.[3] # Discovery The adipose differentiation related protein (ADRP) was first characterized as an mRNA molecule that express early in adipocyte differentiation.[4] The full length cDNA was cloned by rapid amplification of cDNA ends method and sequence analysis results in a protein with 425 amino acids that is unique and similar sequences had not previously been reported.[4] # Gene location In human, the gene for adipose differentiation related protein is located at short p arm of chromosome 9 at region 22 band 1 from base pair 19108391 to 19127606 (GRCh38.p7) (map).[5] # Protein structure The proposed models for adipose differentiation related protein (perilipin 2) is maintained by the protein model portal.[6] It is based on homology modelling and no models were found with greater than 90 percent homology. Perlipin2 has three different functional domains . 1-115 amino acid sequences at N-terminal is highly similar with other perlipin family proteins and is required for stabilization of lipid droplets, 103-215 mid- region is needed for binding at lipid droplets while the C-terminal sequence from 220-437 forms four helix bundle.[7] # Function Perlipin 2 was thought to be expressed only in adipose tissues previously.[8] However, later on it was found to be expressed in all types of cells including many non-adipose tissues.[8] The function of perlipin 2 involves the formation of lipid droplets, formation of fatty liver by increasing uptake of fatty acids etc. Decreased expression of perlipin 2 decreases the fatty liver while increase expression of perlipin is associated with several metabolic diseases like type 2 diabetes, insulin resistance, heart diseases. Moreover, its expression was also found to be linked with other age related diseases.[3] This protein is associated with the globule surface membrane material and is major constituent of the globule surface. Increase in mRNA levels is one of the earliest indications of adipocyte differentiation.[2] Pre-adipocytes are undifferentiated fibroblasts that can be stimulated to form adipocytes. Recent studies shed light into potential molecular mechanisms in the fate determination of pre-adipocytes although the exact lineage of adipocyte is still unclear.[9] # Mutation In humans, a substitution mutation at the C-terminal region of perlipin 2 was shown to affect both the structure and function of the protein.[7] At 251 position , serine residue was substituted by proline which results in the disruption of predicted alpha helical structure of the protein as well as reduction in the plasma triglycerides and lipolysis.[10] Thus, mutation in perlipin 2 may influence the development of different metabolic diseases in human. # In vitro and animal studies ## Metabolic disorders and liver diseases Conditions like obesity, type 2 diabetes are related with metabolic disorders. It involves increase accumulation of lipid due to impaired fatty acid metabolism. Alcoholic liver diseases and non-alcoholic fatty liver disease are two types of conditions associated with lipid accumulation at liver.[11] Obesity is related with increase accumulation of lipid droplets in non-adipose tissues causing lipotoxicity. The expression of perlipin 2 at normal level appears necessary to induce obesity in mouse model. Increased activity of perlipin 2 increases the resistance to insulin thereby promoting type 2 diabetes.[11] ## Cardiovascular diseases Age related diseases like atherosclerosis, hypertension accounts many deaths in elderly people.[12] Accumulation of lipid droplets induce the modification of macrophages to foam cells. Lysis of foam cells resulted in Atherosclerotic plaques and such plaques rupture and blocked the thrombotic vessel.[12] Perlipin 2 protein around the macrophages and foam cells was found to play important role in formation of atheroma. Downregulation of perlipin 2 inhibits the lipid droplet accumulation and decreases the likelihood to convert macrophages to foam cells.[13] ## Cancer Another factor which increases the risk for cancer is aging process.[14] Analysis of body fluids like urine and blood from circulation from different types of cancer for example colorectal cancer, Burkitt cancer, lung adenocarcinoma showed increase level of Perlipin 2.[15] Perlipin 2 can also serve as a biomarker for early detection of some type of cancer.[16]	https://www.wikidoc.org/index.php/Perilipin-2
82480882d88ba97c020b4ed6b5d2ad07d0abafcd	wikidoc	Perilipin-3	Perilipin-3 Mannose-6-phosphate receptor binding protein 1 (M6PRBP1) is a protein which in humans is encoded by the M6PRBP1 gene. Its gene product, as well as the gene itself, is commonly known as TIP47. # Function Mannose 6-phosphate receptors (MPRs) deliver lysosomal hydrolase from the Golgi to endosomes and then return to the Golgi complex. The protein encoded by this gene interacts with the cytoplasmic domains of both cation-independent and cation-dependent MPRs, and is required for endosome-to-Golgi transport. This protein also binds directly to the GTPase RAB9 (RAB9A), a member of the RAS oncogene family. The interaction with RAB9 has been shown to increase the affinity of this protein for its cargo. The mannose-6-phosphate receptor-binding properties of TIP47 are disputed, despite the designation of M6PRBP1 as TIP47's gene symbol. TIP47 protein is most commonly described in the scientific literature as a coat protein for lipid droplets. TIP47 belongs to the peripilin protein family and shares significant homology with the other genes of this family, including perilipin and adipophilin. # Interactions M6PRBP1 has been shown to interact with both Mannose 6-phosphate receptors.	Perilipin-3 Mannose-6-phosphate receptor binding protein 1 (M6PRBP1) is a protein which in humans is encoded by the M6PRBP1 gene.[1] Its gene product, as well as the gene itself, is commonly known as TIP47. # Function Mannose 6-phosphate receptors (MPRs) deliver lysosomal hydrolase from the Golgi to endosomes and then return to the Golgi complex. The protein encoded by this gene interacts with the cytoplasmic domains of both cation-independent and cation-dependent MPRs, and is required for endosome-to-Golgi transport. This protein also binds directly to the GTPase RAB9 (RAB9A), a member of the RAS oncogene family. The interaction with RAB9 has been shown to increase the affinity of this protein for its cargo.[2] The mannose-6-phosphate receptor-binding properties of TIP47 are disputed,[3] despite the designation of M6PRBP1 as TIP47's gene symbol. TIP47 protein is most commonly described in the scientific literature as a coat protein for lipid droplets.[4] TIP47 belongs to the peripilin protein family and shares significant homology with the other genes of this family, including perilipin and adipophilin.[5] # Interactions M6PRBP1 has been shown to interact with both Mannose 6-phosphate receptors.[6][7]	https://www.wikidoc.org/index.php/Perilipin-3
e08adeee10a91dc0eb61fbbd6a02b356bcf91493	wikidoc	Perilipin-4	Perilipin-4 Perilipin 4, also known as S3-12, is a protein that in humans is encoded by the PLIN4 gene on chromosome 19. It is highly expressed in white adipose tissue, with lower expression in heart, skeletal muscle, and brown adipose tissue. PLIN4 coats lipid droplets in adipocytes to protect them from lipases. The PLIN4 gene may be associated with insulin resistance and obesity risk. # Structure ## Gene The PLIN4 gene resides on chromosome 19 at the band 19p13.3 and contains 9 exons. ## Protein This protein belongs to the perilipin family and contains 27 33-amino acid approximate tandem repeats. It is also one of the perilipin members of the PATS (PLIN, ADFP, TIP47, S3-12) family, which is named after structural proteins that share high amino acid sequence similarity and associate with lipid droplets. It shares a conserved C-terminal of 14 amino acid residues that folds into a hydrophobic cleft with other PATS members; however, it is missing the conserved N-terminal region of approximately 100 amino acid residues. Within the sequence of 33-amino acid repeats, PLIN4 contains a long stretch of imperfect 11-mer repeats predicted to form amphipathic helices with three helical turns per 11 amino acid residues. This 11-mer repeats tract is proposed to anchor the protein to the phospholipid monolayer of lipid droplets for its assembly, though no targeting sequence has yet been found in PLIN4. # Function PLIN4 is a member of the perilipin family, a group of proteins that coat lipid droplets in adipocytes, the adipose tissue cells that are responsible for storing fat. Perilipin acts as a protective coating from the body’s natural lipases, such as hormone-sensitive lipase, which break triglycerides into glycerol and free fatty acids for use in metabolism, a process called lipolysis. In humans, perilipin is expressed as 5 different isoforms; it is currently understood that the level of expression for each isoform is dependent on factors such as sex, body mass index, and level of endurance exercise. PLIN4 is hyperphosphorylated by PKA following β-adrenergic receptor activation. Phosphorylated perilipin changes conformation, exposing the stored lipids to hormone-sensitive lipase-mediated lipolysis. Although PKA also phosphorylates hormone-sensitive lipase, which can increase its activity, the more than 50-fold increase in fat mobilization (triggered by epinephrine) is primarily due to perilipin phosphorylation. # Clinical significance The proteins in the Perilipin family are crucial regulators of lipid storage. PLIN4 expression is elevated in obese animals and humans. Perilipin-null mice eat more food than wild-type mice, but gain 1/3 less fat than wild-type mice on the same diet; perilipin-null mice are thinner, with more lean muscle mass. Perilipin-null mice also exhibit enhanced leptin production and a greater tendency to develop insulin resistance than wild-type mice. The PLIN4 gene, along with PLIN2, PLIN3, and PLIN5, have been associated with variance in body-weight regulation and may be a genetic influence on obesity risk in humans. # Interactions PLIN4 has been shown to interact with Caspase 8 and Ubiquitin C.	Perilipin-4 Perilipin 4, also known as S3-12, is a protein that in humans is encoded by the PLIN4 gene on chromosome 19.[1][2] It is highly expressed in white adipose tissue, with lower expression in heart, skeletal muscle, and brown adipose tissue.[3] PLIN4 coats lipid droplets in adipocytes to protect them from lipases.[4][5] The PLIN4 gene may be associated with insulin resistance and obesity risk.[6] # Structure ## Gene The PLIN4 gene resides on chromosome 19 at the band 19p13.3 and contains 9 exons.[1] ## Protein This protein belongs to the perilipin family and contains 27 33-amino acid approximate tandem repeats.[7] It is also one of the perilipin members of the PATS (PLIN, ADFP, TIP47, S3-12) family, which is named after structural proteins that share high amino acid sequence similarity and associate with lipid droplets.[2] It shares a conserved C-terminal of 14 amino acid residues that folds into a hydrophobic cleft with other PATS members; however, it is missing the conserved N-terminal region of approximately 100 amino acid residues. Within the sequence of 33-amino acid repeats, PLIN4 contains a long stretch of imperfect 11-mer repeats predicted to form amphipathic helices with three helical turns per 11 amino acid residues. This 11-mer repeats tract is proposed to anchor the protein to the phospholipid monolayer of lipid droplets for its assembly, though no targeting sequence has yet been found in PLIN4.[3] # Function PLIN4 is a member of the perilipin family, a group of proteins that coat lipid droplets in adipocytes,[4] the adipose tissue cells that are responsible for storing fat. Perilipin acts as a protective coating from the body’s natural lipases, such as hormone-sensitive lipase,[5] which break triglycerides into glycerol and free fatty acids for use in metabolism, a process called lipolysis.[8] In humans, perilipin is expressed as 5 different isoforms; it is currently understood that the level of expression for each isoform is dependent on factors such as sex, body mass index, and level of endurance exercise.[9] PLIN4 is hyperphosphorylated by PKA following β-adrenergic receptor activation. Phosphorylated perilipin changes conformation, exposing the stored lipids to hormone-sensitive lipase-mediated lipolysis. Although PKA also phosphorylates hormone-sensitive lipase, which can increase its activity, the more than 50-fold increase in fat mobilization (triggered by epinephrine) is primarily due to perilipin phosphorylation. # Clinical significance The proteins in the Perilipin family are crucial regulators of lipid storage.[8] PLIN4 expression is elevated in obese animals and humans. Perilipin-null mice eat more food than wild-type mice, but gain 1/3 less fat than wild-type mice on the same diet; perilipin-null mice are thinner, with more lean muscle mass.[10] Perilipin-null mice also exhibit enhanced leptin production and a greater tendency to develop insulin resistance than wild-type mice. The PLIN4 gene, along with PLIN2, PLIN3, and PLIN5, have been associated with variance in body-weight regulation and may be a genetic influence on obesity risk in humans.[6] # Interactions PLIN4 has been shown to interact with Caspase 8 and Ubiquitin C.[11]	https://www.wikidoc.org/index.php/Perilipin-4
199002d8ea1b67d540f303c9ffdafc302142578f	wikidoc	Perilipin-5	Perilipin-5 Perilipin 5, also known as Oxpatperilipin 5 or PLIN5, is a protein that belongs to perilipin family. This protein group has been shown to be responsible for lipid droplet's biogenesis, structure and degradation. In particular, Perilipin 5 is a lipid droplet-associated protein whose function is to keep the balance between lipolysis and lipogenesis, as well as maintaining lipid droplet homeostasis. For example, in oxidative tissues, muscular tissues and cardiac tissues, PLIN5 promotes association between lipid droplets and mitochondria. Inside the cell, PLIN5 can be found in multiple intracellular structures including lipid droplets, endoplasmic reticulum, mitochondria, and the cytosol.The wrong expression of this protein has been proven to be related with diseases such as skeletal muscle diseases, liver diseases or carcinogenesis. # Perilipin Protein Family PLIN5 is the fifth of the 5 perilipins which can be found on humans. All of them (PLIN1,ADRP,TIP47,S3-12 and PLIN5) have similar funcionality, relating to lipid droplets. They have a 1,252% similarity with 76 identical positions. On the other hand, PLIN5 has its most similarity with PLINS 2 and 3, with over 150 similar positions and 18,644% similarity. # Structure Perilipin 5 is a relatively large protein. It is composed of 463 amino acids, weighing an average of 50.8 kDa. It contains four basic regions: - from amino acid 1 to 173: key region for lipid droplet targeting. - from amino acid 1 to 108: interaction with LIPE, a gene that encodes the formation of hormone-sensitive lipase, also known as HSL, whose main function is to mobilize the previously stored fats. - from amino acid 185 to 463: interactions with PNPLA2 and ABHD5. - from amino acid 444 to 463: targets mitochondria for lipid droplet-mitochondria association. PLIN5 is expressed in 183 organs, having its highest expression level on the stomach fundus. Protein Kinase A (PKA) phosphorylates residues 2, 148 and 322. Phosphorylation by PKA enables lipolysis probably by promoting the release of ABHD5 from the perilipin scaffold. ## Evolution Perilipins are considered to have evolved from a common ancestral gene. This family began to split during the first and second vertebrate genome duplication, giving birth to six types of PLIN genes, expressed throughout the animal kingdom. However, not all types are present in all animals. In fish, PLIN 1 to 6 can be found, whereas in mammals only PLIN1 to 5. # Function Perilipin 5 is a protein often found in the adipose tissue, especially in those with high oxidative stress, including the heart, liver, skeletal muscle and brown adipose tissue (BAT). The perilipin family contributes to the creation of lipid droplets and it also plays a pivotal role in determining what the lipid droplet's function is within the cell. In addition, perilipin 5 regulates the activation of hepatic stellate cell, implicated in fibrosis, which is the creation of new tissue to repair the one damaged. ## Beta oxidation PLIN5, as well as the other members of this protein family, is involved in lipid storage and also has energetic functions. Perilipin 5 coats the lipid droplet acting as a barrier to triglyceride, thus increasing its storage. Under basal condition, PLIN5 decreases lipolysis to prevent energy waste. If energy is needed, perilipin facilitates lipid droplets with lipases and promotes enzymatic activity, regulating energy consumption. ## Perilipin 5-Nucleus interactions The mechanism by which OXPAT5 balances energy remain to be fully clarified. It interacts mainly with LDs, though recent data suggest that this protein also targets the nucleus. When needed, perilipin 5 is phosphorylated by protein kinase A, which allows it to access the nucleus and enter the complex SIRT1/PGC-1α, involved in fatty acid oxidation. PLIN5 removes SIRT1 inhibitor DBC1, therefore increasing its activity. As a consequence, PGC-1α boost activity levels activating certain types of genes that enhances mitochondrial function. ## Mitochondria and Perilipin 5 Higher levels of perilipin 5 are closely related to the association between lipid droplet and mitochondria. This is useful in case of starvation (energy shortage). When energy is needed and no glucose is available, the cell uses lipids to feed itself. In order to do that, lipid droplets move towards the mitochondria to transfer the stored fatty acids. The perilipin family opens the channel, giving way to lipids to access the mitochondria. On the other hand, this association may occur with the aim of protecting the mitochondria against toxic levels of fatty acids in the cytosol. ## Mean Corspuscular Volume PLIN5 is an enhancer of the erythrocytes count in blood, as well as hemoglobin concentration. ## Lipid Droplet Formation Mammalian Plin's are not necessary for Lipid Droplet biogenesis, but as they are the primary regulators of lipolysis, they control cellular TAG/CE levels, long-chains whose functions is to provide enough metabolic precursors as polar lipids, which will then create Lipid Droplets. # Clinical importance PLIN5 is an important regulator of cardiac and liver LDs. Both overexpression and deficiency result in serious consequences. ## Overexpression Perilipin 5 overexpression causes LD enlargement, accumulation of triglycerides (TAG) and mitochondria disfunction, causing severe health issues. ### Cardiac steatosis An increase in PLIN5 expression leads to the accumulation of triglyceride content and to the enlargement of LDs and a reduction in its number. This results in cardiac steatosis, an abnormal retention of lipids within a cell. Despite massive steatosis, overexpression of cardiac PLIN5 is compatible with normal heart function and lifespan. Overexpression of PLIN5 also results in concentric hypertrophia on the left ventricle. ### Fragmentation of mitochondria Overexpression of PLIN5 causes a decrease in mitochondria function as it leads to the "recruitment" of mitochondria to the LD and its fragmentation. This results in smaller mitochondrial structures partly or completely surrounding individual LDs or entire LD cluster. Such LD-mitochondria assemblies typically move in unison due to their tight association. This aberrant mitochondrial phenotype was only observed in close proximity to LDs. Fractions of mitochondria located apart from LD were still elongated. ### Fatty liver disease PLIN5 plays an important role in regulating lipid accumulation and its breakdown in the liver. It appears that statins, a class of lipid-lowering medication, were effective in treating fatty liver diseases in non-alcoholic patients, as it decreased the hepatic expression of PLIN5, thus decreasing lipid accumulation. ## Deficiency When LDs are lost due to a deficiency in PLIN5, FAs are not sequestered as TAG in LD and therefore larger amounts of FAs are oxidized in the mitochondria leading to an excess generation of reactive oxygen species (ROS). Medium and high concentrations of ROS can induce apoptosis and eventually cause necrosis through oxidative stress. PLIN deficiency also reduces superoxide dismutase (SOD) activity. Furthermore, deficiency in PLIN5 initiates excessive phosforilation of PI3K/Akt which contributes to ischemia-reperfusion injury aggravation. PLIN5-knockout diabetic mice might avoid excess accumulation of lipotoxic molecules such as DAG and ceramide, a common problem among diabetic patients. The built up of DAG and ceramide disrupts several signaling pathways, including PKC pathway. However, in humans, the association is not clear and the packaging of TAG into lipid droplets may be of critical importance in determining whether the accumulation of excess lipids exert a toxic effect on the myocardium. It was found that a deficiency in Plin5 reduces mitochondrial oxidative capacity in mouses. Mitochondria from hearts suffering from a Plin5 deficiency had a membrana whose fatty acyl composition was altered, and its depolarization was compromised. It was also discovered in mice that, if a whole body defficiency of Plin5 was to happen, cardiac lipid droplet formation ability would be reduced, increasing fatty acid oxidations and promoting cardiac dysfunction. This, however, could be prevented by anti-oxidative therapy. ### Atherosclerosis Deficiency in PLIN5 increases monocytes which are critical participants in the inflammation process. Because inflammation is essential to atherosclerosis, a deficiency in PLIN5 increases atherosclerosis risk.	Perilipin-5 Perilipin 5, also known as Oxpatperilipin 5 or PLIN5, is a protein that belongs to perilipin family. This protein group has been shown to be responsible for lipid droplet's biogenesis, structure and degradation.[1] In particular, Perilipin 5 is a lipid droplet-associated protein whose function is to keep the balance between lipolysis and lipogenesis, as well as maintaining lipid droplet homeostasis. For example, in oxidative tissues, muscular tissues and cardiac tissues, PLIN5 promotes association between lipid droplets and mitochondria.[2] Inside the cell, PLIN5 can be found in multiple intracellular structures including lipid droplets, endoplasmic reticulum, mitochondria, and the cytosol.[3]The wrong expression of this protein has been proven to be related with diseases such as skeletal muscle diseases, liver diseases or carcinogenesis.[4] # Perilipin Protein Family PLIN5 is the fifth of the 5 perilipins which can be found on humans. All of them (PLIN1,ADRP,TIP47,S3-12 and PLIN5) have similar funcionality, relating to lipid droplets. They have a 1,252% similarity with 76 identical positions. On the other hand, PLIN5 has its most similarity with PLINS 2 and 3, with over 150 similar positions and 18,644% similarity. # Structure Perilipin 5 is a relatively large protein. It is composed of 463 amino acids, weighing an average of 50.8 kDa. It contains four basic regions: - from amino acid 1 to 173: key region for lipid droplet targeting. - from amino acid 1 to 108: interaction with LIPE, a gene that encodes the formation of hormone-sensitive lipase, also known as HSL, whose main function is to mobilize the previously stored fats. - from amino acid 185 to 463: interactions with PNPLA2 and ABHD5. - from amino acid 444 to 463: targets mitochondria for lipid droplet-mitochondria association. PLIN5 is expressed in 183 organs, having its highest expression level on the stomach fundus. Protein Kinase A (PKA) phosphorylates residues 2, 148 and 322. Phosphorylation by PKA enables lipolysis probably by promoting the release of ABHD5 from the perilipin scaffold. ## Evolution Perilipins are considered to have evolved from a common ancestral gene. This family began to split during the first and second vertebrate genome duplication,[5] giving birth to six types of PLIN genes, expressed throughout the animal kingdom. However, not all types are present in all animals. In fish, PLIN 1 to 6 can be found, whereas in mammals only PLIN1 to 5.[6] # Function Perilipin 5 is a protein often found in the adipose tissue, especially in those with high oxidative stress, including the heart, liver, skeletal muscle and brown adipose tissue (BAT).[7][8] The perilipin family contributes to the creation of lipid droplets and it also plays a pivotal role in determining what the lipid droplet's function is within the cell.[9] In addition, perilipin 5 regulates the activation of hepatic stellate cell, implicated in fibrosis, which is the creation of new tissue to repair the one damaged.[10] ## Beta oxidation PLIN5, as well as the other members of this protein family, is involved in lipid storage and also has energetic functions. Perilipin 5 coats the lipid droplet acting as a barrier to triglyceride, thus increasing its storage.[11] Under basal condition, PLIN5 decreases lipolysis to prevent energy waste. If energy is needed, perilipin facilitates lipid droplets with lipases and promotes enzymatic activity, regulating energy consumption.[12] ## Perilipin 5-Nucleus interactions The mechanism by which OXPAT5 balances energy remain to be fully clarified. It interacts mainly with LDs, though recent data suggest that this protein also targets the nucleus. When needed, perilipin 5 is phosphorylated by protein kinase A, which allows it to access the nucleus and enter the complex SIRT1/PGC-1α, involved in fatty acid oxidation. PLIN5 removes SIRT1 inhibitor DBC1, therefore increasing its activity. As a consequence, PGC-1α boost activity levels activating certain types of genes that enhances mitochondrial function.[13] ## Mitochondria and Perilipin 5 Higher levels of perilipin 5 are closely related to the association between lipid droplet and mitochondria. This is useful in case of starvation (energy shortage). When energy is needed and no glucose is available, the cell uses lipids to feed itself. In order to do that, lipid droplets move towards the mitochondria to transfer the stored fatty acids. The perilipin family opens the channel, giving way to lipids to access the mitochondria. On the other hand, this association may occur with the aim of protecting the mitochondria against toxic levels of fatty acids in the cytosol.[14] ## Mean Corspuscular Volume PLIN5 is an enhancer of the erythrocytes count in blood, as well as hemoglobin concentration.[15] ## Lipid Droplet Formation Mammalian Plin's are not necessary for Lipid Droplet biogenesis, but as they are the primary regulators of lipolysis, they control cellular TAG/CE levels, long-chains whose functions is to provide enough metabolic precursors as polar lipids, which will then create Lipid Droplets. # Clinical importance PLIN5 is an important regulator of cardiac and liver LDs. Both overexpression and deficiency result in serious consequences. ## Overexpression Perilipin 5 overexpression causes LD enlargement, accumulation of triglycerides (TAG) and mitochondria disfunction, causing severe health issues. ### Cardiac steatosis An increase in PLIN5 expression leads to the accumulation of triglyceride content and to the enlargement of LDs and a reduction in its number. This results in cardiac steatosis, an abnormal retention of lipids within a cell. Despite massive steatosis, overexpression of cardiac PLIN5 is compatible with normal heart function and lifespan.[16] Overexpression of PLIN5 also results in concentric hypertrophia on the left ventricle.[17] ### Fragmentation of mitochondria Overexpression of PLIN5 causes a decrease in mitochondria function as it leads to the "recruitment" of mitochondria to the LD and its fragmentation. This results in smaller mitochondrial structures partly or completely surrounding individual LDs or entire LD cluster. Such LD-mitochondria assemblies typically move in unison due to their tight association. This aberrant mitochondrial phenotype was only observed in close proximity to LDs. Fractions of mitochondria located apart from LD were still elongated.[18] ### Fatty liver disease PLIN5 plays an important role in regulating lipid accumulation and its breakdown in the liver. It appears that statins, a class of lipid-lowering medication, were effective in treating fatty liver diseases in non-alcoholic patients, as it decreased the hepatic expression of PLIN5, thus decreasing lipid accumulation.[19] ## Deficiency When LDs are lost due to a deficiency in PLIN5, FAs are not sequestered as TAG in LD and therefore larger amounts of FAs are oxidized in the mitochondria leading to an excess generation of reactive oxygen species (ROS). Medium and high concentrations of ROS can induce apoptosis and eventually cause necrosis through oxidative stress.[20] PLIN deficiency also reduces superoxide dismutase (SOD) activity. Furthermore, deficiency in PLIN5 initiates excessive phosforilation of PI3K/Akt which contributes to ischemia-reperfusion injury aggravation. PLIN5-knockout diabetic mice might avoid excess accumulation of lipotoxic molecules such as DAG and ceramide, a common problem among diabetic patients. The built up of DAG and ceramide disrupts several signaling pathways, including PKC pathway. However, in humans, the association is not clear and the packaging of TAG into lipid droplets may be of critical importance in determining whether the accumulation of excess lipids exert a toxic effect on the myocardium. It was found that a deficiency in Plin5 reduces mitochondrial oxidative capacity in mouses. Mitochondria from hearts suffering from a Plin5 deficiency had a membrana whose fatty acyl composition was altered, and its depolarization was compromised.[21] It was also discovered in mice that, if a whole body defficiency of Plin5 was to happen, cardiac lipid droplet formation ability would be reduced, increasing fatty acid oxidations and promoting cardiac dysfunction. This, however, could be prevented by anti-oxidative therapy. ### Atherosclerosis Deficiency in PLIN5 increases monocytes which are critical participants in the inflammation process. Because inflammation is essential to atherosclerosis, a deficiency in PLIN5 increases atherosclerosis risk.[22]	https://www.wikidoc.org/index.php/Perilipin-5
f6c7d00b05b551fc0082918f366010fac83fe92c	wikidoc	Periodicity	Periodicity In Chemistry, periodic trends are the tendencies of certain elemental characteristics to increase or decrease as one progresses from one corner of the Periodic table of elements. # Acidity The Lewis acidity of each element tends to increase when moving from left to right in the periodic table. However, it decreases going down the table. This is due to the electronegativity of the elements. Elements to the right tend to have a greater way of attracting electrons then those on the left, making the left ones more basic whilst the right ones are acidic. The Lewis acidity decreases going down however in a group as is evident to increasing metallic nature of the elements in group four. # Atomic radius The atomic radius is the distance from the atomic nucleus to the outermost stable electron orbital in an atom that is at equilibrium. The atomic radius tends to decrease as one progresses across a period because the effective nuclear charge increases, thereby attracting the orbiting electrons and lessening the radius. The atomic radius also will usually increase as one descends a group of the period table because the energy level (shell) increases down the group causing the outer shell electrons to be further away from the nucleus, thereby heavily increasing the atomic size. However, diagonally, the number of protons has a larger effect than the sizeable radius. For example, lithium (145 pm) has a smaller atomic radius than magnesium (150 pm). Atomic radii decrease left to right across a period. (it's just that simple...) # Ionization potential The ionization potential (or the ionization energy) is the miniumum energy required to remove one electron from each atom in a mole of atoms in the gaseous state. The first ionization energy is the energy required to remove one, the nth ionization energy is the energy required to remove the atom's nth electron, not including the n-1 electrons before it. Trend-wise, the ionization potentials tend to increase while one progresses across a period because the greater number of protons (higher nuclear charge) attract the orbiting electrons more strongly, thereby increasing the energy required to remove one of the electrons. As one progresses down a group on the periodic table, the ionization energy will likely decrease, due to the greater number of shells, thereby positioning the valence electrons further from the protons, which attract them less, thereby requiring less energy to remove them. There will be an increase of ionization energy from left to right of a given period and a decrease from top to bottom. As a rule, it requires far less energy to remove an outer-shell electron than an inner-shell electron. As a result the ionization energies for a given element will increase steadily within a given shell, and when starting on the next shell down will show a drastic jump in ionization energy. Simply put, the lower the principal quantum number, the higher the ionization energy for the electrons within that shell. # Electron affinity The electron affinity is (officially) the energy required to detach an electron from a singly-charged anion. More commonly, the electron affinity measures the energy released when an electron is added to a stable atom, thereby creating an anion. As one progresses across a period, the electron affinity will increase, due to the larger attraction from the nucleus, and the atom "wanting" the electron more as it reaches maximum stability. Down a group, the electron affinity decreases because of a large increase in the atomic radius and the number of electrons that decrease the stability of the atom, repulsing each other. # Electronegativity Electronegativity is a measure of the ability of an atom or molecule to attract electrons in the context of a chemical bond. The type of bond formed is largely determined by the difference in electronegativity between the atoms involved, using the Pauling scale. Trend-wise, as one moves horizontally across a period in the periodic table, the electronegativity increases due to the stronger attraction that the atoms obtain as the nuclear charge increases. Moving down a group, the electronegativity decreases due to the larger distance between the nucleus and the valence electron shell, thereby decreasing the attraction, making the atom have less of an attraction for electrons or protons # Metallic character Metallic character refers to the chemical properties associated with elements classified as metals. These properties, which arise from the element's ability to lose electrons, are: the displacement of hydrogen from dilute acids; the formation of basic oxides; the formation of ionic chlorides; and their reduction reaction, as in the thermite process. As one moves across a period from left to right in the periodic table, the metallic character decreases, as the atoms are more likely to gain electrons to fill their valence shell rather than to lose them to remove the shell. Down a group, the metallic character increases, due to the lesser attraction from the nucleus to the valence electrons (in turn due to the atomic radius), thereby allowing easier loss of the outer electrons or protons # Nuclear charge Increases going from top to bottom, and left to right across the periodic table. The increase in nuclear charge is greater going from top to bottom of the periodic table, than going from left to right in the periodic table. This is due to as you go from left to right in the periodic table an extra proton is added to the nucleus, the proton carries a positive charge, so the charge of the nucleus increases for each proton added. Whereas when you go down a group there is a greater increase, this is due to there being a larger number of protons added each time. The increase in nuclear charge is equal to the number of elements between the element in the period after the first element in the group and the number before the element in the next period. For example, the nuclear charge from Carbon to Silicon will increase by 8, this is because an extra proton is added for each element, nitrogen, oxygen, fluorine, neon, sodium, magnesium, aluminium and one more added to the nucleus of silicon. # Shielding The shielding of outer level electrons increases as you go down the groups in the periodic table. This is because there are extra levels of electrons between the nucleus and outer electrons. However as you go across a period the shielding does not increase. This is because there are no extra levels of electrons between the nucleus and outer level of electrons, only extra electrons are added to the outer level of electrons as you go across the period.	Periodicity In Chemistry, periodic trends are the tendencies of certain elemental characteristics to increase or decrease as one progresses from one corner of the Periodic table of elements. # Acidity The Lewis acidity of each element tends to increase when moving from left to right in the periodic table. However, it decreases going down the table. This is due to the electronegativity of the elements. Elements to the right tend to have a greater way of attracting electrons then those on the left, making the left ones more basic whilst the right ones are acidic. The Lewis acidity decreases going down however in a group as is evident to increasing metallic nature of the elements in group four. # Atomic radius The atomic radius is the distance from the atomic nucleus to the outermost stable electron orbital in an atom that is at equilibrium. The atomic radius tends to decrease as one progresses across a period because the effective nuclear charge increases, thereby attracting the orbiting electrons and lessening the radius. The atomic radius also will usually increase as one descends a group of the period table because the energy level (shell) increases down the group causing the outer shell electrons to be further away from the nucleus, thereby heavily increasing the atomic size. However, diagonally, the number of protons has a larger effect than the sizeable radius. For example, lithium (145 pm) has a smaller atomic radius than magnesium (150 pm). Atomic radii decrease left to right across a period. (it's just that simple...) # Ionization potential The ionization potential (or the ionization energy) is the miniumum energy required to remove one electron from each atom in a mole of atoms in the gaseous state. The first ionization energy is the energy required to remove one, the nth ionization energy is the energy required to remove the atom's nth electron, not including the n-1 electrons before it. Trend-wise, the ionization potentials tend to increase while one progresses across a period because the greater number of protons (higher nuclear charge) attract the orbiting electrons more strongly, thereby increasing the energy required to remove one of the electrons. As one progresses down a group on the periodic table, the ionization energy will likely decrease, due to the greater number of shells, thereby positioning the valence electrons further from the protons, which attract them less, thereby requiring less energy to remove them. There will be an increase of ionization energy from left to right of a given period and a decrease from top to bottom. As a rule, it requires far less energy to remove an outer-shell electron than an inner-shell electron. As a result the ionization energies for a given element will increase steadily within a given shell, and when starting on the next shell down will show a drastic jump in ionization energy. Simply put, the lower the principal quantum number, the higher the ionization energy for the electrons within that shell. # Electron affinity The electron affinity is (officially) the energy required to detach an electron from a singly-charged anion. More commonly, the electron affinity measures the energy released when an electron is added to a stable atom, thereby creating an anion. As one progresses across a period, the electron affinity will increase, due to the larger attraction from the nucleus, and the atom "wanting" the electron more as it reaches maximum stability. Down a group, the electron affinity decreases because of a large increase in the atomic radius and the number of electrons that decrease the stability of the atom, repulsing each other. # Electronegativity Electronegativity is a measure of the ability of an atom or molecule to attract electrons in the context of a chemical bond. The type of bond formed is largely determined by the difference in electronegativity between the atoms involved, using the Pauling scale. Trend-wise, as one moves horizontally across a period in the periodic table, the electronegativity increases due to the stronger attraction that the atoms obtain as the nuclear charge increases. Moving down a group, the electronegativity decreases due to the larger distance between the nucleus and the valence electron shell, thereby decreasing the attraction, making the atom have less of an attraction for electrons or protons # Metallic character Metallic character refers to the chemical properties associated with elements classified as metals. These properties, which arise from the element's ability to lose electrons, are: the displacement of hydrogen from dilute acids; the formation of basic oxides; the formation of ionic chlorides; and their reduction reaction, as in the thermite process. As one moves across a period from left to right in the periodic table, the metallic character decreases, as the atoms are more likely to gain electrons to fill their valence shell rather than to lose them to remove the shell. Down a group, the metallic character increases, due to the lesser attraction from the nucleus to the valence electrons (in turn due to the atomic radius), thereby allowing easier loss of the outer electrons or protons # Nuclear charge Increases going from top to bottom, and left to right across the periodic table. The increase in nuclear charge is greater going from top to bottom of the periodic table, than going from left to right in the periodic table. This is due to as you go from left to right in the periodic table an extra proton is added to the nucleus, the proton carries a positive charge, so the charge of the nucleus increases for each proton added. Whereas when you go down a group there is a greater increase, this is due to there being a larger number of protons added each time. The increase in nuclear charge is equal to the number of elements between the element in the period after the first element in the group and the number before the element in the next period. For example, the nuclear charge from Carbon to Silicon will increase by 8, this is because an extra proton is added for each element, nitrogen, oxygen, fluorine, neon, sodium, magnesium, aluminium and one more added to the nucleus of silicon. # Shielding The shielding of outer level electrons increases as you go down the groups in the periodic table. This is because there are extra levels of electrons between the nucleus and outer electrons. However as you go across a period the shielding does not increase. This is because there are no extra levels of electrons between the nucleus and outer level of electrons, only extra electrons are added to the outer level of electrons as you go across the period. Template:WS	https://www.wikidoc.org/index.php/Period
de9a856d10b1fff8deb76acb7dcdd2e28eac31ba	wikidoc	Periodinane	Periodinane Periodinanes are chemical compounds containing hypervalent iodine. These iodine compounds are hypervalent because the iodine atom in it contains more than the 8 electrons in the valence shell required for the octet rule. When iodine is complexed with a monodentate electronegative ligand such as chlorine, iodine compounds occur with a +3 oxidation number as iodine(III) or λ3-iodanes or as a +5 oxidation number as iodine(V) or λ5-iodanes. Iodine itself contains 7 valence electrons and in a λ3-iodane three more are donated by the ligands making it a decet structure. λ5-iodanes are dodecet molecules. In an ordinary iodine compound such as iodobenzene the number of valence electrons is eight as expected. In order to get from iodine to a hypervalent iodine compound it gets oxidized with removal of first 3 electrons and then 5 electrons. The ligands in turn contribute electrons pairs and form coordinate covalent bonds by adding a total of 6 or 10 electrons back to iodine. In the L-I-N notation L stand for the number of electrons donated by ligands and N the number of ligands. # Periodinane compounds The concept of hypervalent iodine was developed by J.J. Musher in 1969. In order to accommodate the excess of electrons in hypervalent compounds the 3-center-4-electron bond was introduced in analogy with the 3-center-2-electron bond observed in electron deficient compounds. One such bond exists in iodine(III) compounds and two such bonds reside in iodine(V) compounds. The first hypervalent iodine compound, dichloroiodobenzene (C6H5Cl2I) was prepared in 1886 by the German chemist C. Willgerodt by passing chlorine gas through iodobenzene in a cooled solution of chloroform. λ3-iodanes such as diarylchloroiodanes have a pseudotrigonal bipyramidal geometry displaying apicophilicity with a phenyl group and a chlorine group at the apical positions and other phenyl group with two lone pair electrons in the equatorial positions. The λ5-iodanes such as the Dess-Martin periodinane have square pyramidal geometries with 4 heteroatoms in basal positions and one apical phenyl group. Classical organic procedures exist for the preparation of iodosobenzene diacetate from peracetic acid and acetic acid . Phenyliodine bis(trifluoroacetate) or PIFA is a related compound based on trifluoroacetic acid The acetate can be hydrolysed with water to iodoxybenzene or iodylbenzene C6H5O2I This compound was first prepared by Willgerodt by disproportionation of iodosylbenzene under steam distillation to iodylbenzene and iodobenzene is a known oxidizing agent. Iodosobenzene diacetate can also be hydrolyzed to iodosylbenzene with sodium hydroxide which is actually a polymer with the molecular formula (C6H5OI)n . Iodosylbenzene is used in organic oxidations. Dess-Martin periodinane (1983) is another powerful oxidant and an improvement of the IBX acid already in existence in 1893. The IBX acid is prepared from 2-iodobenzoic acid and potassium bromate and sulfuric acid and is insoluble in most solvents whereas the Dess-Martin reagent prepared from reaction of the IBX acid with acetic anhydride is very soluble. The oxidation mechanism ordinarily consists of a ligand exchange reaction followed by a reductive elimination. # Periodinane uses The predominant use of hypervalent iodine compounds is that of oxidizing reagent replacing many toxic reagents based on heavy metals . Current research focuses on their use in carbon-carbon and carbon-heteroatom bond forming reactions. In one study such reaction, an intramolecular C-N coupling of an alkoxyhydroxylamine to its anisole group is accomplished with a catalytic amount of aryliodide in trifluoroethanol : In this reaction the periodinane (depicted as intermediate A) is formed by oxidation of the aryliodide with the sacrificial catalyst mCPBA which in turn converts the hydroxylamine group to a nitrenium ion B. This ion is the electrophile in ipso addition to the aromatic ring forming a lactam with a enone group.	Periodinane Periodinanes are chemical compounds containing hypervalent iodine. These iodine compounds are hypervalent because the iodine atom in it contains more than the 8 electrons in the valence shell required for the octet rule. When iodine is complexed with a monodentate electronegative ligand such as chlorine, iodine compounds occur with a +3 oxidation number as iodine(III) or λ3-iodanes or as a +5 oxidation number as iodine(V) or λ5-iodanes. Iodine itself contains 7 valence electrons and in a λ3-iodane three more are donated by the ligands making it a decet structure. λ5-iodanes are dodecet molecules. In an ordinary iodine compound such as iodobenzene the number of valence electrons is eight as expected. In order to get from iodine to a hypervalent iodine compound it gets oxidized with removal of first 3 electrons and then 5 electrons. The ligands in turn contribute electrons pairs and form coordinate covalent bonds by adding a total of 6 or 10 electrons back to iodine. In the L-I-N notation L stand for the number of electrons donated by ligands and N the number of ligands. # Periodinane compounds The concept of hypervalent iodine was developed by J.J. Musher in 1969. In order to accommodate the excess of electrons in hypervalent compounds the 3-center-4-electron bond was introduced in analogy with the 3-center-2-electron bond observed in electron deficient compounds. One such bond exists in iodine(III) compounds and two such bonds reside in iodine(V) compounds. The first hypervalent iodine compound, dichloroiodobenzene (C6H5Cl2I) was prepared in 1886 by the German chemist C. Willgerodt [1] by passing chlorine gas through iodobenzene in a cooled solution of chloroform. λ3-iodanes such as diarylchloroiodanes have a pseudotrigonal bipyramidal geometry displaying apicophilicity with a phenyl group and a chlorine group at the apical positions and other phenyl group with two lone pair electrons in the equatorial positions. The λ5-iodanes such as the Dess-Martin periodinane have square pyramidal geometries with 4 heteroatoms in basal positions and one apical phenyl group. Classical organic procedures exist for the preparation of iodosobenzene diacetate from peracetic acid and acetic acid [2]. Phenyliodine bis(trifluoroacetate) or PIFA is a related compound based on trifluoroacetic acid The acetate can be hydrolysed with water to iodoxybenzene or iodylbenzene C6H5O2I [3] This compound was first prepared by Willgerodt by disproportionation of iodosylbenzene under steam distillation to iodylbenzene and iodobenzene is a known oxidizing agent. Iodosobenzene diacetate can also be hydrolyzed to iodosylbenzene with sodium hydroxide which is actually a polymer with the molecular formula (C6H5OI)n [4]. Iodosylbenzene is used in organic oxidations. Dess-Martin periodinane (1983) is another powerful oxidant and an improvement of the IBX acid already in existence in 1893. The IBX acid is prepared from 2-iodobenzoic acid and potassium bromate and sulfuric acid [5] and is insoluble in most solvents whereas the Dess-Martin reagent prepared from reaction of the IBX acid with acetic anhydride is very soluble. The oxidation mechanism ordinarily consists of a ligand exchange reaction followed by a reductive elimination. # Periodinane uses The predominant use of hypervalent iodine compounds is that of oxidizing reagent replacing many toxic reagents based on heavy metals [6]. Current research focuses on their use in carbon-carbon and carbon-heteroatom bond forming reactions. In one study such reaction, an intramolecular C-N coupling of an alkoxyhydroxylamine to its anisole group is accomplished with a catalytic amount of aryliodide in trifluoroethanol [7]: In this reaction the periodinane (depicted as intermediate A) is formed by oxidation of the aryliodide with the sacrificial catalyst mCPBA which in turn converts the hydroxylamine group to a nitrenium ion B. This ion is the electrophile in ipso addition to the aromatic ring forming a lactam with a enone group.	https://www.wikidoc.org/index.php/Periodinane
ede17d4205295d1c9d796c5483fd8cdd853b5dca	wikidoc	Peristalsis	Peristalsis # Overview Peristalsis is the rhythmic contraction of smooth muscles to propel contents through the digestive tract. The word is derived from New Latin and comes from the Greek peristaltikos, peristaltic, from peristellein, "to wrap around," and stellein, "to place." In much of the gastrointestinal tract, smooth muscles contract in sequence to produce a peristaltic wave which forces a ball of food (called bolus while in the esophagus and gastrointestinal tract and chyme in the stomach) along the gastrointestinal tract. Peristaltic movement is initiated by circular smooth muscles contracting behind the chewed material to prevent it from moving back into the mouth, followed by a contraction of longitudinal smooth muscles which pushes the digested food forward. # In the esophagus After food is chewed into a bolus, it is swallowed to move it into the esophagus. Smooth muscles will contract behind the bolus to prevent it from being squeezed back onto the mouth, then rhythmic, unidirectional waves of contractions will work to rapidly force the food into the stomach. This process works in one direction only and its sole purpose is to move food from the mouth into the stomach. In the esophagus, two types of peristalsis occur. - First, there is a primary peristaltic wave; once the bolus enters the esophagus during swallowing. The primary peristaltic wave forces the bolus down the esophagus and into the stomach in a wave lasting about 8-9 seconds. The wave travels down to the stomach even if the bolus of food descends at a greater rate than the wave itself, and will continue even if for some reason the bolus gets stuck further up the esophagus. - In the event that the bolus gets stuck or moves slower than the primary peristaltic wave (as can happen when it is poorly lubricated), stretch receptors in the esophageal lining are stimulated and a local reflex response causes a secondary peristaltic wave around the bolus, forcing it further down the esophagus, and these secondary waves will continue indefinitely until the bolus enters the stomach. # In the small intestine Once processed and digested by the stomach, the milky chyme is squeezed through the pyloric valve into the small intestine. Once past the stomach a typical peristaltic wave will only last for a few seconds, traveling at only a few centimeters per second. Its primary purpose is to mix the chyme in the intestine rather than to move it forward in the intestine. Through this process of mixing and continued digestion and absorption of nutrients, the chyme gradually works its way through the small intestine to the large intestine. During vomiting the direction of peristalsis reverses to move food back into the stomach, though the propulsion of food up the esophagus and out the mouth comes from contraction of the abdominal muscles; peristalsis does not reverse in the esophagus. As opposed to the more continuous peristalsis of the small intestines, fecal contents are propelled into the large intestine by periodic mass movements. These mass movements occur one to three times per day in the large intestines and colon, and help propel the contents from the large intestine through the colon to the rectum. # Causes of Excess Peristalsis - Cholinergic reaction - Pesticide poisoning	Peristalsis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Peristalsis is the rhythmic contraction of smooth muscles to propel contents through the digestive tract. The word is derived from New Latin and comes from the Greek peristaltikos, peristaltic, from peristellein, "to wrap around," and stellein, "to place." In much of the gastrointestinal tract, smooth muscles contract in sequence to produce a peristaltic wave which forces a ball of food (called bolus while in the esophagus and gastrointestinal tract and chyme in the stomach) along the gastrointestinal tract. Peristaltic movement is initiated by circular smooth muscles contracting behind the chewed material to prevent it from moving back into the mouth, followed by a contraction of longitudinal smooth muscles which pushes the digested food forward. # In the esophagus After food is chewed into a bolus, it is swallowed to move it into the esophagus. Smooth muscles will contract behind the bolus to prevent it from being squeezed back onto the mouth, then rhythmic, unidirectional waves of contractions will work to rapidly force the food into the stomach. This process works in one direction only and its sole purpose is to move food from the mouth into the stomach. In the esophagus, two types of peristalsis occur. - First, there is a primary peristaltic wave; once the bolus enters the esophagus during swallowing. The primary peristaltic wave forces the bolus down the esophagus and into the stomach in a wave lasting about 8-9 seconds. The wave travels down to the stomach even if the bolus of food descends at a greater rate than the wave itself, and will continue even if for some reason the bolus gets stuck further up the esophagus. - In the event that the bolus gets stuck or moves slower than the primary peristaltic wave (as can happen when it is poorly lubricated), stretch receptors in the esophageal lining are stimulated and a local reflex response causes a secondary peristaltic wave around the bolus, forcing it further down the esophagus, and these secondary waves will continue indefinitely until the bolus enters the stomach. # In the small intestine Once processed and digested by the stomach, the milky chyme is squeezed through the pyloric valve into the small intestine. Once past the stomach a typical peristaltic wave will only last for a few seconds, traveling at only a few centimeters per second. Its primary purpose is to mix the chyme in the intestine rather than to move it forward in the intestine. Through this process of mixing and continued digestion and absorption of nutrients, the chyme gradually works its way through the small intestine to the large intestine. During vomiting the direction of peristalsis reverses to move food back into the stomach, though the propulsion of food up the esophagus and out the mouth comes from contraction of the abdominal muscles; peristalsis does not reverse in the esophagus. As opposed to the more continuous peristalsis of the small intestines, fecal contents are propelled into the large intestine by periodic mass movements. These mass movements occur one to three times per day in the large intestines and colon, and help propel the contents from the large intestine through the colon to the rectum. # Causes of Excess Peristalsis - Cholinergic reaction - Pesticide poisoning # External links - Interactive 3D display of swallow waves at menne-biomed.de - Peristalsis at the US National Library of Medicine Medical Subject Headings (MeSH) - Essentials of Human Physiology by Thomas M. Nosek. Section 6/6ch3/s6ch3_9. de:Peristaltik he:תנועה פריסטלטית id:Peristaltik nl:Peristaltiek sk:Peristaltika sr:Перисталтика sv:Peristaltik ta:சுற்றிழுப்பசைவு Template:WH Template:WS	https://www.wikidoc.org/index.php/Peristalsis
5843443190a2edd49c716e74fcbcd4416ae15570	wikidoc	Permutation	Permutation In several fields of mathematics the term permutation is used with different but closely related meanings. They all relate to the notion of mapping the elements of a set to other elements of the same set, i.e., exchanging (or "permuting") elements of a set. # Definitions The general concept of permutation can be defined more formally in different contexts: ## In combinatorics In combinatorics, a permutation is usually understood to be a sequence containing each element from a finite set once, and only once. The concept of sequence is distinct from that of a set, in that the elements of a sequence appear in some order: the sequence has a first element (unless it is empty), a second element (unless its length is less than 2), and so on. In contrast, the elements in a set have no order; {1, 2, 3} and {3, 2, 1} are different ways to denote the same set. However, there is also a traditional more general meaning of the term "permutation" used in combinatorics. In this more general sense, permutations are those sequences in which, as before, each element occurs at most once, but not all elements of the given set need to be used. For a related notion in which the ordering of the selected elements form a set, for which the ordering is irrelevant, see Combination. ## In group theory In group theory and related areas, the elements of a permutation need not be arranged in a linear order, or indeed in any order at all. Under this refined definition, a permutation is a bijection from a finite set onto itself. This allows for the definition of groups of permutations; see Permutation group. # Counting permutations In this section only, the traditional definition from combinatorics is used: a permutation is an ordered sequence of elements selected from a given finite set, without repetitions, and not necessarily using all elements of the given set. For example, given the set of letters {C, E, G, I, N, R}, some permutations are RING, RICE, NICER, REIGN and CRINGE, but also RNCGI – the sequence need not spell out an existing word. ENGINE, on the other hand, is not a permutation, because it uses the elements E and N twice. If n denotes the size of the set – the number of elements available for selection – and only permutations are considered that use all n elements, then the total number of possible permutations is equal to n!, where "!" is the factorial operator. This can be shown informally as follows. In constructing a permutation, there are n possible choices for the first element of the sequence. Once it has been chosen, elements are left, so for the second element there are only possible choices. For the first two elements together, that gives us For selecting the third element, there are then elements left, giving, for the first three elements together, Continuing in this way until there are only 2 elements left, there are 2 choices, giving for the number of possible permutations consisting of elements: The last choice is now forced, as there is exactly one element left. In a formula, this is the number (which is the same as before because the factor 1 does not make a difference). This number is, by definition, the same as n!. In general the number of permutations is denoted by P(n, r), nPr, or sometimes P_r^n, where: - n is the number of elements available for selection, and - r is the number of elements to be selected (0 ≤ r ≤ n). For the case where it has just been shown that . The general case is given by the formula: As before, this can be shown informally by considering the construction of an arbitrary permutation, but this time stopping when the length r has been reached. The construction proceeds initially as above, but stops at length r. The number of possible permutations that has then been reached is: So: But if n! = P(n, r) × (n − r)!, then For example, if there is a total of 10 elements and we are selecting a sequence of three elements from this set, then the first selection is one from 10 elements, the next one from the remaining 9, and finally from the remaining 8, giving . In this case, n = 10 and r = 3. Using the formula to calculate P(10,3), In the special case where n = r the formula above simplifies to: The reason why 0! = 1 is that 0! is an empty product, which always equals 1. In the example given in the header of this article, with 6 integers {1..6}, this would be: P(6,6) = 6! / (6−6)! = (1×2×3×4×5×6) / 0! = 720 / 1 = 720. Since it may be impractical to calculate n! if the value of n is very large, a more efficient algorithm is to calculate: Other, older notations include nPr, Pn,r, or nPr. A common modern notation is (n)r which is called a falling factorial. However, the same notation is used for the rising factorial (also called Pochhammer symbol) With the rising factorial notation, the number of permutations is (n − r + 1)r. # Permutations in group theory As explained in a previous section, in group theory the term permutation (of a set) is reserved for a bijective map (bijection) from a finite set onto itself. The earlier example, of making permutations out of numbers 1 to 10, would be translated as a map from the set {1, …, 10} to itself. # Notation There are two main notations for such permutations. In relation notation, one can just arrange the "natural" ordering of the elements being permuted on a row, and the new ordering on another row: 2 & 5 & 4 & 3 & 1\end{pmatrix} = (2,5,4,3,1) = \begin{pmatrix}1 & 2 & 5 \end{pmatrix} \begin{pmatrix}3 & 4 \end{pmatrix} = \begin{pmatrix}3 & 4 \end{pmatrix} \begin{pmatrix}1 & 2 & 5 \end{pmatrix} stands for the permutation s of the set {1,2,3,4,5} defined by s(1)=2, s(2)=5, s(3)=4, s(4)=3, s(5)=1. If we have a finite set E of n elements, it is by definition in bijection with the set {1,…,n}, where this bijection f corresponds just to numbering the elements. Once they are numbered, we can identify the permutations of the set E with permutations of the set {1,…,n}. (In more mathematical terms, the function that maps a permutation s of E to the permutation f o s o f−1 of {1,…,n} is a morphism from the symmetric group of E into that of {1,…,n}, see below.) Alternatively, we can write the permutation in terms of how the elements change when the permutation is successively applied. This is referred to as the permutation's decomposition in a product of disjoint cycles. It works as follows: starting from one element x, we write the sequence (x s(x) s2(x) …) until we get back the starting element (at which point we close the parenthesis without writing it for a second time). This is called the cycle associated to x's orbit following s. Then we take an element we did not write yet and do the same thing, until we have considered all elements. In the above example, we get: s = (1 2 5) (3 4). Each cycle (x1 x2 … xL) stands for the permutation that maps xi on xi+1 (i=1…L−1) and xL on x1, and leaves all other elements invariant. L is called the length of the cycle. Since these cycles have by construction disjoint supports (i.e. they act non-trivially on disjoint subsets of E), they do commute (for example, (1 2 5) (3 4) = (3 4)(1 2 5)). The order of the cycles in the (composition) product does not matter, while the order of the elements in each cycles does matter (up to cyclic change; see also cycles and fixed points). Obviously, a 1-cycle (cycle of length 1) is the same as fixing the element contained in it, so there is no use in writing it explicitly. Some authors' definition of a cycle do not include cycles of length 1. Cycles of length two are called transpositions; such permutations merely exchange the place of two elements. (Conversely, a matrix transposition is itself an important example of a permutation.) # Product and inverse of permutations One can define the product of two permutations as follows. If we have two permutations, P and Q, the action of first performing P and then Q will be the same as performing some single permutation R. The product of P and Q is then defined to be that permutation R. Viewing permutations as bijections, the product of two permutations is thus the same as their composition as functions. There is no universally agreed notation for the product operation between permutations, and depending on the author a formula like PQ may mean either P ∘ Q or Q ∘ P. Since function composition is associative, so is the product operation on permutations: (P ∘ Q) ∘ R = P ∘ (Q ∘ R). Likewise, since bijections have inverses, so do permutations, and both P ∘ P−1 and P−1 ∘ P are the "identity permutation" (see below) that leaves all positions unchanged. Thus, it can be seen that permutations form a group. As for any group, there is a group isomorphism on permutation groups, obtained by assigning to each permutation its inverse, and this isomorphism is an involution, giving a dual view on any abstract result. Since (P ∘ Q)−1 = Q−1 ∘ P−1, from an abstract point of view it is immaterial whether PQ represents "P before Q" or "P after Q". For concrete permutations, the distinction is, of course, quite material. # Special permutations If we think of a permutation that "changes" the position of the first element to the first element, the second to the second, and so on, we really have not changed the positions of the elements at all. Because of its action, we describe it as the identity permutation because it acts as an identity function. Conversely, a permutation which changes the position of all elements (no element is mapped to itself) is called a derangement. If one has some permutation, called P, one may describe a permutation, written P−1, which undoes the action of applying P. In essence, performing P then P−1 is equivalent to performing the identity permutation. One always has such a permutation since a permutation is a bijective map. Such a permutation is called the inverse permutation. It is computed by exchanging each number and the number of the place which it occupies. An even permutation is a permutation which can be expressed as the product of an even number of transpositions, and the identity permutation is an even permutation as it equals (1 2)(1 2). An odd permutation is a permutation which can be expressed as the product of an odd number of transpositions. It can be shown that every permutation is either odd or even and can't be both. One theorem regarding the inverse permutation is the effect of a conjugation of a permutation by a permutation in a permutation group. If we have a permutation Q=(i1 i2 … in) and a permutation P, then PQP−1 = (P(i1) P(i2) … P(in)). We can also represent a permutation in matrix form; the resulting matrix is known as a permutation matrix. # Permutations in computing Some of the older textbooks look at permutations as assignments, as mentioned above. In computer science terms, these are assignment operations, with values assigned to variables Each value should be assigned only once. The assignment/substitution difference is then illustrative of one way in which functional programming and imperative programming differ — pure functional programming has no assignment mechanism. The mathematics convention is nowadays that permutations are just functions and the operation on them is function composition; functional programmers follow this. In the assignment language a substitution is an instruction to switch round the values assigned, simultaneously; a well-known problem. # Numbering permutations Factoradic numbers can be used to assign unique numbers to permutations, such that given a factoradic of k one can quickly find the corresponding permutation. ## Algorithms to generate permutations ### Unordered generation For every number k, with 0 ≤ k < n!, the following algorithm generates a unique permutation of the initial sequence sj, j=1…n: The first line in the for loop is constructing the Factorial base representation of k -- the important thing here is that for each k, it generates a unique corresponding sequence of n integers where the first number is in {0,1}, the second is in {0,1,2}, etc. Thus what the second line is doing is , at each step, swapping the jth element with one of the elements that are currently before it. If we consider the swaps in reverse order, we see that it implements a backwards Selection sort, first putting the nth element in the correct place, then the n-1st, etc. Since there is exactly one way to selection sort a permutation, this algorithm generates a unique permutation for each choice of k. The Fisher-Yates shuffle is based on the same principle as this algorithm. ### Lexicographical order generation For every number k, with 0 ≤ k < n!, the following algorithm generates the corresponding lexicographical permutation of the initial sequence sj, j= 1…n: Notation - k / j denotes integer division of k by j, i.e. the integral quotient without any remainder, and - k mod j is the remainder following integer division of k by j. - s denotes the nth element of sequence s. # Software and hardware implementations ## Calculator functions Most calculators have a built-in function for calculating the number of permutations, called nPr or PERM on many. The permutations function is often only available through several layers of menus; how to access the function is usually indicated in the documentation for calculators that support it. ## Spreadsheet functions Most spreadsheet software also provides a built-in function for calculating the number of permutations, called PERMUT in many popular spreadsheets. Apple's Numbers software notably does not currently include such a function.	Permutation In several fields of mathematics the term permutation is used with different but closely related meanings. They all relate to the notion of mapping the elements of a set to other elements of the same set, i.e., exchanging (or "permuting") elements of a set. # Definitions The general concept of permutation can be defined more formally in different contexts: ## In combinatorics In combinatorics, a permutation is usually understood to be a sequence containing each element from a finite set once, and only once. The concept of sequence is distinct from that of a set, in that the elements of a sequence appear in some order: the sequence has a first element (unless it is empty), a second element (unless its length is less than 2), and so on. In contrast, the elements in a set have no order; {1, 2, 3} and {3, 2, 1} are different ways to denote the same set. However, there is also a traditional more general meaning of the term "permutation" used in combinatorics. In this more general sense, permutations are those sequences in which, as before, each element occurs at most once, but not all elements of the given set need to be used. For a related notion in which the ordering of the selected elements form a set, for which the ordering is irrelevant, see Combination. ## In group theory In group theory and related areas, the elements of a permutation need not be arranged in a linear order, or indeed in any order at all. Under this refined definition, a permutation is a bijection from a finite set onto itself. This allows for the definition of groups of permutations; see Permutation group. # Counting permutations In this section only, the traditional definition from combinatorics is used: a permutation is an ordered sequence of elements selected from a given finite set, without repetitions, and not necessarily using all elements of the given set. For example, given the set of letters {C, E, G, I, N, R}, some permutations are RING, RICE, NICER, REIGN and CRINGE, but also RNCGI – the sequence need not spell out an existing word. ENGINE, on the other hand, is not a permutation, because it uses the elements E and N twice. If n denotes the size of the set – the number of elements available for selection – and only permutations are considered that use all n elements, then the total number of possible permutations is equal to n!, where "!" is the factorial operator. This can be shown informally as follows. In constructing a permutation, there are n possible choices for the first element of the sequence. Once it has been chosen, elements are left, so for the second element there are only possible choices. For the first two elements together, that gives us For selecting the third element, there are then elements left, giving, for the first three elements together, Continuing in this way until there are only 2 elements left, there are 2 choices, giving for the number of possible permutations consisting of elements: The last choice is now forced, as there is exactly one element left. In a formula, this is the number (which is the same as before because the factor 1 does not make a difference). This number is, by definition, the same as n!. In general the number of permutations is denoted by P(n, r), nPr, or sometimes <math>P_r^n</math>, where: - n is the number of elements available for selection, and - r is the number of elements to be selected (0 ≤ r ≤ n). For the case where it has just been shown that . The general case is given by the formula: As before, this can be shown informally by considering the construction of an arbitrary permutation, but this time stopping when the length r has been reached. The construction proceeds initially as above, but stops at length r. The number of possible permutations that has then been reached is: So: But if n! = P(n, r) × (n − r)!, then . For example, if there is a total of 10 elements and we are selecting a sequence of three elements from this set, then the first selection is one from 10 elements, the next one from the remaining 9, and finally from the remaining 8, giving . In this case, n = 10 and r = 3. Using the formula to calculate P(10,3), In the special case where n = r the formula above simplifies to: The reason why 0! = 1 is that 0! is an empty product, which always equals 1. In the example given in the header of this article, with 6 integers {1..6}, this would be: P(6,6) = 6! / (6−6)! = (1×2×3×4×5×6) / 0! = 720 / 1 = 720. Since it may be impractical to calculate <math>n!</math> if the value of n is very large, a more efficient algorithm is to calculate: Other, older notations include nPr, Pn,r, or nPr. A common modern notation is (n)r which is called a falling factorial. However, the same notation is used for the rising factorial (also called Pochhammer symbol) With the rising factorial notation, the number of permutations is (n − r + 1)r. # Permutations in group theory As explained in a previous section, in group theory the term permutation (of a set) is reserved for a bijective map (bijection) from a finite set onto itself. The earlier example, of making permutations out of numbers 1 to 10, would be translated as a map from the set {1, …, 10} to itself. # Notation There are two main notations for such permutations. In relation notation, one can just arrange the "natural" ordering of the elements being permuted on a row, and the new ordering on another row: 1 & 2 & 3 & 4 & 5 \\ 2 & 5 & 4 & 3 & 1\end{pmatrix} = (2,5,4,3,1) = \begin{pmatrix}1 & 2 & 5 \end{pmatrix} \begin{pmatrix}3 & 4 \end{pmatrix} = \begin{pmatrix}3 & 4 \end{pmatrix} \begin{pmatrix}1 & 2 & 5 \end{pmatrix}</math> stands for the permutation s of the set {1,2,3,4,5} defined by s(1)=2, s(2)=5, s(3)=4, s(4)=3, s(5)=1. If we have a finite set E of n elements, it is by definition in bijection with the set {1,…,n}, where this bijection f corresponds just to numbering the elements. Once they are numbered, we can identify the permutations of the set E with permutations of the set {1,…,n}. (In more mathematical terms, the function that maps a permutation s of E to the permutation f o s o f−1 of {1,…,n} is a morphism from the symmetric group of E into that of {1,…,n}, see below.) Alternatively, we can write the permutation in terms of how the elements change when the permutation is successively applied. This is referred to as the permutation's decomposition in a product of disjoint cycles. It works as follows: starting from one element x, we write the sequence (x s(x) s2(x) …) until we get back the starting element (at which point we close the parenthesis without writing it for a second time). This is called the cycle associated to x's orbit following s. Then we take an element we did not write yet and do the same thing, until we have considered all elements. In the above example, we get: s = (1 2 5) (3 4). Each cycle (x1 x2 … xL) stands for the permutation that maps xi on xi+1 (i=1…L−1) and xL on x1, and leaves all other elements invariant. L is called the length of the cycle. Since these cycles have by construction disjoint supports (i.e. they act non-trivially on disjoint subsets of E), they do commute (for example, (1 2 5) (3 4) = (3 4)(1 2 5)). The order of the cycles in the (composition) product does not matter, while the order of the elements in each cycles does matter (up to cyclic change; see also cycles and fixed points). Obviously, a 1-cycle (cycle of length 1) is the same as fixing the element contained in it, so there is no use in writing it explicitly. Some authors' definition of a cycle do not include cycles of length 1. Cycles of length two are called transpositions; such permutations merely exchange the place of two elements. (Conversely, a matrix transposition is itself an important example of a permutation.) # Product and inverse of permutations One can define the product of two permutations as follows. If we have two permutations, P and Q, the action of first performing P and then Q will be the same as performing some single permutation R. The product of P and Q is then defined to be that permutation R. Viewing permutations as bijections, the product of two permutations is thus the same as their composition as functions. There is no universally agreed notation for the product operation between permutations, and depending on the author a formula like PQ may mean either P ∘ Q or Q ∘ P. Since function composition is associative, so is the product operation on permutations: (P ∘ Q) ∘ R = P ∘ (Q ∘ R). Likewise, since bijections have inverses, so do permutations, and both P ∘ P−1 and P−1 ∘ P are the "identity permutation" (see below) that leaves all positions unchanged. Thus, it can be seen that permutations form a group. As for any group, there is a group isomorphism on permutation groups, obtained by assigning to each permutation its inverse, and this isomorphism is an involution, giving a dual view on any abstract result. Since (P ∘ Q)−1 = Q−1 ∘ P−1, from an abstract point of view it is immaterial whether PQ represents "P before Q" or "P after Q". For concrete permutations, the distinction is, of course, quite material. # Special permutations If we think of a permutation that "changes" the position of the first element to the first element, the second to the second, and so on, we really have not changed the positions of the elements at all. Because of its action, we describe it as the identity permutation because it acts as an identity function. Conversely, a permutation which changes the position of all elements (no element is mapped to itself) is called a derangement. If one has some permutation, called P, one may describe a permutation, written P−1, which undoes the action of applying P. In essence, performing P then P−1 is equivalent to performing the identity permutation. One always has such a permutation since a permutation is a bijective map. Such a permutation is called the inverse permutation. It is computed by exchanging each number and the number of the place which it occupies. An even permutation is a permutation which can be expressed as the product of an even number of transpositions, and the identity permutation is an even permutation as it equals (1 2)(1 2). An odd permutation is a permutation which can be expressed as the product of an odd number of transpositions. It can be shown that every permutation is either odd or even and can't be both. One theorem regarding the inverse permutation is the effect of a conjugation of a permutation by a permutation in a permutation group. If we have a permutation Q=(i1 i2 … in) and a permutation P, then PQP−1 = (P(i1) P(i2) … P(in)). We can also represent a permutation in matrix form; the resulting matrix is known as a permutation matrix. # Permutations in computing Some of the older textbooks look at permutations as assignments, as mentioned above. In computer science terms, these are assignment operations, with values assigned to variables Each value should be assigned only once. The assignment/substitution difference is then illustrative of one way in which functional programming and imperative programming differ — pure functional programming has no assignment mechanism. The mathematics convention is nowadays that permutations are just functions and the operation on them is function composition; functional programmers follow this. In the assignment language a substitution is an instruction to switch round the values assigned, simultaneously; a well-known problem. # Numbering permutations Factoradic numbers can be used to assign unique numbers to permutations, such that given a factoradic of k one can quickly find the corresponding permutation. ## Algorithms to generate permutations ### Unordered generation For every number k, with 0 ≤ k < n!, the following algorithm generates a unique permutation of the initial sequence sj, j=1…n: The first line in the for loop is constructing the Factorial base representation of k -- the important thing here is that for each k, it generates a unique corresponding sequence of n integers where the first number is in {0,1}, the second is in {0,1,2}, etc. Thus what the second line is doing is , at each step, swapping the jth element with one of the elements that are currently before it. If we consider the swaps in reverse order, we see that it implements a backwards Selection sort, first putting the nth element in the correct place, then the n-1st, etc. Since there is exactly one way to selection sort a permutation, this algorithm generates a unique permutation for each choice of k. The Fisher-Yates shuffle is based on the same principle as this algorithm. ### Lexicographical order generation For every number k, with 0 ≤ k < n!, the following algorithm generates the corresponding lexicographical permutation of the initial sequence sj, j= 1…n: Notation - k / j denotes integer division of k by j, i.e. the integral quotient without any remainder, and - k mod j is the remainder following integer division of k by j. - s[n] denotes the nth element of sequence s. # Software and hardware implementations ## Calculator functions Most calculators have a built-in function for calculating the number of permutations, called nPr or PERM on many. The permutations function is often only available through several layers of menus; how to access the function is usually indicated in the documentation for calculators that support it. ## Spreadsheet functions Most spreadsheet software also provides a built-in function for calculating the number of permutations, called PERMUT in many popular spreadsheets. Apple's Numbers software notably does not currently include such a function.[1]	https://www.wikidoc.org/index.php/Permutation
0403567257b4f65cbf1d02c450bf18d63a686389	wikidoc	Peroxy acid	Peroxy acid # Overview A peroxy acid (often spelled as one word, peroxyacid, and sometimes called peracid) is an acid in which an acidic -OH group has been replaced by an -OOH group. They are formed chiefly by elements in groups 14, 15 and 16 of the periodic table, though boron and certain transition elements are also known to form peroxy acids. Sulfur and phosphorus form the largest range of peroxy acids, including some condensed form such as peroxydiphosphoric acid, H4P2O8 and peroxydisulfuric acid, H2S2O8. Because they are generally very powerful oxidizing agents, most peroxyacids are prepared by electrolytic oxidation of ordinary oxyacids. Typically a high current density must be used to form the peroxyacid in good yield: the electrolysis of sulfuric acid being the most important example. Peroxy acids are generally not very stable in solution and decompose to ordinary oxyacids and oxygen, but relatively more stable anhydrous forms can be made by reacting hydrogen peroxide with chlorosulfonic acid or phosphoryl chloride. All peroxy acids are very powerful oxidizing agents. Some such acids are peroxy-carboxylic acids, such as meta-chloroperoxybenzoic acid (mCPBA), which is used as a reagent in the Baeyer-Villiger oxidation and in oxidation of carbon-carbon double bonds in alkenes to generate epoxides (oxiranes). Sodium peroxy carbonate, Na2CO4, is widely used as a household bleaching agent for textiles, whilst sodium, potassium and ammonium peroxydisulfates (Na2S2O8, K2S2O8 and (NH4)2S2O8) are widely used as general purpose oxidizing agents in the laboratory.	Peroxy acid # Overview Template:Double image stack A peroxy acid (often spelled as one word, peroxyacid, and sometimes called peracid) is an acid in which an acidic -OH group has been replaced by an -OOH group. They are formed chiefly by elements in groups 14, 15 and 16 of the periodic table, though boron and certain transition elements are also known to form peroxy acids. Sulfur and phosphorus form the largest range of peroxy acids, including some condensed form such as peroxydiphosphoric acid, H4P2O8 and peroxydisulfuric acid, H2S2O8. Because they are generally very powerful oxidizing agents, most peroxyacids are prepared by electrolytic oxidation of ordinary oxyacids. Typically a high current density must be used to form the peroxyacid in good yield: the electrolysis of sulfuric acid being the most important example. Peroxy acids are generally not very stable in solution and decompose to ordinary oxyacids and oxygen, but relatively more stable anhydrous forms can be made by reacting hydrogen peroxide with chlorosulfonic acid or phosphoryl chloride. All peroxy acids are very powerful oxidizing agents. Some such acids are peroxy-carboxylic acids, such as meta-chloroperoxybenzoic acid (mCPBA), which is used as a reagent in the Baeyer-Villiger oxidation and in oxidation of carbon-carbon double bonds in alkenes to generate epoxides (oxiranes). Sodium peroxy carbonate, Na2CO4, is widely used as a household bleaching agent for textiles, whilst sodium, potassium and ammonium peroxydisulfates (Na2S2O8, K2S2O8 and (NH4)2S2O8) are widely used as general purpose oxidizing agents in the laboratory.	https://www.wikidoc.org/index.php/Peroxy_acid
4c3c882503aaffce36bfb015e4ddaeec5d19448c	wikidoc	Personality	Personality # Overview Personality may refer to: - Personality psychology is the theory and study of personality types, personality traits and individual differences - Personality development, the study of human personality development over time - Personality disorders, a class of mental disorders that is characterized by long-lasting rigid patterns of thought and actions - Personality pathology is characterized by adaptive inflexibility, vicious cycles of maladaptive behavior, and emotional instability under stress - Personality quiz, a series of questions (usually multiple-choice) intended to reveal something about the person who answers them - Personality tests aim to describe aspects of a person's character, thoughts, and feelings - Personality type refers to the psychological classification of different types of people - Personality traits refers to patterns of relatively enduring characteristics of human behavior - Personality alteration, a theory often associated with cults or brainwashing # Sociology - Cult of personality, political institution in which a leader uses mass media to create a larger-than-life public image - Personality rights, consisting of the rights to publicity and to privacy cs:Osobnost da:Personlighed de:Persönlichkeit et:Isiksus it:Personalità nl:Persoonlijkheid no:Personlighet simple:Personality uk:Особистість	Personality Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Personality may refer to: - Personality psychology is the theory and study of personality types, personality traits and individual differences - Personality development, the study of human personality development over time - Personality disorders, a class of mental disorders that is characterized by long-lasting rigid patterns of thought and actions - Personality pathology is characterized by adaptive inflexibility, vicious cycles of maladaptive behavior, and emotional instability under stress - Personality quiz, a series of questions (usually multiple-choice) intended to reveal something about the person who answers them - Personality tests aim to describe aspects of a person's character, thoughts, and feelings - Personality type refers to the psychological classification of different types of people - Personality traits refers to patterns of relatively enduring characteristics of human behavior - Personality alteration, a theory often associated with cults or brainwashing # Sociology - Cult of personality, political institution in which a leader uses mass media to create a larger-than-life public image - Personality rights, consisting of the rights to publicity and to privacy Template:WH Template:WS cs:Osobnost da:Personlighed de:Persönlichkeit et:Isiksus it:Personalità nl:Persoonlijkheid no:Personlighet simple:Personality uk:Особистість	https://www.wikidoc.org/index.php/Personality
7b08f24d9994b06fa6db724560c40cb37e77e237	wikidoc	Pexacerfont	Pexacerfont # Overview Pexacerfont (BMS-562086) is a drug developed by Bristol-Myers Squibb which acts as a CRF-1 antagonist. Corticotropin releasing factor (CRF), also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress and drug addiction. This then triggers the release of corticotropin (ACTH), another hormone which is involved in the physiological response to stress. Chronic release of CRF and ACTH is believed to be directly or indirectly involved in many of the harmful physiological effects of chronic stress, such as excessive glucocorticoid release, stomach ulcers, anxiety, depression, and development of high blood pressure and consequent cardiovascular problems. Pexacerfont is a recently developed CRF-1 antagonist which is currently in clinical trials for the treatment of anxiety disorders, and has also been proposed to be useful for the treatment of depression and irritable bowel syndrome. # See Also - Antalarmin - Corticotropin releasing hormone antagonists	Pexacerfont Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Pexacerfont (BMS-562086) is a drug developed by Bristol-Myers Squibb which acts as a CRF-1 antagonist. Corticotropin releasing factor (CRF), also known as Corticotropin releasing hormone, is an endogenous peptide hormone which is released in response to various triggers such as chronic stress and drug addiction. This then triggers the release of corticotropin (ACTH), another hormone which is involved in the physiological response to stress. Chronic release of CRF and ACTH is believed to be directly or indirectly involved in many of the harmful physiological effects of chronic stress, such as excessive glucocorticoid release, stomach ulcers, anxiety, depression, and development of high blood pressure and consequent cardiovascular problems.[1] Pexacerfont is a recently developed CRF-1 antagonist which is currently in clinical trials for the treatment of anxiety disorders,[2] and has also been proposed to be useful for the treatment of depression and irritable bowel syndrome.[3] # See Also - Antalarmin - Corticotropin releasing hormone antagonists	https://www.wikidoc.org/index.php/Pexacerfont
f743607f6bb143263ee59ad609f8fca4cc9fbb71	wikidoc	Phallolysin	Phallolysin Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Phallolysin is a toxic haemolysin that has been isolated from the death cap Amanita phalloides.	Phallolysin Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Phallolysin is a toxic haemolysin that has been isolated from the death cap Amanita phalloides. Template:SIB Template:WH Template:WS	https://www.wikidoc.org/index.php/Phallolysin
e017a815e1f0c198721dc48199b3b64dec68b035	wikidoc	Phenadoxone	Phenadoxone Phenadoxone (Heptalgin®, Heptazone) is an opioid analgesic of the open chain class (methadone and relatives) invented in Germany in 1947. It is one of a handful of useful synthetic analgesics which were used in the United States for various lengths of time in the 20 or so years after the end of the Second World War but which were withdrawn from the market for various or no known reason and which now are mostly in Schedule I of the United States' Controlled Substances Act of 1970, or (like phenazocine and bezitramide) in Schedule II but not produced or marketed in the US. Others on this list are ketobemidone (Ketogin®), dextromoramide (Dimorlin®, Palfium® and others), phenazocine (Narphen® and Prinadol®), dipipanone (Diconal®, Pipadone® and Wellconal®), piminodine (Alvodine®), propiram (Algeril®), anileridine (Leritine®) and alphaprodine (Nisentil®). Phenadoxone is generally considered to be a strong opioid analgesic and is regulated in much the same way as morphine where it is used. The usual starting dose is 10-20 mg and it has a duration of analgesic effect of 1 to 4 hours. By comparison, methadone has an analgesic effect lasting from 3 to 6 hours although for use in opioid maintenance the dose is different from that used for analgesia and the sought effect of suppressing withdrawal symptoms and part of the rush of heroin can last for 24 to 72 hours. Phenadoxone is not used at this time for purposes other than pain relief. Worldwide consumption of phenadoxone has actually increased slightly in recent years according a recent report from the World Health Organisation. Like its drug subcategory prototype methadone, phenadoxone can be used as the opioid analgesic in Brompton Mixture, aka Brompton cocktail. Phenadoxone is most used at the current time in Denmark and various countries in eastern Europe.	Phenadoxone Phenadoxone (Heptalgin®, Heptazone) is an opioid analgesic of the open chain class (methadone and relatives) invented in Germany in 1947. It is one of a handful of useful synthetic analgesics which were used in the United States for various lengths of time in the 20 or so years after the end of the Second World War but which were withdrawn from the market for various or no known reason and which now are mostly in Schedule I of the United States' Controlled Substances Act of 1970, or (like phenazocine and bezitramide) in Schedule II but not produced or marketed in the US. Others on this list are ketobemidone (Ketogin®), dextromoramide (Dimorlin®, Palfium® and others), phenazocine (Narphen® and Prinadol®), dipipanone (Diconal®, Pipadone® and Wellconal®), piminodine (Alvodine®), propiram (Algeril®), anileridine (Leritine®) and alphaprodine (Nisentil®). Phenadoxone is generally considered to be a strong opioid analgesic and is regulated in much the same way as morphine where it is used. The usual starting dose is 10-20 mg and it has a duration of analgesic effect of 1 to 4 hours. By comparison, methadone has an analgesic effect lasting from 3 to 6 hours although for use in opioid maintenance the dose is different from that used for analgesia and the sought effect of suppressing withdrawal symptoms and part of the rush of heroin can last for 24 to 72 hours. Phenadoxone is not used at this time for purposes other than pain relief. Worldwide consumption of phenadoxone has actually increased slightly in recent years according a recent report from the World Health Organisation. Like its drug subcategory prototype methadone, phenadoxone can be used as the opioid analgesic in Brompton Mixture, aka Brompton cocktail. Phenadoxone is most used at the current time in Denmark and various countries in eastern Europe.	https://www.wikidoc.org/index.php/Phenadoxone
b518a72aec642a1aab0d01f84d585b130f1dafb9	wikidoc	Phenazocine	Phenazocine # Overview Phenazocine (brand names Prinadol, Narphen) is an opioid analgesic drug, which is related to pentazocine and has a similar profile of effects. Effects of phenazocine include analgesia and euphoria, also may include dysphoria and hallucinations at high doses, most likely due to action at κ-opioid and σ receptors. Phenazocine appears to be a much stronger analgesic with fewer side effects than pentazocine, probably due to a more favorable μ/κ binding ratio. Phenazocine is a much more potent analgesic than pentazocine and other drugs in the benzomorphan series, most probably due to the presence of an N-phenethyl substitution, which is known to boost μ-opioid activity in many classes of opioid analgesics. Consequently phenazocine is some 4x the potency of morphine as an analgesic. Also it does not cause spasm of the sphincter of Oddi, making it more suitable than morphine for the treatment of biliary or pancreatic pain. # History Phenazocine was invented in the 1950s. It was one of a number of benzomorphan opioids (including pentazocine, dezocine, and cyclazocine) developed in the search for non-addictive strong analgesics. Phenazocine was once widely used, and was mainly supplied as 5 mg tablets of the hydrobromide salt for sublingual use (Narphen, Prinadol and other names), but its use was discontinued in the United Kingdom in 2001. Phenazocine was briefly used in the United States but fell out of favour for the above-mentioned reasons;Template:Which it remains a Schedule II substance under the Comprehensive Drug Abuse Control & Prevention Act (aka Controlled Substances Act) of 1970 (CSA) but is not manufactured; other Schedule II narcotics not in use in the United States include bezitramide and metopon. The DEA ACSCN for phenazocine is 9715 and its 2013 annual manufacturing quota was 6 grammes	Phenazocine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Phenazocine (brand names Prinadol, Narphen) is an opioid analgesic drug, which is related to pentazocine and has a similar profile of effects. Effects of phenazocine include analgesia and euphoria, also may include dysphoria and hallucinations at high doses, most likely due to action at κ-opioid and σ receptors.[1] Phenazocine appears to be a much stronger analgesic with fewer side effects than pentazocine, probably due to a more favorable μ/κ binding ratio. Phenazocine is a much more potent analgesic than pentazocine and other drugs in the benzomorphan series, most probably due to the presence of an N-phenethyl substitution, which is known to boost μ-opioid activity in many classes of opioid analgesics.[2] Consequently phenazocine is some 4x the potency of morphine as an analgesic. Also it does not cause spasm of the sphincter of Oddi, making it more suitable than morphine for the treatment of biliary or pancreatic pain.[3] # History Phenazocine was invented in the 1950s.[4][5] It was one of a number of benzomorphan opioids (including pentazocine, dezocine, and cyclazocine) developed in the search for non-addictive strong analgesics. Phenazocine was once widely used, and was mainly supplied as 5 mg tablets of the hydrobromide salt for sublingual use (Narphen, Prinadol and other names), but its use was discontinued in the United Kingdom in 2001.[6] Phenazocine was briefly used in the United States but fell out of favour for the above-mentioned reasons;Template:Which[citation needed] it remains a Schedule II substance under the Comprehensive Drug Abuse Control & Prevention Act (aka Controlled Substances Act) of 1970 (CSA) but is not manufactured; other Schedule II narcotics not in use in the United States include bezitramide and metopon. The DEA ACSCN for phenazocine is 9715 and its 2013 annual manufacturing quota was 6 grammes [7]	https://www.wikidoc.org/index.php/Phenazocine
e43f20eff21309db9f4de69d1b89f76ec3849cf3	wikidoc	Pheniramine	Pheniramine Pheniramine (INN, trade name Avil, among others) is an antihistamine with anticholinergic properties used to treat allergic conditions such as hay fever or urticaria. It has relatively strong sedative effects, and may sometimes be used off-label as an over-the-counter sleeping pill in a similar manner to other sedating antihistamines such as diphenhydramine. Pheniramine is also commonly found in eyedrops used for the treatment of allergic conjunctivitis. Pheniramine is generally sold in combination with other medications, rather than as a stand-alone drug, although some formulations are available containing pheniramine by itself. As an example, Neo Citran contains pheniramine. # Chemical relatives Derivatives of pheniramine include chlorphenamine, dexchlorpheniramine, dexbrompheniramine, deschlorpheniramine, triprolidine, and brompheniramine. Two other halogenated derivatives, iodopheniramine and fluorpheniramine, are currently in use for research on combination therapies for malaria and some cancers. The halogenation of pheniramine increases its potency by 20-fold. # Side effects Pheniramine may cause drowsiness, bradycardia and over-dosage may lead to sleep disorders. Overdose may lead to seizures, especially in combination with alcohol. People combining with cortisol in the long term should avoid pheniramine as it may cause lowered levels of adrenaline (epinephrine) which may lead to loss of consciousness.	Pheniramine Pheniramine (INN, trade name Avil, among others) is an antihistamine with anticholinergic properties used to treat allergic conditions such as hay fever or urticaria. It has relatively strong sedative effects, and may sometimes be used off-label as an over-the-counter sleeping pill in a similar manner to other sedating antihistamines such as diphenhydramine. Pheniramine is also commonly found in eyedrops used for the treatment of allergic conjunctivitis. Pheniramine is generally sold in combination with other medications, rather than as a stand-alone drug, although some formulations are available containing pheniramine by itself. As an example, Neo Citran contains pheniramine. # Chemical relatives Derivatives of pheniramine include chlorphenamine, dexchlorpheniramine, dexbrompheniramine, deschlorpheniramine, triprolidine, and brompheniramine. Two other halogenated derivatives, iodopheniramine and fluorpheniramine, are currently in use for research on combination therapies for malaria and some cancers. The halogenation of pheniramine increases its potency by 20-fold. # Side effects Pheniramine may cause drowsiness, bradycardia and over-dosage may lead to sleep disorders. Overdose may lead to seizures, especially in combination with alcohol. People combining with cortisol in the long term should avoid pheniramine as it may cause lowered levels of adrenaline (epinephrine) which may lead to loss of consciousness.	https://www.wikidoc.org/index.php/Pheniramine
228c2eafa4f128d1170ee72c22d059443df359df	wikidoc	Phlyctenule	Phlyctenule # Overview A phlyctenule (also called phlycten) is medical term for a small whitish bump or blister found on eye. Characteristic nodular affection occurring as an allergic response of the conjunctival and corneal epithelium to some endogenous allergens to which they have become sensitized. It is a collection of white blood cells (primarily polymorphonuclear leukocytes and lymphocytes) in response to staphylococcus or other bacteria. In underdeveloped regions Tuberculosis is the most common cause. The condition may improve with proper hygiene. Medical treatment may consist of the use of artificial tears eye drops, vasoconstrictors (such as Tetrahydrozoline), or corticosteroid eyedrops. ## Etiological factors - tuberculous protein - staphyloccus protein-most common - others- moraxella axenfeld bacillus and certain parasites. ## Predisposing factors - age—3-15 yrs - sex—f>m - under nourished - living conditions- over crowded and unhygienic conditions - season- more in spring and summer ## Symptoms - mild discomfort and irritation - reflex watering - associated mucopurulent conjunctivitis due to secondary bacterial infection ## Signs - 1.Phlyctenular conjunctivitis presents in three forms- - A. Simple - Most common - Presence of pinkish white nodule surrounded by hyperemia on the bulbar conjunctiva, usually near the limbus. - Mostly presents as solitary nodule,sometimes more may be present. - In a few days, nodule ulcerates at apex, which later on gets epithelialised. - remaining of conjunctiva is normal. - Presence of very large phlycten with necrosis and ulceration. - Leads to severe pustular conjunctivitis. - C. Miliary - Multiple phlyctens arranged haphazardly or in the form of ring around limbus. - 2. Lacrimation without discharge - 3. May be associated with enlarged tonsils and cervical nodes - 4. Phlyctenular keratitis: - Corneal involvement may present as: - 1. Ulcerative PKC - A. Sacrofulous ulcer - B. Fascicular ulcer - C. Miliary ulcer - 2. Diffuse infiltrative keratitis ## Treatment - Local- - Topical steroid-dexamethasone or betamethasone - Antibiotic drops and ointment - Atropine 1% eye ointment once daily if cornea is involved - Specific: - Tuberculosis should be excluded by Chest x-ray, mantoux test, ESR and if necessary full dose ATT should be given. - Septic focus in the form of tonsillitis, adenoiditis, teeth caries should be treated by antibiotics and necessary surgical interventions. - parasitic infestation should be ruled out and treated if necessary. - General- - High protein diet and Vit. A, C, and D supplementation	Phlyctenule # Overview A phlyctenule (also called phlycten[1]) is medical term for a small whitish bump or blister found on eye. Characteristic nodular affection occurring as an allergic response of the conjunctival and corneal epithelium to some endogenous allergens to which they have become sensitized. It is a collection of white blood cells (primarily polymorphonuclear leukocytes and lymphocytes) in response to staphylococcus or other bacteria. In underdeveloped regions Tuberculosis is the most common cause. The condition may improve with proper hygiene. Medical treatment may consist of the use of artificial tears eye drops, vasoconstrictors (such as Tetrahydrozoline), or corticosteroid eyedrops. ## Etiological factors - tuberculous protein - staphyloccus protein-most common - others- moraxella axenfeld bacillus and certain parasites. ## Predisposing factors - age—3-15 yrs - sex—f>m - under nourished - living conditions- over crowded and unhygienic conditions - season- more in spring and summer ## Symptoms - mild discomfort and irritation - reflex watering - associated mucopurulent conjunctivitis due to secondary bacterial infection ## Signs - 1.Phlyctenular conjunctivitis presents in three forms- - A. Simple - Most common - Presence of pinkish white nodule surrounded by hyperemia on the bulbar conjunctiva, usually near the limbus. - Mostly presents as solitary nodule,sometimes more may be present. - In a few days, nodule ulcerates at apex, which later on gets epithelialised. - remaining of conjunctiva is normal. - Presence of very large phlycten with necrosis and ulceration. - Leads to severe pustular conjunctivitis. - C. Miliary - Multiple phlyctens arranged haphazardly or in the form of ring around limbus. - 2. Lacrimation without discharge - 3. May be associated with enlarged tonsils and cervical nodes - 4. Phlyctenular keratitis: - Corneal involvement may present as: - 1. Ulcerative PKC - A. Sacrofulous ulcer - B. Fascicular ulcer - C. Miliary ulcer - 2. Diffuse infiltrative keratitis ## Treatment - Local- - Topical steroid-dexamethasone or betamethasone - Antibiotic drops and ointment - Atropine 1% eye ointment once daily if cornea is involved - Specific: - Tuberculosis should be excluded by Chest x-ray, mantoux test, ESR and if necessary full dose ATT should be given. - Septic focus in the form of tonsillitis, adenoiditis, teeth caries should be treated by antibiotics and necessary surgical interventions. - parasitic infestation should be ruled out and treated if necessary. - General- - High protein diet and Vit. A, C, and D supplementation	https://www.wikidoc.org/index.php/Phlyctenule
7417fe77cbd8329ad021d7dd4d2dfb87df1ffb7a	wikidoc	Phosphatase	Phosphatase Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group (see dephosphorylation). This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their substrates by using energetic molecules like ATP. A common phosphatase in many organisms is alkaline phosphatase. Phosphatases can be categorised into two main categories: Cysteine-dependent Phosphatases (CDPs) and metallo-phosphatases (which are dependent on metal ions in their active sites for activity). ## Mechanism CDPs catalyse the hydrolysis of a phosphoester bond via a phospho-cysteine intermediate . The free cysteine nucleophile forms a bond with the phosphorus atom of the phosphate moiety, and the P-O bond linking the phosphate group to the tyrosine is protonated, either by a suitably positioned acidic amino acid residue (Asp in the diagram below) or a water molecule. The phospho-cysteine intermediate is then hydrolysed by another water molecule, thus regenerating the active site for another dephosphorylation reaction. Metallo-phosphatases (eg PP2C) co-ordinate 2 catalytically essential metal ions within their active site. There is currently some confusion of the identity of these metal ions, as successive attempts to identify them yield different answers. There is currently evidence that these metals could be Magnesium, Manganese, Iron, Zinc, or any combination thereof. It is thought that a hydroxyl ion bridging the two metal ions takes part in nucleophilic attack on the phosphorus ion. ## Sub-types Phosphatases can be subdivided based upon their substrate specificity. ## Physiological Relevance Phosphatases act in opposition to kinases/phosphorylases, which add phosphate groups to proteins. The addition of a phosphate group may activate or de-activate an enzyme (e.g., Kinase signalling pathways ) or enable a protein-protein interaction to occur (e.g., SH3 domains ); therefore phosphatases are integral to many signal transduction pathways. It should be noted that phosphate addition and removal do not necessarily correspond to enzyme activation or inhibition, and that several enzymes have separate phosphorylation sites for activating or inhibiting functional regulation. CDK, for example, can be either activated or deactivated depending on the specific amino acid residue being phosphorylated. Phosphates are important in signal transduction because they regulate the proteins to which they are attached. To reverse the regulatory effect, the phosphate is removed. This occurs on its own by hydrolysis, or is mediated by protein phosphatases. ## Protein Phosphatases ### Serine/threonine-specific protein phosphatases Serine and threonine phosphates are stable under physiological conditions, so a phosphatase has to remove the phosphate to reverse the regulation. There are four known groups: - PP1 (α, β, γ1, γ2) - PP2A - PP2B (AKA calcineurin) - PP2C - PP4 - PP5 The first three have sequence homology in the catalytic domain, but differ in substrate specifity. Ser/Thr-specific protein phosphatases are regulated by their location within the cell and by specific inhibitor proteins.	Phosphatase Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group (see dephosphorylation). This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their substrates by using energetic molecules like ATP. A common phosphatase in many organisms is alkaline phosphatase. Phosphatases can be categorised into two main categories: Cysteine-dependent Phosphatases (CDPs) and metallo-phosphatases (which are dependent on metal ions in their active sites for activity). ## Mechanism CDPs catalyse the hydrolysis of a phosphoester bond via a phospho-cysteine intermediate [1]. The free cysteine nucleophile forms a bond with the phosphorus atom of the phosphate moiety, and the P-O bond linking the phosphate group to the tyrosine is protonated, either by a suitably positioned acidic amino acid residue (Asp in the diagram below) or a water molecule. The phospho-cysteine intermediate is then hydrolysed by another water molecule, thus regenerating the active site for another dephosphorylation reaction. Metallo-phosphatases (eg PP2C) co-ordinate 2 catalytically essential metal ions within their active site. There is currently some confusion of the identity of these metal ions, as successive attempts to identify them yield different answers. There is currently evidence that these metals could be Magnesium, Manganese, Iron, Zinc, or any combination thereof. It is thought that a hydroxyl ion bridging the two metal ions takes part in nucleophilic attack on the phosphorus ion. ## Sub-types Phosphatases can be subdivided based upon their substrate specificity. ## Physiological Relevance Phosphatases act in opposition to kinases/phosphorylases, which add phosphate groups to proteins. The addition of a phosphate group may activate or de-activate an enzyme (e.g., Kinase signalling pathways[7] ) or enable a protein-protein interaction to occur (e.g., SH3 domains [8]); therefore phosphatases are integral to many signal transduction pathways. It should be noted that phosphate addition and removal do not necessarily correspond to enzyme activation or inhibition, and that several enzymes have separate phosphorylation sites for activating or inhibiting functional regulation. CDK, for example, can be either activated or deactivated depending on the specific amino acid residue being phosphorylated. Phosphates are important in signal transduction because they regulate the proteins to which they are attached. To reverse the regulatory effect, the phosphate is removed. This occurs on its own by hydrolysis, or is mediated by protein phosphatases. ## Protein Phosphatases ### Serine/threonine-specific protein phosphatases Serine and threonine phosphates are stable under physiological conditions, so a phosphatase has to remove the phosphate to reverse the regulation. There are four known groups: - PP1 (α, β, γ1, γ2) - PP2A - PP2B (AKA calcineurin) - PP2C - PP4 - PP5 The first three have sequence homology in the catalytic domain, but differ in substrate specifity. Ser/Thr-specific protein phosphatases are regulated by their location within the cell and by specific inhibitor proteins.	https://www.wikidoc.org/index.php/Phosphatase
362b70f4f9bb668fb39ddf22576eec52448c4aa4	wikidoc	Phytoalexin	Phytoalexin Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Phytoalexins are antibiotics produced by plants that are under attack. Phytoalexins tend to fall into several classes including terpenoids, glycosteroids and alkaloids; however, researchers often find it convenient to extend the definition to include all phytochemicals that are part of the plant's defensive arsenal. Phytoalexins produced in plants act as toxins to the attacking organism. They may puncture the cell wall, delay maturation, disrupt metabolism or prevent reproduction of the pathogen in question. However, phytoalexins are often targeted to specific predators; a plant that has anti-insect phytoalexins may not have the ability to repel a fungal attack. When a plant cell recognizes particles from damaged cells or particles from the pathogen, the plant launches a two-pronged resistance: a general short-term response and a delayed long-term specific response. As part of the induced resistance, the short-term response, the plant deploys free radicals such as superoxide and hydrogen peroxide to kill invading cells. In pathogen interactions, the common short-term response is the hypersensitive response, wherein apoptosis-compromised cells commit suicide in order to create a physical barrier for the invader. Long-term resistance, or systemic acquired resistance (SAR), involves communication of the damaged tissue with the rest of the plant using plant hormones such as jasmonic acid, ethylene, abscisic acid or salicylic acid. The reception of the signal leads to global changes within the plant, which induce genes that protect from further pathogen intrusion, including enzymes involved in the production of phytoalexins. Often, if jasmonates or ethylene (both gaseous hormones) is released from the wounded tissue, neighboring plants also manufacture phytoalexins in response. For herbivores, common vectors for disease, these and other wound response aromatics seem to act as a warning that the plant is no longer edible. Also, in accordance with the old adage, "an enemy of my enemy is my friend," the aromatics may alert natural enemies of the plant invaders that lunch is available.	Phytoalexin Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Phytoalexins are antibiotics produced by plants that are under attack. Phytoalexins tend to fall into several classes including terpenoids, glycosteroids and alkaloids; however, researchers often find it convenient to extend the definition to include all phytochemicals that are part of the plant's defensive arsenal. Phytoalexins produced in plants act as toxins to the attacking organism. They may puncture the cell wall, delay maturation, disrupt metabolism or prevent reproduction of the pathogen in question. However, phytoalexins are often targeted to specific predators; a plant that has anti-insect phytoalexins may not have the ability to repel a fungal attack. When a plant cell recognizes particles from damaged cells or particles from the pathogen, the plant launches a two-pronged resistance: a general short-term response and a delayed long-term specific response. As part of the induced resistance, the short-term response, the plant deploys free radicals such as superoxide and hydrogen peroxide to kill invading cells. In pathogen interactions, the common short-term response is the hypersensitive response, wherein apoptosis-compromised cells commit suicide in order to create a physical barrier for the invader. Long-term resistance, or systemic acquired resistance (SAR), involves communication of the damaged tissue with the rest of the plant using plant hormones such as jasmonic acid, ethylene, abscisic acid or salicylic acid. The reception of the signal leads to global changes within the plant, which induce genes that protect from further pathogen intrusion, including enzymes involved in the production of phytoalexins. Often, if jasmonates or ethylene (both gaseous hormones) is released from the wounded tissue, neighboring plants also manufacture phytoalexins in response. For herbivores, common vectors for disease, these and other wound response aromatics seem to act as a warning that the plant is no longer edible. Also, in accordance with the old adage, "an enemy of my enemy is my friend," the aromatics may alert natural enemies of the plant invaders that lunch is available.	https://www.wikidoc.org/index.php/Phytoalexin
9ea8e952cc2f20bcce946ca66aaedc6deaa53f79	wikidoc	Piceatannol	Piceatannol Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview Piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene) is a phenolic. It is a metabolite of resveratrol, so its not surpising that it is found in red wine. LMP2A, a viral protein tyrosine kinase implicated in leukemia, Non-Hodgkin's lymphoma, and other diseases associated with Epstein-Barr Virus, were found to be blocked by picetannol in vitro, and a target for therapeutic anti-cancer and anti-EBV drugs. # See Also - pterostilbene - resveratrol - Medline on Picetannol	Piceatannol Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview Piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene) is a phenolic. It is a metabolite of resveratrol, so its not surpising that it is found in red wine. LMP2A, a viral protein tyrosine kinase implicated in leukemia, Non-Hodgkin's lymphoma, and other diseases associated with Epstein-Barr Virus, were found to be blocked by picetannol in vitro, and a target for therapeutic anti-cancer and anti-EBV drugs.[1] # See Also - pterostilbene - resveratrol - Medline on Picetannol Template:SIB Template:WH Template:WS - ↑ [2]	https://www.wikidoc.org/index.php/Piceatannol
81b942df39acbf5a1e20eb6bc7c979d0c50aa675	wikidoc	Pimethixene	Pimethixene Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview Pimethixene is an antihistamine often used to treat hyperactivity, anxiety, sleep disorders, and allergy. It is also used for anesthesia and as a bronchodilator (to dilate the bronchi and bronchioles for more airflow).	Pimethixene Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview Pimethixene is an antihistamine often used to treat hyperactivity, anxiety, sleep disorders, and allergy. It is also used for anesthesia and as a bronchodilator (to dilate the bronchi and bronchioles for more airflow). Template:SIB Template:WH Template:WS	https://www.wikidoc.org/index.php/Pimethixene
8d496cd7239d8c354e1500a07eb46991c852b086	wikidoc	Pimobendane	Pimobendane # Overview Pimobendan (or pimobendane)(INN) is a veterinary medication manufactured by Boehringer Ingelheim under the trade names Vetmedin and Acardi (Japan). It is both a calcium sensitizer and a selective inhibitor of phosphodiesterase III (PDE3) with positive inotropic and vasodilator effects. Pimobendan is used in the management of heart failure in dogs, most commonly caused by myxomatous mitral valve disease (also previously known as endocardiosis), or dilated cardiomyopathy. Research has shown that pimobendan increases survival time and improves quality of life in canine patients with congestive heart failure secondary to mitral valve disease when compared with benazepril, an angiotensin-converting-enzyme (ACE) inhibitor. Under the trade name Acardi, it is available for human use in Japan. # Mechanism of action Pimobendan is a positive inotrope (increases myocardial contractility). It sensitizes and increases the binding efficiency of cardiac troponin in the myofibril to the calcium ions that are already present in systole. In normal hearts it increases the consumption of oxygen and energy to the same degree as dobutamine but in diseased hearts it may not. Pimobendan also causes peripheral vasodilation by inhibiting the function of phosphodiesterase III. This results in decreased resistance to blood flow through systemic arterioles, which decreases afterload (decreases the failing heart's workload) and reduces the amount of mitral regurgitation. # Pharmacokinetics Pimobendan is absorbed rapidly when given via the oral route and has a bioavailability of 60-65%. Bioavailability is markedly decreased when ingested with food. It is metabolized into an active metabolite (desmethylpimobendan) by the liver. The parent compound, pimobendan, is a potent calcium sensitizer while desmethylpimobendan is a more potent phosphodiesterase III inhibitor. The half-life of pimobendan in the blood is 0.4 hours and the half-life of its metabolite is 2 hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% bound to plasma proteins in circulation. This may have implications in patients suffering from low blood protein levels (hypoproteinemia/hypoalbuminemia) and in patients that are on concurrent therapies that are also highly protein bound. # Combinations Pimobendan is often used in combination with three other drugs to palliate dogs with heart failure (pulmonary edema, pleural effusion, ascites). These are: - Furosemide, a diuretic, to reduce edema and effusion. - Spironolactone, an aldosterone antagonist. This has two actions, firstly, as a potassium-sparing diuretic, although its diuretic properties are small compared with those of furosemide. Secondly, it reduces aldosterone-mediated myocardial fibrosis, possibly slowing the progression of heart disease. - An ACE inhibitor, often enalapril (trade name Enacard) or benazepril (Fortekor). These drugs inhibit the action of angiotensin-converting enzyme, producing a balanced vasodilation, along with other potentially favorable effects. Other drugs may also be used as required to manage certain arrhythmias that are often associated with heart disease. # Synthesis Pimobendan can be synthesized beginning with anisoyl chloride.	Pimobendane Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Pimobendan (or pimobendane)(INN) is a veterinary medication manufactured by Boehringer Ingelheim under the trade names Vetmedin and Acardi (Japan). It is both a calcium sensitizer and a selective inhibitor of phosphodiesterase III (PDE3) with positive inotropic and vasodilator effects. Pimobendan is used in the management of heart failure in dogs, most commonly caused by myxomatous mitral valve disease (also previously known as endocardiosis), or dilated cardiomyopathy.[1] Research has shown that pimobendan increases survival time and improves quality of life in canine patients with congestive heart failure secondary to mitral valve disease when compared with benazepril, an angiotensin-converting-enzyme (ACE) inhibitor.[2] Under the trade name Acardi, it is available for human use in Japan.[3] # Mechanism of action Pimobendan is a positive inotrope (increases myocardial contractility). It sensitizes and increases the binding efficiency of cardiac troponin in the myofibril to the calcium ions that are already present in systole. In normal hearts it increases the consumption of oxygen and energy to the same degree as dobutamine but in diseased hearts it may not.[4] [5] Pimobendan also causes peripheral vasodilation by inhibiting the function of phosphodiesterase III. This results in decreased resistance to blood flow through systemic arterioles, which decreases afterload (decreases the failing heart's workload) and reduces the amount of mitral regurgitation.[6][7] # Pharmacokinetics Pimobendan is absorbed rapidly when given via the oral route and has a bioavailability of 60-65%.[8] Bioavailability is markedly decreased when ingested with food. It is metabolized into an active metabolite (desmethylpimobendan) by the liver. The parent compound, pimobendan, is a potent calcium sensitizer while desmethylpimobendan is a more potent phosphodiesterase III inhibitor.[9] The half-life of pimobendan in the blood is 0.4 hours and the half-life of its metabolite is 2 hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% bound to plasma proteins in circulation. This may have implications in patients suffering from low blood protein levels (hypoproteinemia/hypoalbuminemia) and in patients that are on concurrent therapies that are also highly protein bound. # Combinations Pimobendan is often used in combination with three other drugs to palliate dogs with heart failure (pulmonary edema, pleural effusion, ascites). These are: - Furosemide, a diuretic, to reduce edema and effusion. - Spironolactone, an aldosterone antagonist. This has two actions, firstly, as a potassium-sparing diuretic, although its diuretic properties are small compared with those of furosemide. Secondly, it reduces aldosterone-mediated myocardial fibrosis, possibly slowing the progression of heart disease. - An ACE inhibitor, often enalapril (trade name Enacard) or benazepril (Fortekor). These drugs inhibit the action of angiotensin-converting enzyme, producing a balanced vasodilation, along with other potentially favorable effects. Other drugs may also be used as required to manage certain arrhythmias that are often associated with heart disease. # Synthesis Pimobendan can be synthesized beginning with anisoyl chloride.	https://www.wikidoc.org/index.php/Pimobendan
464f66148001d398ebd2cf11588d614f63a461d3	wikidoc	Pineocytoma	Pineocytoma Synonyms and keywords: Pineocytomas; Pinealocytoma; Pinealocytomas; PC; Pineal gland tumor; Brain tumor # Overview Pineocytoma is a benign, slowly growing pineal parenchymal tumor. The pineal gland, in the brain secretes melatonin which regulates sleep cycle . Pineocytomas most often occur in adults as a solid mass, although they may appear to have fluid-filled (cystic) spaces on images of the brain. Signs and symptoms of pineocytomas include headaches, nausea, vision abnormalities, and Parinaud syndrome. Pineocytomas are usually slow-growing and rarely spread to other parts of the body. Treatment includes surgery to remove the pineocytoma; most of these tumors do not regrow (recur) after surgery. # Classification The 2007 WHO classification of central nervous system tumors divides pineal gland tumors into four groups: - Pineocytoma (grade I) - Pineal parenchymal tumors of intermediate differentiation (grade II or III) - Papillary tumor of the pineal region (grade II or III) - Pineoblastoma (grade IV) According to the WHO classification of tumors of the central nervous system, pineocytoma is classified into a WHO grade I tumor. # Pathophysiology ## Pathogenesis - Due to the pineal gland's location, any tumor or cyst formation would lead to the compression of the aqueduct of Sylvius. - The aqueduct of Sylvius allows the cerebrospinal fluid to circulate out. - When there is a blockage in aqueduct of Sylvius by an abnormal pineal gland, the passage of the duct is blocked, and CSF pressure builds up, leading to hydrocephalus. Results in nausea, vomiting, visual changes, headaches, seizures, and memory changes. - Results in nausea, vomiting, visual changes, headaches, seizures, and memory changes. - Increase in intracranial pressure can even be life-threatening, prompting emergency treatment. - The hydrocephalus can be relieved by the placement of a VP shunt or ventriculostomy. - Vision changes would also occur due to an involvement of the tectal region. The tectal region helps dictate eye movements. Fault in the tectal region causes double vision, an issue with focusing on objects, and eye movement impairment. - The tectal region helps dictate eye movements. - Fault in the tectal region causes double vision, an issue with focusing on objects, and eye movement impairment. - The pineal gland can cause Parinaud syndrome due to the increasing size of the gland compressing the pretectal area and superior colliculi of the midbrain. Parinaud syndrome prevents a person from moving his or her eyes up and down. - Parinaud syndrome prevents a person from moving his or her eyes up and down. - The thalamus can be affected, and if so, there can be disturbances on that side of the body which would result in weakness and loss of sensation. - The tumor's effect on the hypothalamus will lead to weight gain, disruption of sleep, disruption of temperature control, and water regulation. - Cerebellar involvement would result in motor impairment. If the tumor of the pineal gland is present in childhood, then endocrine dysfunctions can also result such as precocious pseudopuberty, diabetes insipidus, and a slowed growth rate. - If the tumor of the pineal gland is present in childhood, then endocrine dysfunctions can also result such as precocious pseudopuberty, diabetes insipidus, and a slowed growth rate. ## Gross Pathology On gross pathology, pineocytoma is characterized by solid, sometimes with focal areas of cystic change, gray, well-circumscribed mass with or without hemorrhage. ## Microscopic Pathology On microscopic histopathological analysis, pineocytoma is characterized by: - Cytologically benign cells (uniform size of nuclei, regular nuclear membrane, light chromatin) - Pineocytomatous/neurocytic rosette, which is an irregular circular/flower-like arrangement of cells with a large meshwork of fibers (neuropil) at the center. ## Immunohistochemistry Pineocytoma is demonstrated by positivity to tumor markers such as: - Synaptophysin - Neuron-specific enolase - GFAP - Chromogranin A - PLAP - Ki-67 - Beta tubulin III # Differentiating Pineocytoma from other Diseases Pineocytoma must be differentiated from: - Pineal parenchymal tumor with intermediate differentiation - Papillary tumor of the pineal region - Pineoblastoma - Pineal germinoma - Pineal embryonal carcinoma - Pineal choriocarcinoma - Pineal yolk sac carcinoma (endodermal sinus tumor) - Pineal teratoma - Pineal cyst - Astrocytoma of the pineal gland - Meningioma near pineal gland - Pineal metastasis - Cavernoma in pineal region - Aneurysm in pineal region For differentiating pineal gland tumors from other cranial tumors click here For differentiating among different types of pineal gland tumors click here # Epidemiology ## Prevalence - Pineocytoma constitutes approximately 45% of the pineal parenchymal tumors. - Pineocytoma constitutes approximately 0.4 - 1% of the intracranial neoplasms. ## Age - Pineocytoma is a rare disease that tends to affect all age groups, most commonly in the second decade of life. # Natural History, Complication and Prognosis ## Natural History If left untreated, patients with pineocytoma may progress to develop seizures, obstructive hydrocephalus, local recurrence, and CSF metastasis. ## Complications Common complications of pineocytoma include: - Obstructive hydrocephalus - Local recurrence - CSF metastasis - Distant metastasis (most commonly, lung) ## Prognosis - Prognosis is generally excellent, and the 5-year survival rate of patients with pineocytoma is approximately 86%. - Pineocytoma has the most favorable prognosis among all the pineal gland tumors. - Clark et al. after performing a systematic review of the literature reported that the 1- and 5-year progression free survival (PFS) rates for patients that underwent resection versus the biopsy group were 97% and 90%, and 89% and 75% respectively. The 1- and 5-year PFS rates for the gross total resection group versus the group undergoing subtotal resection combined with radiation therapy were 100% and 94%, and 100% and 84% respectively. # Diagnosis ## History When evaluating a patient for pineocytoma, you should take a detailed history of the presenting symptom (onset, duration, and progression), other associated symptoms, and a thorough family and past medical history review. ## Symptoms - The clinical presentation of pineocytoma is mainly from the obstructive hydrocephalus secondary to compression of the tectum of the midbrain and obstruction of the aqueduct. Pineal tumors cause neurologic dysfunction by direct invasion, compression, or obstruction of cerebrospinal fluid (CSF) flow. The rate of tumor growth determines the rapidity of symptom onset and is an important prognostic factor. - Pineal tumors cause neurologic dysfunction by direct invasion, compression, or obstruction of cerebrospinal fluid (CSF) flow. - The rate of tumor growth determines the rapidity of symptom onset and is an important prognostic factor. - Pineal gland tumors share some common clinical and radiographic features based upon their anatomic location. Symptoms of pineocytoma include: - Hydrocephalus is common, manifested by headaches, lethargy, and signs of increased intracranial pressure. - Progressive local tumor growth may result in cranial neuropathies or hypothalamic dysfunction. Sleepiness Irritability Personality changes Double vision Trouble coordinating motor movements Difficulty walking Slowed growth - Sleepiness - Irritability - Personality changes - Double vision - Trouble coordinating motor movements - Difficulty walking - Slowed growth ## Staging The staging work-up for pineal tumors include - Contrast-enhanced MRI of the brain and the entire spine. - The cerebrospinal fluid (CSF) for cytological examination. ## Physical Examination Compression of the superior colliculi can lead to a characteristic gaze palsy, known as Parinaud syndrome. Common physical examination findings of pineocytoma include: ## HEENT - Bulging soft spots (fontanelles) - Eyes that are constantly looking down (sunsetting sign) - Deficiency in upward-gaze - Pupillary light-near dissociation (pupils respond to near stimuli but not light) - Convergence-retraction nystagmus ## Neurological - Mental retardation - Muscle spasms - Loss of bladder control - Ataxia ## Laboratory Diagnosis There are no specific laboratory findings for pineocytoma. However, the following findings are of significant - Both serum and CSF should be assayed for alpha-fetoprotein and beta human chorionic gonadotropin (beta-hCG) to help diagnose a germ cell tumor. - Immunohistochemistry may be of value in detecting these markers or placental alkaline phosphatase. ## CT - Head CT scan may be diagnostic of pineocytoma. - Findings on CT scan suggestive of pineocytoma include a mass of intermediate density similar to the adjacent brain with peripheral calcifications. ## MRI - Brain MRI may be diagnostic of pineocytoma. - Features on MRI suggestive of pineocytoma include: ## Other Diagnostic Studies Stereotactic biopsy - A direct, visually guided biopsy of the pineal gland mass with open or neuroendoscopic surgery has been preferred due to concerns about injury to the deep cerebral veins. - An open procedure also allows CSF to be obtained for Tumor marker studies Permits direct visualization of the third ventricle for staging purposes Sllows a third ventriculostomy to be performed for CSF diversion if needed. - Tumor marker studies - Permits direct visualization of the third ventricle for staging purposes - Sllows a third ventriculostomy to be performed for CSF diversion if needed. - The diagnostic yield of stereotactic biopsy ranges from 94 to 100 percent. - If the biopsy is nondiagnostic, equivocal, or suggests a benign tumor such as mature teratoma or meningioma, surgery is recommended to establish a definitive diagnosis or to identify focal areas of malignant disease # Treatment - The mainstay of therapy for pineocytoma is surgery (gross total or subtotal resection). - The treatment of PPTs must be guided by the histologic sub type can be assessed by tissue diagnosis - Empiric therapy is recommended in nongerminomatous GCT in a patient with characteristic neuroimaging studies and elevated serum or CSF levels of the tumor markers alpha-fetoprotein and/or the beta subunit of human chorionic gonadotropin. - Empiric therapy for patient with germinoma can be initiated based upon the imaging presence of “bi focal” tumors, CSF beta-hCG <50 mIU/mL, and no elevation of alpha-fetoprotein. - Successful treatment of pineocytomas requires surgery with or without RT, while the best results with pineoblastomas are seen with multimodality approaches that include chemotherapy. - The main goal of open surgery on pineocytoma is the complete tumor removal with minimal morbidity, whenever possible. However, even if gross total excision cannot be achieved, establishment of an accurate diagnosis, maximal cytoreduction, and restoration of the CSF pathway may be achieved. - Radiotherapy administration to subtotally resected tumor is not associated with an increase in either tumor control or survival. - Stereotactically guided iodine-125 seed implantation has been proposed as a potential alternative to microsurgery in de novo diagnosed pineocytomas, since it was proven efficient and safe. - Patients with pineocytoma will develop hydrocephalus in majority of the cases and they will require CSF diversion. Ventriculo-peritoneal (V-P) shunt placement is a viable option with low morbidity and mortality rate. However, shunt malfunction in this population is as high as 20%. In addition, tumor metastasis through a CSF shunt has been reported. Endoscopic third ventriculostomy (ETVC) is an alternative option, which also permits a biopsy of the tumor in the same procedure. Ahn et al. reported that the biopsy samples, obtained in the lateral ventricle or pineal region, were more favorable towards a successful diagnosis than those in the thalamus or tectal region. Neuroendoscopic biopsy procedures have been proven safe with low complication rates.	Pineocytoma Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2] Aditya Ganti M.B.B.S. [3] Synonyms and keywords: Pineocytomas; Pinealocytoma; Pinealocytomas; PC; Pineal gland tumor; Brain tumor # Overview Pineocytoma is a benign, slowly growing pineal parenchymal tumor. The pineal gland, in the brain secretes melatonin which regulates sleep cycle . Pineocytomas most often occur in adults as a solid mass, although they may appear to have fluid-filled (cystic) spaces on images of the brain. Signs and symptoms of pineocytomas include headaches, nausea, vision abnormalities, and Parinaud syndrome. Pineocytomas are usually slow-growing and rarely spread to other parts of the body. Treatment includes surgery to remove the pineocytoma; most of these tumors do not regrow (recur) after surgery.[1] # Classification The 2007 WHO classification of central nervous system tumors divides pineal gland tumors into four groups: - Pineocytoma (grade I) - Pineal parenchymal tumors of intermediate differentiation (grade II or III) - Papillary tumor of the pineal region (grade II or III) - Pineoblastoma (grade IV) According to the WHO classification of tumors of the central nervous system, pineocytoma is classified into a WHO grade I tumor.[2] # Pathophysiology ## Pathogenesis - Due to the pineal gland's location, any tumor or cyst formation would lead to the compression of the aqueduct of Sylvius. - The aqueduct of Sylvius allows the cerebrospinal fluid to circulate out. - When there is a blockage in aqueduct of Sylvius by an abnormal pineal gland, the passage of the duct is blocked, and CSF pressure builds up, leading to hydrocephalus. Results in nausea, vomiting, visual changes, headaches, seizures, and memory changes. - Results in nausea, vomiting, visual changes, headaches, seizures, and memory changes. - Increase in intracranial pressure can even be life-threatening, prompting emergency treatment. - The hydrocephalus can be relieved by the placement of a VP shunt or ventriculostomy. - Vision changes would also occur due to an involvement of the tectal region. The tectal region helps dictate eye movements. Fault in the tectal region causes double vision, an issue with focusing on objects, and eye movement impairment. - The tectal region helps dictate eye movements. - Fault in the tectal region causes double vision, an issue with focusing on objects, and eye movement impairment. - The pineal gland can cause Parinaud syndrome due to the increasing size of the gland compressing the pretectal area and superior colliculi of the midbrain. Parinaud syndrome prevents a person from moving his or her eyes up and down. - Parinaud syndrome prevents a person from moving his or her eyes up and down. - The thalamus can be affected, and if so, there can be disturbances on that side of the body which would result in weakness and loss of sensation. - The tumor's effect on the hypothalamus will lead to weight gain, disruption of sleep, disruption of temperature control, and water regulation. - Cerebellar involvement would result in motor impairment. If the tumor of the pineal gland is present in childhood, then endocrine dysfunctions can also result such as precocious pseudopuberty, diabetes insipidus, and a slowed growth rate. - If the tumor of the pineal gland is present in childhood, then endocrine dysfunctions can also result such as precocious pseudopuberty, diabetes insipidus, and a slowed growth rate. ## Gross Pathology On gross pathology, pineocytoma is characterized by solid, sometimes with focal areas of cystic change, gray, well-circumscribed mass with or without hemorrhage.[3][4] ## Microscopic Pathology On microscopic histopathological analysis, pineocytoma is characterized by:[5] - Cytologically benign cells (uniform size of nuclei, regular nuclear membrane, light chromatin) - Pineocytomatous/neurocytic rosette, which is an irregular circular/flower-like arrangement of cells with a large meshwork of fibers (neuropil) at the center. ## Immunohistochemistry Pineocytoma is demonstrated by positivity to tumor markers such as:[7][8][9][10] - Synaptophysin - Neuron-specific enolase - GFAP - Chromogranin A - PLAP - Ki-67 - Beta tubulin III # Differentiating Pineocytoma from other Diseases Pineocytoma must be differentiated from:[11] - Pineal parenchymal tumor with intermediate differentiation - Papillary tumor of the pineal region - Pineoblastoma - Pineal germinoma - Pineal embryonal carcinoma - Pineal choriocarcinoma - Pineal yolk sac carcinoma (endodermal sinus tumor) - Pineal teratoma - Pineal cyst - Astrocytoma of the pineal gland - Meningioma near pineal gland - Pineal metastasis - Cavernoma in pineal region - Aneurysm in pineal region For differentiating pineal gland tumors from other cranial tumors click here For differentiating among different types of pineal gland tumors click here # Epidemiology ## Prevalence - Pineocytoma constitutes approximately 45% of the pineal parenchymal tumors.[10][12] - Pineocytoma constitutes approximately 0.4 - 1% of the intracranial neoplasms.[13] ## Age - Pineocytoma is a rare disease that tends to affect all age groups, most commonly in the second decade of life.[12] # Natural History, Complication and Prognosis ## Natural History If left untreated, patients with pineocytoma may progress to develop seizures, obstructive hydrocephalus, local recurrence, and CSF metastasis.[14][15] ## Complications Common complications of pineocytoma include:[15][10] - Obstructive hydrocephalus - Local recurrence - CSF metastasis - Distant metastasis (most commonly, lung) ## Prognosis - Prognosis is generally excellent, and the 5-year survival rate of patients with pineocytoma is approximately 86%.[15] - Pineocytoma has the most favorable prognosis among all the pineal gland tumors.[16] - Clark et al. after performing a systematic review of the literature reported that the 1- and 5-year progression free survival (PFS) rates for patients that underwent resection versus the biopsy group were 97% and 90%, and 89% and 75% respectively. The 1- and 5-year PFS rates for the gross total resection group versus the group undergoing subtotal resection combined with radiation therapy were 100% and 94%, and 100% and 84% respectively.[17] # Diagnosis ## History When evaluating a patient for pineocytoma, you should take a detailed history of the presenting symptom (onset, duration, and progression), other associated symptoms, and a thorough family and past medical history review. ## Symptoms - The clinical presentation of pineocytoma is mainly from the obstructive hydrocephalus secondary to compression of the tectum of the midbrain and obstruction of the aqueduct.[14] Pineal tumors cause neurologic dysfunction by direct invasion, compression, or obstruction of cerebrospinal fluid (CSF) flow. The rate of tumor growth determines the rapidity of symptom onset and is an important prognostic factor. - Pineal tumors cause neurologic dysfunction by direct invasion, compression, or obstruction of cerebrospinal fluid (CSF) flow. - The rate of tumor growth determines the rapidity of symptom onset and is an important prognostic factor. - Pineal gland tumors share some common clinical and radiographic features based upon their anatomic location. Symptoms of pineocytoma include: - Hydrocephalus is common, manifested by headaches, lethargy, and signs of increased intracranial pressure. - Progressive local tumor growth may result in cranial neuropathies or hypothalamic dysfunction. Sleepiness Irritability Personality changes Double vision Trouble coordinating motor movements Difficulty walking Slowed growth - Sleepiness - Irritability - Personality changes - Double vision - Trouble coordinating motor movements - Difficulty walking - Slowed growth ## Staging The staging work-up for pineal tumors include - Contrast-enhanced MRI of the brain and the entire spine. - The cerebrospinal fluid (CSF) for cytological examination. ## Physical Examination Compression of the superior colliculi can lead to a characteristic gaze palsy, known as Parinaud syndrome. Common physical examination findings of pineocytoma include:[14] ## HEENT - Bulging soft spots (fontanelles) - Eyes that are constantly looking down (sunsetting sign) - Deficiency in upward-gaze - Pupillary light-near dissociation (pupils respond to near stimuli but not light) - Convergence-retraction nystagmus ## Neurological - Mental retardation - Muscle spasms - Loss of bladder control - Ataxia ## Laboratory Diagnosis There are no specific laboratory findings for pineocytoma. However, the following findings are of significant - Both serum and CSF should be assayed for alpha-fetoprotein and beta human chorionic gonadotropin (beta-hCG) to help diagnose a germ cell tumor. - Immunohistochemistry may be of value in detecting these markers or placental alkaline phosphatase. ## CT - Head CT scan may be diagnostic of pineocytoma. - Findings on CT scan suggestive of pineocytoma include a mass of intermediate density similar to the adjacent brain with peripheral calcifications.[18] ## MRI - Brain MRI may be diagnostic of pineocytoma. - Features on MRI suggestive of pineocytoma include:[18] ## Other Diagnostic Studies Stereotactic biopsy - A direct, visually guided biopsy of the pineal gland mass with open or neuroendoscopic surgery has been preferred due to concerns about injury to the deep cerebral veins. - An open procedure also allows CSF to be obtained for Tumor marker studies Permits direct visualization of the third ventricle for staging purposes Sllows a third ventriculostomy to be performed for CSF diversion if needed. - Tumor marker studies - Permits direct visualization of the third ventricle for staging purposes - Sllows a third ventriculostomy to be performed for CSF diversion if needed. - The diagnostic yield of stereotactic biopsy ranges from 94 to 100 percent. - If the biopsy is nondiagnostic, equivocal, or suggests a benign tumor such as mature teratoma or meningioma, surgery is recommended to establish a definitive diagnosis or to identify focal areas of malignant disease # Treatment - The mainstay of therapy for pineocytoma is surgery (gross total or subtotal resection).[15][16][17] - The treatment of PPTs must be guided by the histologic sub type can be assessed by tissue diagnosis - Empiric therapy is recommended in nongerminomatous GCT in a patient with characteristic neuroimaging studies and elevated serum or CSF levels of the tumor markers alpha-fetoprotein and/or the beta subunit of human chorionic gonadotropin. - Empiric therapy for patient with germinoma can be initiated based upon the imaging presence of “bi focal” tumors, CSF beta-hCG <50 mIU/mL, and no elevation of alpha-fetoprotein. - Successful treatment of pineocytomas requires surgery with or without RT, while the best results with pineoblastomas are seen with multimodality approaches that include chemotherapy. - The main goal of open surgery on pineocytoma is the complete tumor removal with minimal morbidity, whenever possible. However, even if gross total excision cannot be achieved, establishment of an accurate diagnosis, maximal cytoreduction, and restoration of the CSF pathway may be achieved. - Radiotherapy administration to subtotally resected tumor is not associated with an increase in either tumor control or survival.[17] - Stereotactically guided iodine-125 seed implantation has been proposed as a potential alternative to microsurgery in de novo diagnosed pineocytomas, since it was proven efficient and safe. - Patients with pineocytoma will develop hydrocephalus in majority of the cases and they will require CSF diversion. Ventriculo-peritoneal (V-P) shunt placement is a viable option with low morbidity and mortality rate. However, shunt malfunction in this population is as high as 20%. In addition, tumor metastasis through a CSF shunt has been reported. Endoscopic third ventriculostomy (ETVC) is an alternative option, which also permits a biopsy of the tumor in the same procedure. Ahn et al. reported that the biopsy samples, obtained in the lateral ventricle or pineal region, were more favorable towards a successful diagnosis than those in the thalamus or tectal region. Neuroendoscopic biopsy procedures have been proven safe with low complication rates.[17]	https://www.wikidoc.org/index.php/Pinealocytoma
d1c386906e4d0449945165d088d2588d8a919290	wikidoc	Piperaquine	Piperaquine # Overview Piperaquine is an antimalarial drug, a bisquinoline first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based antimalarials became available. However, Chinese scientists have been studying whether piperaquine can still be used therapeutically in combination with artemisinin. Piperaquine is characterized by slow absorption and a long biological half-life, making it a good partner drug with artemisinin derivatives which are fast acting but have a short biological half-life. The fixed-dose combination dihydroartemisinin-piperaquine (Eurartesim) was submitted for approval to the European Medicines Agency in 2009.	Piperaquine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Piperaquine is an antimalarial drug, a bisquinoline first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. Usage declined in the 1980s as piperaquine-resistant strains of P. falciparum arose and artemisinin-based antimalarials became available. However, Chinese scientists have been studying whether piperaquine can still be used therapeutically in combination with artemisinin.[1] Piperaquine is characterized by slow absorption and a long biological half-life,[2] making it a good partner drug with artemisinin derivatives which are fast acting but have a short biological half-life.[3] The fixed-dose combination dihydroartemisinin-piperaquine (Eurartesim) was submitted for approval to the European Medicines Agency in 2009.[4]	https://www.wikidoc.org/index.php/Piperaquine
d8a89c25aa99940e9fc9240065e916f4de42565b	wikidoc	Piperocaine	Piperocaine Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Piperocaine is a local anesthetic drug used as its hydrochloride salt for infiltration and nerve blocks.	Piperocaine Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Piperocaine is a local anesthetic drug used as its hydrochloride salt for infiltration and nerve blocks. # External links - Voltage and time-dependent actions of piperocaine on the ion channel of the acetylcholine receptor Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Piperocaine
ee1e3fd527722fd6111e26714f7578a9316b1a08	wikidoc	Piritramide	Piritramide # Overview Piritramide (R-3365, trade names Dipidolor, Piridolan, Pirium and others) is a synthetic opioid analgesic (narcotic painkiller) that is marketed in certain European countries including: Austria, Belgium, Czech Republic, Germany and the Netherlands. It comes in free form, is about 0.75x times as potent as morphine and is given parenterally (by injection) for the treatment of severe pain. Nausea, vomiting, respiratory depression and constipation are believed to be less frequent with piritramide than with morphine (which is the gold standard opioid against which other opioids are compared and contrasted against) and it produces more rapid-onset analgesia (pain relief) when compared to morphine and pethidine, after intravenous administration the onset of analgesia is as little as 1–2 minutes, which may be related to its great lipophilicity. The analgesic and sedative effects of piritramide are believed to be potentiated with phenothiazines and its emetic (nausea/vomiting-inducing) effects are suppressed. The volume of distribution is 0.7-1 L/kg after a single dose, 4.7-6 L/kg after steady-state concentrations are achieved and up to 11.1 L/kg after prolonged dosing. # History & Regulation Piritramide was developed and patented in the Netherlands, at Janssen, in 1960. It is part of an eponymous two-member class of opioids in clinical use with the other being bezitramide (Burgodin). The closest chemical and structural relatives of piritramide in clinical use include the diphenoxylate family, fentanyl (both Janssen discoveries) and somewhat more distantly alphaprodine. Not being in clinical use in the United States, it is a Schedule I Narcotic controlled substance with a DEA ACSCN of 9642 and manufacturing quota of zero. It presumably has abuse potential, and appears on the European black market on occasion and has a handful of street names including "Pierrette" and "P". LEXIS-NEXIS and other database searches do not show mentions of law enforcement contact with this drug in the United States. Piritramide is specifically exempted from the Canadian controlled-substances law, and its relative bezitramide is a Schedule II controlled substance in the US, although not used there as of 2014. # Synthesis - DE 1238472	Piritramide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Piritramide (R-3365, trade names Dipidolor, Piridolan, Pirium and others) is a synthetic opioid analgesic (narcotic painkiller) that is marketed in certain European countries including: Austria, Belgium, Czech Republic, Germany and the Netherlands.[2] It comes in free form, is about 0.75x times as potent as morphine and is given parenterally (by injection) for the treatment of severe pain.[2][3] Nausea, vomiting, respiratory depression and constipation are believed to be less frequent with piritramide than with morphine (which is the gold standard opioid against which other opioids are compared and contrasted against) and it produces more rapid-onset analgesia (pain relief) when compared to morphine and pethidine, after intravenous administration the onset of analgesia is as little as 1–2 minutes, which may be related to its great lipophilicity.[4] The analgesic and sedative effects of piritramide are believed to be potentiated with phenothiazines and its emetic (nausea/vomiting-inducing) effects are suppressed.[4] The volume of distribution is 0.7-1 L/kg after a single dose, 4.7-6 L/kg after steady-state concentrations are achieved and up to 11.1 L/kg after prolonged dosing.[4] # History & Regulation Piritramide was developed and patented in the Netherlands, at Janssen, in 1960. It is part of an eponymous two-member class of opioids in clinical use with the other being bezitramide (Burgodin). The closest chemical and structural relatives of piritramide in clinical use include the diphenoxylate family, fentanyl (both Janssen discoveries) and somewhat more distantly alphaprodine. Not being in clinical use in the United States, it is a Schedule I Narcotic controlled substance with a DEA ACSCN of 9642 and manufacturing quota of zero.[5] It presumably has abuse potential, and appears on the European black market on occasion and has a handful of street names including "Pierrette" and "P".[6] LEXIS-NEXIS and other database searches do not show mentions of law enforcement contact with this drug in the United States. Piritramide is specifically exempted from the Canadian controlled-substances law, and its relative bezitramide is a Schedule II controlled substance in the US, although not used there as of 2014. # Synthesis - DE 1238472	https://www.wikidoc.org/index.php/Piritramide
8a363d55c0f5aad7b0e7eb424e76d24795bcff9e	wikidoc	Plakoglobin	Plakoglobin Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the JUP gene. Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic component of desmosomes and adherens junctions structures located within intercalated discs of cardiac muscle that function to anchor sarcomeres and join adjacent cells in cardiac muscle. Mutations in plakoglobin are associated with arrhythmogenic right ventricular dysplasia. # Structure Human plakoglobin is 81.7 kDa in molecular weight and 745 amino acids long. The JUP gene contains 13 exons spanning 17 kb on chromosome 17q21. Plakoglobin is a member of the catenin family, since it contains a distinct repeating amino acid motif called the armadillo repeat. Plakoglobin is highly homologous to β-catenin; both have 12 armadillo repeats as well as N-terminal and C-terminal globular domains of unknown structure. Plakoglobin was originally identified as a component of desmosomes, where it can bind to the cadherin family member desmoglein I. Plakoglobin also associates with classical cadherins such as E-cadherin; in that context, it was called gamma-catenin. Plakoglobin forms distinct complexes with cadherins and desmosomal cadherins. # Function Plakoglobin is a major cytoplasmic component of both desmosomes and adherens junctions, and is the only known constituent common to submembranous plaques in both of these structures, which are located at the intercalated disc (ICD) of cardiomyocytes. Plakoglobin links cadherins to the actin cytoskeleton. Plakoglobin binds to conserved regions of desmoglein and desmocollin at intracellular catenin-binding sites to assemble desmosomes. Plakoglobin is essential for normal development of intercalated discs and stability of cardiac muscle. Transgenic mice homozygous for a null mutation of the JUP gene die around embryonic day 12 from substantial defects in adherens junctions and a lack of functional desmosomes in the heart. Further studies showed that cardiac fibers obtained from JUP-null embryonic mice had decreased passive compliance albeit normal attachment of sarcomeres to adherens junctions. In additional studies, an inducible cardiac-specific plakoglobin knockout mice were generated. Transgenic mice displayed a similar phenotype as arrhythmogenic right ventricular cardiomyopathy patients, with loss of cardiomyocytes, fibrosis and cardiac dysfunction, as well as alterations in desmosome protein content and gap junction remodeling. Hearts also exhibited increases in β-catenin signaling. Further investigations on the role of β-catenin and plakoglobin in the heart generated a double knockout of these two proteins. Mice exhibited cardiomyopathy, fibrosis, conduction abnormalities and sudden cardiac death, presumably via spontaneous lethal ventricular arrhythmias. Mice also showed a decrease in gap junction structures at intercalated discs. Intracellular plakoglobin expression s controlled by Wnt signaling and ubiquitin-proteasome-dependent degradation. Phosphorylation of N-terminal Serines by a “destruction complex” composed of glycogen synthase kinase 3β (GSK3β) and scaffold proteins adenomatous polyposis coli (APC) and axin targets plakoglobin for degradation.. The phosphorylated motif is recognized by β-TrCP, a ubiquitin ligase that targets plakoglobin 26S proteasome-dependent degradation. Plakoglobin is also O-glycosylated near its N-terminal destruction box. # Clinical significance Mutation of the JUP gene encoding plakoglobin has been implicated as one of the causes of the cardiomyopathy known as arrhythmogenic right ventricular dysplasia (ARVD) or arrhythmogenic right ventricular cardiomyopathy; mutations in JUP specifically causes an autosomal recessive form referred to as Naxos disease. This form of was first identified in a small cluster of families on the Greek island of Naxos. The phenotype of the Naxos disease variant of ARVD is unique in that it involves the hair and skin as well as the right ventricle. Affected individuals have kinky, wooly hair; there is also palmar and plantar erythema at birth that progresses to keratosis as the palms and soles of the feet are used in crawling and walking. These findings co-segregate 100% with the development of ARVD by early adolescence. It has become clear that ARVD/ARVC is a disease of the cardiac muscle desmosome; advances in molecular genetics have illuminated this notion. Studies investigating the role of plakoglobin in disease pathology have found that suppression of desmoplakin expression by siRNA led to the nuclear localization of plakoglobin, resulting in a reduction in Wnt signaling via Tcf/Lef1 and ensued pathogenesis of ARVC. Specifically, adipogenic factor expression was induced and cardiac progenitor cells at the epicardium were differentiated to adipocytes. Non-invasive cardiac screening identified T-wave inversion, abnormalities in right ventricular wall motion, and frequent ventricular extrasystoles as sensitive and specific markers of a JUP mutation. Additional studies have shown that immunohistochemical analysis of cardiac muscle desmosomal proteins is also a sensitive and specific diagnostic text for ARVD/ARVC. Abnormal distribution of plakoglobin due to mutations in genes encoding for Desmoglein 1 and 3 have also been implicated in Pemphigus vulgaris. # Interactions Plakoglobin has been shown to interact with: - APC, - CTNNA1, - CTNNB1, - CDH1, - CDH2, - CDH3, - CDH5, - DSG2, - DSP, - MUC1, - PKP2, - PTPkappa (PTPRK), - PTPrho (PTPRT), and - PDLIM3.	Plakoglobin Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the JUP gene.[1] Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic component of desmosomes and adherens junctions structures located within intercalated discs of cardiac muscle that function to anchor sarcomeres and join adjacent cells in cardiac muscle. Mutations in plakoglobin are associated with arrhythmogenic right ventricular dysplasia. # Structure Human plakoglobin is 81.7 kDa in molecular weight and 745 amino acids long.[2] The JUP gene contains 13 exons spanning 17 kb on chromosome 17q21.[3] Plakoglobin is a member of the catenin family, since it contains a distinct repeating amino acid motif called the armadillo repeat.[1] Plakoglobin is highly homologous to β-catenin; both have 12 armadillo repeats as well as N-terminal and C-terminal globular domains of unknown structure.[4] Plakoglobin was originally identified as a component of desmosomes, where it can bind to the cadherin family member desmoglein I. Plakoglobin also associates with classical cadherins such as E-cadherin; in that context, it was called gamma-catenin. Plakoglobin forms distinct complexes with cadherins and desmosomal cadherins. # Function Plakoglobin is a major cytoplasmic component of both desmosomes and adherens junctions, and is the only known constituent common to submembranous plaques in both of these structures,[5] which are located at the intercalated disc (ICD) of cardiomyocytes. Plakoglobin links cadherins to the actin cytoskeleton. Plakoglobin binds to conserved regions of desmoglein and desmocollin at intracellular catenin-binding sites to assemble desmosomes.[6][7] Plakoglobin is essential for normal development of intercalated discs and stability of cardiac muscle. Transgenic mice homozygous for a null mutation of the JUP gene die around embryonic day 12 from substantial defects in adherens junctions and a lack of functional desmosomes in the heart.[8][9] Further studies showed that cardiac fibers obtained from JUP-null embryonic mice had decreased passive compliance albeit normal attachment of sarcomeres to adherens junctions.[10] In additional studies, an inducible cardiac-specific plakoglobin knockout mice were generated. Transgenic mice displayed a similar phenotype as arrhythmogenic right ventricular cardiomyopathy patients, with loss of cardiomyocytes, fibrosis and cardiac dysfunction, as well as alterations in desmosome protein content and gap junction remodeling. Hearts also exhibited increases in β-catenin signaling.[11][12] Further investigations on the role of β-catenin and plakoglobin in the heart generated a double knockout of these two proteins. Mice exhibited cardiomyopathy, fibrosis, conduction abnormalities and sudden cardiac death, presumably via spontaneous lethal ventricular arrhythmias. Mice also showed a decrease in gap junction structures at intercalated discs.[13] Intracellular plakoglobin expression s controlled by Wnt signaling and ubiquitin-proteasome-dependent degradation. Phosphorylation of N-terminal Serines by a “destruction complex” composed of glycogen synthase kinase 3β (GSK3β) and scaffold proteins adenomatous polyposis coli (APC) and axin targets plakoglobin for degradation.[14][15][16][31–33]. The phosphorylated motif is recognized by β-TrCP, a ubiquitin ligase that targets plakoglobin 26S proteasome-dependent degradation.[17] Plakoglobin is also O-glycosylated near its N-terminal destruction box. # Clinical significance Mutation of the JUP gene encoding plakoglobin has been implicated as one of the causes of the cardiomyopathy known as arrhythmogenic right ventricular dysplasia (ARVD) or arrhythmogenic right ventricular cardiomyopathy; mutations in JUP specifically causes an autosomal recessive form referred to as Naxos disease.[18][19][20] This form of was first identified in a small cluster of families on the Greek island of Naxos. The phenotype of the Naxos disease variant of ARVD is unique in that it involves the hair and skin as well as the right ventricle. Affected individuals have kinky, wooly hair; there is also palmar and plantar erythema at birth that progresses to keratosis as the palms and soles of the feet are used in crawling and walking.[21][22][23] These findings co-segregate 100% with the development of ARVD by early adolescence. It has become clear that ARVD/ARVC is a disease of the cardiac muscle desmosome; advances in molecular genetics have illuminated this notion.[24][25][26][27][28][29][30][31][32] Studies investigating the role of plakoglobin in disease pathology have found that suppression of desmoplakin expression by siRNA led to the nuclear localization of plakoglobin, resulting in a reduction in Wnt signaling via Tcf/Lef1 and ensued pathogenesis of ARVC.[33] Specifically, adipogenic factor expression was induced and cardiac progenitor cells at the epicardium were differentiated to adipocytes.[34] Non-invasive cardiac screening identified T-wave inversion, abnormalities in right ventricular wall motion, and frequent ventricular extrasystoles as sensitive and specific markers of a JUP mutation.[35] Additional studies have shown that immunohistochemical analysis of cardiac muscle desmosomal proteins is also a sensitive and specific diagnostic text for ARVD/ARVC.[36] Abnormal distribution of plakoglobin due to mutations in genes encoding for Desmoglein 1 and 3 have also been implicated in Pemphigus vulgaris.[37][38] # Interactions Plakoglobin has been shown to interact with: - APC,[39][40] - CTNNA1,[41][42][43] - CTNNB1,[44][45] - CDH1,[39][44][46][47][48] - CDH2,[41][49] - CDH3,[50] - CDH5,[51][52] - DSG2,[53][54][55] - DSP,[56][57] - MUC1,[58] - PKP2,[59] - PTPkappa (PTPRK),[60] - PTPrho (PTPRT),[61] and - PDLIM3.[62]	https://www.wikidoc.org/index.php/Plakoglobin
afd414417b3142285debeb3fcb64736c879ca745	wikidoc	Plane joint	Plane joint A gliding joint (arthrodial joint, plane articulation) is a synovial joint which admits of only gliding movement. The gliding joint allows one bone to slide over the other. The gliding joint in your wrist allows to flex your wrist. It also makes very small side motions. There are also gliding joints in your ankles. A gliding joint is a synovial joint, and a synovial joint allows lots of movement.	Plane joint Template:Infobox Anatomy A gliding joint (arthrodial joint, plane articulation) is a synovial joint which admits of only gliding movement.[1] The gliding joint allows one bone to slide over the other. The gliding joint in your wrist allows to flex your wrist. It also makes very small side motions. There are also gliding joints in your ankles. A gliding joint is a synovial joint, and a synovial joint allows lots of movement.	https://www.wikidoc.org/index.php/Plane_joint
f2dc19593f8cb2601ab56c9cd7643379b4769d5c	wikidoc	Plasma cell	Plasma cell # Overview Plasma cells (also called plasma B cells or plasmocytes) are cells of the immune system that secrete large amounts of antibodies. They differentiate from B cells upon stimulation by CD4+ lymphocytes. The B cell acts as an antigen presenting cell (APC), consuming an offending pathogen. That pathogen gets taken up by the B cell by receptor mediated endocytosis, and broken down within these endosomes after fusion with lysosomes releasing proteolytic enzymes onto the pathogen. Once the enzymes break down the pathogen, pieces of the pathogen (which are now known as antigenic peptides) are loaded onto MHC II molecules, and presented on its extracellular surface. Once on the extracellular surface, the CD4+ T-helper lymphocyte will bind to the MHC II/Antigen molecule and cause activation of the B cell, which includes differentiation into a plasma cell, and subsequent generation of antibody against the consumed pathogen. # Physiopathology After dividing for around five days, mature B cells differentiate into either plasma B cells or memory B cells. Plasma B cells originate in the bone marrow, then travel to the spleen or lymph nodes to secrete antibodies (approximately 10,000 per second). During the initial stages of an immune response the lifespan of plasma cells is very short, typically only a few days to weeks. However, following the process of affinity maturation, plasma cells can survive for months to years and continue to secrete high levels of antibodies. Memory B cells tend to be longer-lived and can therefore respond quickly upon second exposure to an antigen. The class of antibody that a plasma cell produces depends on signals, called cytokines, from other immune system cells, such as macrophages and T helper cells. This process is called isotype-switching. For example, plasma cells will likely secrete IgG3 antibodies if they matured in the presence of the cytokine interferon-gamma. Since B cell maturation also involves somatic hypermutation, these antibodies have a very high affinity for their antigen. # Microscopic anatomy Plasma cells are large lymphocytes with a considerable nucleus-to-cytoplasm ratio and a characteristic appearance on light microscopy. They have basophilic cytoplasm and an eccentric nucleus with heterochromatin in a characteristic cartwheel arrangement. Their cytoplasm also contains a pale zone that on electron microscopy contains an extensive Golgi apparatus and centrioles. Abundant rough endoplasmic reticulum combined with a well-developed Golgi apparatus makes plasma cells well-suited for secreting immunoglobulins. # Role in disease Cancer of plasma cells is termed multiple myeloma. This condition is frequently identified because malignant plasma cells continue producing an antibody, which can be detected as a paraprotein. Common variable immunodeficiency is thought to be due to a problem in the differentiation from lymphocytes to plasma cells. The result is a low serum antibody level and risk of infections.	Plasma cell Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Plasma cells (also called plasma B cells or plasmocytes) are cells of the immune system that secrete large amounts of antibodies. They differentiate from B cells upon stimulation by CD4+ lymphocytes. The B cell acts as an antigen presenting cell (APC), consuming an offending pathogen. That pathogen gets taken up by the B cell by receptor mediated endocytosis, and broken down within these endosomes after fusion with lysosomes releasing proteolytic enzymes onto the pathogen. Once the enzymes break down the pathogen, pieces of the pathogen (which are now known as antigenic peptides) are loaded onto MHC II molecules, and presented on its extracellular surface. Once on the extracellular surface, the CD4+ T-helper lymphocyte will bind to the MHC II/Antigen molecule and cause activation of the B cell, which includes differentiation into a plasma cell, and subsequent generation of antibody against the consumed pathogen. # Physiopathology After dividing for around five days, mature B cells differentiate into either plasma B cells or memory B cells. Plasma B cells originate in the bone marrow, then travel to the spleen or lymph nodes to secrete antibodies (approximately 10,000 per second). During the initial stages of an immune response the lifespan of plasma cells is very short, typically only a few days to weeks. However, following the process of affinity maturation, plasma cells can survive for months to years and continue to secrete high levels of antibodies. Memory B cells tend to be longer-lived and can therefore respond quickly upon second exposure to an antigen. The class of antibody that a plasma cell produces depends on signals, called cytokines, from other immune system cells, such as macrophages and T helper cells. This process is called isotype-switching. For example, plasma cells will likely secrete IgG3 antibodies if they matured in the presence of the cytokine interferon-gamma. Since B cell maturation also involves somatic hypermutation, these antibodies have a very high affinity for their antigen. # Microscopic anatomy Plasma cells are large lymphocytes with a considerable nucleus-to-cytoplasm ratio and a characteristic appearance on light microscopy. They have basophilic cytoplasm and an eccentric nucleus with heterochromatin in a characteristic cartwheel arrangement. Their cytoplasm also contains a pale zone that on electron microscopy contains an extensive Golgi apparatus and centrioles. Abundant rough endoplasmic reticulum combined with a well-developed Golgi apparatus makes plasma cells well-suited for secreting immunoglobulins. # Role in disease Cancer of plasma cells is termed multiple myeloma. This condition is frequently identified because malignant plasma cells continue producing an antibody, which can be detected as a paraprotein. Common variable immunodeficiency is thought to be due to a problem in the differentiation from lymphocytes to plasma cells. The result is a low serum antibody level and risk of infections.	https://www.wikidoc.org/index.php/Plasma_B_cell
099771aa4d3b4482fa18b069b16b25dba0e9a41f	wikidoc	Plasmavirus	Plasmavirus The Plasmavirus is a family of bacteriophages, viruses that infects bacteria. Virions have an envelope, a nucleoprotein complex, and a capsid. They are 50-125 nm in diameter with a baggy or loose membrane. # Genome The genome is condensed, non segmented and consists of a single molecule of circular, supercoiled double-stranded DNA, 12000 base pairs in length. The genome has a rather high G-C content of around 32 percent. # Infection A productive infectious cycle begins before a lysogenic cycle establishes the virus in the infected bacteria. After initial infection of the viral genome the virus may become latent within the host. Lysogeny involves integration into the host chromosome. # Literature - ↑ Büchen-Osmond, C. (Ed) (2003). 00.053. Plasmaviridae. In: ICTVdB - The Universal Virus Database, version 3. Büchen-Osmond, C. (Ed), ICTVdB Management, The Earth Institute and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. de:Plasmaviridae	Plasmavirus The Plasmavirus is a family of bacteriophages, viruses that infects bacteria. Virions have an envelope, a nucleoprotein complex, and a capsid. They are 50-125 nm in diameter with a baggy or loose membrane. # Genome The genome is condensed, non segmented and consists of a single molecule of circular, supercoiled double-stranded DNA, 12000 base pairs in length. The genome has a rather high G-C content of around 32 percent. [1] # Infection A productive infectious cycle begins before a lysogenic cycle establishes the virus in the infected bacteria. After initial infection of the viral genome the virus may become latent within the host. Lysogeny involves integration into the host chromosome. # Literature - ↑ Büchen-Osmond, C. (Ed) (2003). 00.053. Plasmaviridae. In: ICTVdB - The Universal Virus Database, version 3. Büchen-Osmond, C. (Ed), ICTVdB Management, The Earth Institute and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA. Template:Virus-stub de:Plasmaviridae	https://www.wikidoc.org/index.php/Plasmaviridae
bd0111baa488aa3da9a9fb143ef3d129358c063e	wikidoc	Plecanatide	Plecanatide # 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 Plecanatide is a guanylate cyclase-C agonist that is FDA approved for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Plecanatide is indicated in adults for the treatment of: - chronic idiopathic constipation (CIC). - irritable bowel syndrome with constipation (IBS-C). - The recommended dosage of Plecanatide for the treatment of CIC and IBS-C is 3 mg taken orally once daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Plecanatide Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Plecanatide Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Plecanatide FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Plecanatide Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Plecanatide Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Plecanatide is contraindicated in: - Patients less than 6 years of age due to the risk of serious dehydration. - Patients with known or suspected mechanical gastrointestinal obstruction. # Warnings - Plecanatide is contraindicated in patients less than 6 years of age. The safety and effectiveness of Plecanatide in patients less than 18 years of age have not been established. In young juvenile mice (human age equivalent of approximately 1 month to less than 2 years), Plecanatide increased fluid-secretion into the intestines as a consequence of stimulation of guanylate cyclase-C (GC-C), resulting in mortality in some mice within the first 24 hours, apparently due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences. - Avoid the use of Plecanatide in patients 6 years to less than 18 years of age. Although there were no deaths in older juvenile mice, given the deaths in younger mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of Plecanatide in patients 6 years to less than 18 years of age. - Diarrhea was the most common adverse reaction in four placebo-controlled clinical trials, two in patients with CIC and two in patients with IBS-C. Severe diarrhea was reported in 0.6% of patients in two trials in patients with CIC and in 0.6% of patients in the two trials in patients with IBS-C. If severe diarrhea occurs, suspend dosing and rehydrate the patient. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Demographic characteristics were comparable between the Plecanatide and placebo groups in all studies. Chronic Idiopathic Constipation (CIC) - The safety data described below reflect data from 1733 adult patients with CIC randomized in two double-blind, placebo-controlled clinical trials (Study 1 and Study 2) to receive placebo or 3 mg of Plecanatide once daily for 12 weeks. Most Common Adverse Reactions - Table 1 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the Plecanatide-treated group and at an incidence that was greater than in the placebo group. Diarrhea - The majority of reported cases of diarrhea occurred within 4 weeks of treatment initiation. Severe diarrhea was reported in 0.6% of Plecanatide-treated patients compared to 0.3% of placebo-treated patients. Severe diarrhea was reported to occur within the first 3 days of treatment. Adverse Reactions Leading to Discontinuation - Discontinuations due to adverse reactions occurred in 4% of Plecanatide-treated patients and 2% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 2% of Plecanatide-treated patients and 0.5% of placebo-treated patients withdrew due to diarrhea. Less Common Adverse Reactions - Adverse reactions reported in less than 2% of Plecanatide-treated patients and at an incidence greater than placebo were: sinusitis, upper respiratory tract infection, abdominal distension, flatulence, abdominal tenderness, and increased liver biochemical tests (2 patients with alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal and 3 patients with aspartate aminotransferase (AST) greater than 5 times the upper limit of normal). Irritable Bowel Syndrome with Constipation (IBS-C) - The safety data described below reflect data from 1449 adult patients with IBS-C randomized in two double-blind, placebo-controlled clinical trials (Study 3 and Study 4) to receive placebo or 3 mg Plecanatide once daily for 12 weeks. Most Common Adverse Reactions - Table 2 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients treated with Plecanatide and at an incidence that was greater than in the placebo group. Diarrhea - The majority of reported cases of diarrhea occurred within 4 weeks of treatment initiation. Severe diarrhea was reported in 1% of Plecanatide-treated patients compared to 0.1% of placebo-treated patients . Severe diarrhea was reported to occur within the first day of treatment. Adverse Reactions Leading to Discontinuation - Discontinuations due to adverse reactions occurred in 2.5% of Plecanatide-treated patients and 0.4% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 1.2% of Plecanatide-treated patients and 0% of placebo-treated patients withdrew due to diarrhea. Less Common Adverse Reactions - Adverse reactions reported in 1% or more but less than 2% of Plecanatide-treated patients and at an incidence greater than placebo were: nausea, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and dizziness. Two patients reported increased liver biochemical tests (alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal). ## Postmarketing Experience (Description) # Drug Interactions There is limited information regarding Plecanatide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Plecanatide and its active metabolite are negligibly absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. The available data on Plecanatide use in pregnant women are not sufficient to inform any drug-associated risks for major birth defects and miscarriage. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of Plecanatide in mice and rabbits during organogenesis at doses much higher than the recommended human dosage. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data (Animal) - Pregnant mice and rabbits were administered Plecanatide during the period of organogenesis. There was no evidence of harm to embryo-fetal development at oral doses up to 800 mg/kg/day in mice and 250 mg/kg/day in rabbits. Oral administration of up to 600 mg/kg/day in mice during organogenesis through lactation produced no developmental abnormalities or effects on growth, learning and memory, or fertility in the offspring through maturation. - The maximum recommended human dose is approximately 0.05 mg/kg/day, based on a 60-kg body weight. Limited systemic exposure to Plecanatide was achieved in animals during organogenesis (area under the plasma concentration-time curve (AUCt) = 449 ng∙h/mL in rabbits given 250 mg/kg/day). Plecanatide and its active metabolite are not measurable in human plasma following administration of the recommended clinical dosage. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Plecanatide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Plecanatide during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of Plecanatide in human milk, or its effects on milk production or the breastfed infant. No lactation studies in animals have been conducted. Plecanatide and its active metabolite are negligibly absorbed systemically following oral administration. - It is unknown whether the negligible systemic absorption of Plecanatide by adults will result in a clinically relevant exposure to breastfed infants. Exposure to Plecanatide in breastfed infants has the potential for serious adverse effects. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Plecanatide and any potential adverse effects on the breastfed infant from Plecanatide or from the underlying maternal condition. ### Pediatric Use - Plecanatide is contraindicated in pediatric patients less than 6 years of age. Avoid use of Plecanatide in patients 6 years to less than 18 years of age. The safety and effectiveness of Plecanatide in patients less than 18 years of age have not been established. - In nonclinical studies, deaths occurred within 24 hours in young juvenile mice (human age equivalent of approximately 1 month to less than 2 years) following oral administration of Plecanatide, as described below in Juvenile Animal Toxicity Data. Because of increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop diarrhea and its potentially serious consequences. Plecanatide is contraindicated in patients less than 6 years of age. Given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of Plecanatide in patients 6 years to less than 18 years of age. Juvenile Animal Toxicity Data - Single oral doses of Plecanatide at 0.5 mg/kg and 10 mg/kg caused mortality in young juvenile mice on postnatal days 7 and 14, respectively (human age equivalent of approximately 1 month to less than 2 years). Treatment-related increases in the weight of intestinal contents were observed in juvenile mice following single doses of Plecanatide on postnatal day 14 (human age equivalent of approximately less than 2 years), consistent with increased fluid in the intestinal lumen. Although the recommended human dose is approximately 0.05 mg/kg/day, based on a 60-kg body weight, Plecanatide and its active metabolite are not measurable in adult human plasma, whereas systemic absorption was demonstrated in the juvenile animal toxicity studies. Animal and human doses should not be compared directly for evaluating relative exposure. ### Geriatic Use Chronic Idiopathic Constipation (CIC) - Of 2601 subjects in placebo-controlled clinical trials of Plecanatide, 273 (10%) were 65 years of age and over, and 47 (2%) were 75 years and over. Clinical studies of Plecanatide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from patients 18 years to less than 65 years of age. Irritable Bowel Syndrome with Constipation (IBS-C) - Of 1621 subjects in the placebo-controlled clinical studies of Plecanatide, 134 (8.3%) were 65 years of age and over, and 25 (1.5%) were 75 years and over. Clinical studies of Plecanatide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from patients 18 years to less than 65 years of age. ### Gender There is no FDA guidance on the use of Plecanatide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Plecanatide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Plecanatide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Plecanatide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Plecanatide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Plecanatide in patients who are immunocompromised. # Administration and Monitoring ### Administration - In a clean container, crush the Plecanatide tablet to a powder and mix with 1 teaspoonful of room temperature applesauce. - Consume the entire tablet-applesauce mixture immediately. Do not store the mixture for later use. - Place the Plecanatide tablet in a clean cup. - Pour approximately 30 mL of room temperature water into the cup. - Mix by gently swirling the tablet and water mixture for at least 10 seconds. The Plecanatide tablet will fall apart in the water. - Swallow the entire contents of the tablet water mixture immediately. - If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 10 seconds, and swallow immediately. - Do not store the tablet-water mixture for later use. - Place the Plecanatide tablet in a clean cup with 30 mL of room temperature water. - Mix by gently swirling the tablet and water mixture for at least 15 seconds. The Plecanatide tablet will fall apart in the water. - Flush the nasogastric or gastric feeding tube with 30 mL of water using a catheter tip syringe. - Draw up the mixture using the syringe and immediately administer via the nasogastric or gastric feeding tube. Do not reserve for future use. - If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 15 seconds, and using the same syringe, administer via the nasogastric or gastric feeding tube. - Using the same or a fresh syringe, flush the nasogastric or gastric feeding tube with at least 10 mL of water. ### Monitoring - Improvement in signs or symptoms of chronic idiopathic constipation is indicative of efficacy. # IV Compatibility There is limited information regarding the compatibility of Plecanatide and IV administrations. # Overdosage There is limited information regarding Plecanatide overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Plecanatide is a structural analog of human uroguanylin, and similarly to uroguanylin, Plecanatide functions as a guanylate cyclase-C (GC-C) agonist. Both Plecanatide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation of extracellular cGMP has been associated with a decrease in the activity of pain-sensing nerves in animal models of visceral pain. Elevation of intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, Plecanatide has been shown to increase fluid secretion into the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool consistency. - In an animal model of visceral pain, Plecanatide reduced abdominal muscle contractions, a measure of intestinal pain. ## Structure ## Pharmacodynamics Food Effect - Subjects who received either a low-fat, low calorie (LF-LC) meal or a high fat, high calorie (HF-HC) meal reported looser stools than fasted subjects up to 24 hours after a single dose of Plecanatide 9 mg (3 times the recommended dose). In clinical studies, Plecanatide was administered with or without food. ## Pharmacokinetics Absorption - Plecanatide was minimally absorbed with negligible systemic availability following oral administration. Concentrations of Plecanatide and its active metabolite in plasma were below the limit of quantitation in the majority of analyzed plasma samples after an oral Plecanatide dose of 3 mg. Therefore, standard pharmacokinetic parameters such as AUC, maximum concentration (Cmax), and half-life (t½) could not be calculated. Food Effect - In a crossover study, 24 healthy subjects were given a single dose of Plecanatide 9 mg (3 times the recommended dose) in 3 different states: fasted; following a low-fat, low-calorie meal (LF-LC; approximately 350 calories: 17% from fat, 66% from carbohydrate, and 17% from protein); and following a high-fat, high-calorie meal (HF-HC; approximately 1000 calories: 60% from fat, 25% from carbohydrate, and 15% from protein). Plecanatide was detected in 1 subject (fasted state) at 0.5 and 1 hour post dose. Plecanatide concentrations were below the limit of quantitation for all other time points and for all other subjects. The active metabolite was not detected in any subject. Distribution - Given that Plecanatide concentrations following clinically relevant oral doses were not measurable, Plecanatide is expected to be minimally distributed in tissues. Oral Plecanatide was localized to the GI tract where it exerted its effects as a GC-C agonist with negligible systemic exposure. Plecanatide exhibited little to no binding to human serum albumin or human α-1-acid glycoprotein. Elimination Metabolism - Plecanatide was metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both Plecanatide and the metabolite were proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids. Excretion - No excretion studies have been conducted in humans. Plecanatide and its active metabolite were not measurable in plasma following administration of the recommended clinical doses. Drug Interaction Studies - Neither Plecanatide nor its active metabolite inhibited the cytochrome P450 (CYP) enzymes 2C9 and 3A4, and they did not induce CYP3A4 in vitro. - Plecanatide and its active metabolite were neither substrates nor inhibitors of the transporters P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro. ## Nonclinical Toxicology Carcinogenesis - The carcinogenic potential of Plecanatide was assessed in 2-year carcinogenicity studies in mice and rats. Plecanatide was not tumorigenic in mice at oral doses up to 90 mg/kg/day or in rats at oral doses up to 100 mg/kg/day. Limited systemic exposure to Plecanatide was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. Mutagenesis - Plecanatide was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro mouse lymphoma mutation assay, or the in vivo mouse bone marrow micronucleus assay. Impairment of Fertility - Plecanatide had no effect on fertility or reproductive function in male or female mice at oral doses of up to 600 mg/kg/day. # Clinical Studies - The efficacy of Plecanatide for the management of symptoms of CIC was established in two 12-week, double-blind, placebo-controlled, randomized, multicenter clinical studies in adult patients (Study 1 and Study 2). In the Intention-to-Treat (ITT) population, a total of 905 patients (Study 1) and 870 patients (Study 2) were randomized 1:1 to either placebo or Plecanatide 3 mg, once daily. In clinical studies, study medication was administered without respect to food intake. Demographics for these studies included an overall mean age of 45 years (range 18 to 80 years), 80% female, 72% white, and 24% black. - To be eligible for the studies, patients were required to meet modified Rome III criteria for at least 3 months prior to the screening visit, with symptom onset for at least 6 months prior to diagnosis. Rome III criteria were modified to require that patients report less than 3 defecations per week, rarely have a loose stool without the use of laxatives, not use manual maneuvers to facilitate defecations, and not meet criteria for IBS-C. In addition, patients were required to report at least two of the following symptoms: - Straining during at least 25% of defecations. - Lumpy or hard stool in at least 25% of defecations. - Sensation of incomplete evacuations for at least 25% of defecations. - Sensation of anorectal obstruction/blockage for at least 25% of defecations. - Patients who met these criteria were also required to demonstrate the following during the last 2 weeks of the screening period: - Less than 3 complete spontaneous bowel movements (CSBMs) (a CSBM is an SBM that is associated with a sense of complete evacuation) in each of the two weeks. - Bristol Stool Form Scale (BSFS) of 6 or 7 in less than 25% of spontaneous bowel movements (SBMs) (an SBM is a bowel movement occurring in the absence of laxative use). - One out of the following three: - BSFS of 1 or 2 in at least 25% of defecations. - A straining value recorded on at least 25% of days when a BM was reported. - At least 25% of BMs result in a sense of incomplete evacuation. - The efficacy of Plecanatide was assessed using a responder analysis and change-from-baseline in CSBM and SBM endpoints. Efficacy was assessed using information provided by patients on a daily basis in an electronic diary. - A responder was defined as a patient who had at least 3 CSBMs in a given week and an increase of at least 1 CSBM from baseline in the same week for at least 9 weeks out of the 12 week treatment period and at least 3 of the last 4 weeks of the study. The responder rates are shown in Table 3. - In both studies, improvements in the frequency of CSBMs/week were seen as early as week 1 with improvement maintained through week 12. The difference between the Plecanatide group and the placebo group in the mean change of CSBMs/week frequency from baseline to week 12 was approximately 1.1 CSBMs/week. - Over the 12 week treatment period, improvements were observed in stool frequency (number of CSBMs/week and SBMs/week) and/or stool consistency (as measured by the BSFS), and/or in the amount of straining with bowel movements (amount of time pushing or physical effort to pass stool) in the Plecanatide group as compared to placebo. - Following completion of the study drug treatment period, patients continued to record data in the daily diary for a 2 week Post-Treatment Period. During this time, Plecanatide-treated patients generally returned to baseline for these study endpoints. - In Studies 1 and 2, a third randomized treatment arm of Plecanatide 6 mg once daily did not demonstrate additional treatment benefit and had a greater incidence of adverse reactions than Plecanatide 3 mg once daily. Therefore, Plecanatide 6 mg once daily is not recommended. - The efficacy of Plecanatide for the management of symptoms of IBS-C was established in two 12-week, double-blind, placebo-controlled, randomized, multicenter clinical studies in adult patients (Study 3 and Study 4). In the Intention-to-Treat (ITT) population, a total of 699 patients (Study 3) and 754 patients (Study 4) received treatment with placebo or Plecanatide 3 mg once daily. In clinical studies, study medication was administered without respect to food intake. Demographics for these studies included an overall mean age of 44 years (range 18 to 83 years), 74% female, 73% white, and 22% black. - To be eligible, patients were required to meet the Rome III criteria for IBS for at least 3 months prior to the screening visit, with symptom onset for at least 6 months prior to diagnosis. Diagnosis required recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 or more of 1) improvement with defecation, 2) onset associated with a change in frequency of stool, and 3) onset associated with a change in form (appearance) of stool. Patients also met the IBS-C differentiation criteria for constipation, characterized by a stool pattern such that at least 25% of defecations are hard or lumpy stools and no more than 25% of defecations are loose or watery stool. - Patients who met these criteria were excluded if they demonstrated the following during the last 2 weeks of the screening period: - Worst abdominal pain intensity (WAPI) score of 0 on an 11-point scale for more than 2 days during each week. - An average WAPI of less than 3 for either week. - More than 3 complete spontaneous bowel movements (CSBMs) or more than six spontaneous bowel movements (SBMs) per week in either week. - Bristol Stool Form Scale (BSFS) of 7 for any SBM recorded. - More than 1 day in either week with a BSFS of 6 for any SBM recorded. - No use of rescue laxative (bisacodyl) within 72 hours before randomization. - The efficacy of Plecanatide was assessed using a responder analysis based on abdominal pain intensity and a stool frequency responder (CSBM) endpoint. Efficacy was assessed using information provided by patients on a daily basis through an electronic phone diary system. - A responder was defined as a patient who met both the abdominal pain intensity and stool frequency responder criteria in the same week for at least 6 of the 12 treatment weeks. The abdominal pain intensity and stool frequency responder criteria assessed each week were defined as: - Abdominal pain intensity responder: a patient who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours score (measured daily) of at least 30% compared with baseline weekly average. - Stool frequency responder: a patient who experienced an increase of at least 1 CSBM per week from baseline. - The responder rates are shown in Table 4. - In both studies, the proportion of responders who were also weekly responders for at least 2 of the 4 treatment weeks in month 3, the last month of treatment was greater in the Plecanatide groups compared to placebo. - Over the 12 week treatment period, improvements were observed in both stool consistency (as measured by the BSFS) and in the amount of straining with bowel movements (amount of time pushing or physical effort to pass stool) in the 3 mg Plecanatide group as compared to placebo. - Following completion of the study drug treatment period, patients continued to record data in the daily diary for a 2-week Post-Treatment Period. During this time, Plecanatide-treated patients generally returned to baseline for these study endpoints. - In Studies 3 and 4, a third randomized treatment arm of Plecanatide 6 mg once daily did not demonstrate additional treatment benefit over the 3 mg dose. Therefore, Plecanatide 6 mg once daily is not recommended. # How Supplied - Plecanatide tablets are packaged in an aluminum foil unit dose blister pack of 30 in a child-resistant pack or in a white, opaque, high-density polyethylene round bottle with a screw-top polypropylene child-resistant cap and heat-activated induction seal. Each bottle container-closure system also contains a desiccant and a polyester coil. - Plecanatide 3 mg tablets are white to off-white, plain and round, debossed with "SP" on one side and "3" for 3 mg on the other side and supplied as: ## Storage - Store at room temperature, 20 to 25°C (68 to 77°F); excursions permitted to 15 to 30°C (59 to 86°F). - Keep Plecanatide in a dry place. Protect from moisture. For bottles, keep Plecanatide in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Diarrhea - To stop Plecanatide and contact their healthcare provider if they experience severe diarrhea. Accidental Ingestion - Accidental ingestion of Plecanatide in children, especially in children less than 6 years of age, may result in severe diarrhea and dehydration. Instruct patients to take steps to store Plecanatide securely and out of reach of children and to dispose of unused Plecanatide. Administration and Handling Instructions - To take Plecanatide once daily with or without food. - If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at the same time. - To swallow Plecanatide tablets whole. - If adult patients have swallowing difficulties, Plecanatide tablets can be crushed and administered orally in either applesauce or with water, or administered with water via a nasogastric or gastric feeding tube, as described in the Medication Guide. - To keep Plecanatide in a dry place. Protect from moisture. For bottles, keep Plecanatide in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage. Remove and discard polyester coil after opening. Keep bottles closed tightly. # Precautions with Alcohol Alcohol-Plecanatide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Trulance # Look-Alike Drug Names There is limited information regarding Plecanatide Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Plecanatide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[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 Plecanatide is a guanylate cyclase-C agonist that is FDA approved for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Plecanatide is indicated in adults for the treatment of: - chronic idiopathic constipation (CIC). - irritable bowel syndrome with constipation (IBS-C). - The recommended dosage of Plecanatide for the treatment of CIC and IBS-C is 3 mg taken orally once daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Plecanatide Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Plecanatide Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Plecanatide FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Plecanatide Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Plecanatide Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Plecanatide is contraindicated in: - Patients less than 6 years of age due to the risk of serious dehydration. - Patients with known or suspected mechanical gastrointestinal obstruction. # Warnings - Plecanatide is contraindicated in patients less than 6 years of age. The safety and effectiveness of Plecanatide in patients less than 18 years of age have not been established. In young juvenile mice (human age equivalent of approximately 1 month to less than 2 years), Plecanatide increased fluid-secretion into the intestines as a consequence of stimulation of guanylate cyclase-C (GC-C), resulting in mortality in some mice within the first 24 hours, apparently due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences. - Avoid the use of Plecanatide in patients 6 years to less than 18 years of age. Although there were no deaths in older juvenile mice, given the deaths in younger mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of Plecanatide in patients 6 years to less than 18 years of age. - Diarrhea was the most common adverse reaction in four placebo-controlled clinical trials, two in patients with CIC and two in patients with IBS-C. Severe diarrhea was reported in 0.6% of patients in two trials in patients with CIC and in 0.6% of patients in the two trials in patients with IBS-C. If severe diarrhea occurs, suspend dosing and rehydrate the patient. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. - Demographic characteristics were comparable between the Plecanatide and placebo groups in all studies. Chronic Idiopathic Constipation (CIC) - The safety data described below reflect data from 1733 adult patients with CIC randomized in two double-blind, placebo-controlled clinical trials (Study 1 and Study 2) to receive placebo or 3 mg of Plecanatide once daily for 12 weeks. Most Common Adverse Reactions - Table 1 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the Plecanatide-treated group and at an incidence that was greater than in the placebo group. Diarrhea - The majority of reported cases of diarrhea occurred within 4 weeks of treatment initiation. Severe diarrhea was reported in 0.6% of Plecanatide-treated patients compared to 0.3% of placebo-treated patients. Severe diarrhea was reported to occur within the first 3 days of treatment. Adverse Reactions Leading to Discontinuation - Discontinuations due to adverse reactions occurred in 4% of Plecanatide-treated patients and 2% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 2% of Plecanatide-treated patients and 0.5% of placebo-treated patients withdrew due to diarrhea. Less Common Adverse Reactions - Adverse reactions reported in less than 2% of Plecanatide-treated patients and at an incidence greater than placebo were: sinusitis, upper respiratory tract infection, abdominal distension, flatulence, abdominal tenderness, and increased liver biochemical tests (2 patients with alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal and 3 patients with aspartate aminotransferase (AST) greater than 5 times the upper limit of normal). Irritable Bowel Syndrome with Constipation (IBS-C) - The safety data described below reflect data from 1449 adult patients with IBS-C randomized in two double-blind, placebo-controlled clinical trials (Study 3 and Study 4) to receive placebo or 3 mg Plecanatide once daily for 12 weeks. Most Common Adverse Reactions - Table 2 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients treated with Plecanatide and at an incidence that was greater than in the placebo group. Diarrhea - The majority of reported cases of diarrhea occurred within 4 weeks of treatment initiation. Severe diarrhea was reported in 1% of Plecanatide-treated patients compared to 0.1% of placebo-treated patients [see WARNINGS AND PRECAUTIONS (5.2)]. Severe diarrhea was reported to occur within the first day of treatment. Adverse Reactions Leading to Discontinuation - Discontinuations due to adverse reactions occurred in 2.5% of Plecanatide-treated patients and 0.4% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 1.2% of Plecanatide-treated patients and 0% of placebo-treated patients withdrew due to diarrhea. Less Common Adverse Reactions - Adverse reactions reported in 1% or more but less than 2% of Plecanatide-treated patients and at an incidence greater than placebo were: nausea, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and dizziness. Two patients reported increased liver biochemical tests (alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal). ## Postmarketing Experience (Description) # Drug Interactions There is limited information regarding Plecanatide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Plecanatide and its active metabolite are negligibly absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug. The available data on Plecanatide use in pregnant women are not sufficient to inform any drug-associated risks for major birth defects and miscarriage. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of Plecanatide in mice and rabbits during organogenesis at doses much higher than the recommended human dosage. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data (Animal) - Pregnant mice and rabbits were administered Plecanatide during the period of organogenesis. There was no evidence of harm to embryo-fetal development at oral doses up to 800 mg/kg/day in mice and 250 mg/kg/day in rabbits. Oral administration of up to 600 mg/kg/day in mice during organogenesis through lactation produced no developmental abnormalities or effects on growth, learning and memory, or fertility in the offspring through maturation. - The maximum recommended human dose is approximately 0.05 mg/kg/day, based on a 60-kg body weight. Limited systemic exposure to Plecanatide was achieved in animals during organogenesis (area under the plasma concentration-time curve (AUCt) = 449 ng∙h/mL in rabbits given 250 mg/kg/day). Plecanatide and its active metabolite are not measurable in human plasma following administration of the recommended clinical dosage. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Plecanatide in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Plecanatide during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of Plecanatide in human milk, or its effects on milk production or the breastfed infant. No lactation studies in animals have been conducted. Plecanatide and its active metabolite are negligibly absorbed systemically following oral administration. - It is unknown whether the negligible systemic absorption of Plecanatide by adults will result in a clinically relevant exposure to breastfed infants. Exposure to Plecanatide in breastfed infants has the potential for serious adverse effects. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Plecanatide and any potential adverse effects on the breastfed infant from Plecanatide or from the underlying maternal condition. ### Pediatric Use - Plecanatide is contraindicated in pediatric patients less than 6 years of age. Avoid use of Plecanatide in patients 6 years to less than 18 years of age. The safety and effectiveness of Plecanatide in patients less than 18 years of age have not been established. - In nonclinical studies, deaths occurred within 24 hours in young juvenile mice (human age equivalent of approximately 1 month to less than 2 years) following oral administration of Plecanatide, as described below in Juvenile Animal Toxicity Data. Because of increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop diarrhea and its potentially serious consequences. Plecanatide is contraindicated in patients less than 6 years of age. Given the deaths in young juvenile mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of Plecanatide in patients 6 years to less than 18 years of age. Juvenile Animal Toxicity Data - Single oral doses of Plecanatide at 0.5 mg/kg and 10 mg/kg caused mortality in young juvenile mice on postnatal days 7 and 14, respectively (human age equivalent of approximately 1 month to less than 2 years). Treatment-related increases in the weight of intestinal contents were observed in juvenile mice following single doses of Plecanatide on postnatal day 14 (human age equivalent of approximately less than 2 years), consistent with increased fluid in the intestinal lumen. Although the recommended human dose is approximately 0.05 mg/kg/day, based on a 60-kg body weight, Plecanatide and its active metabolite are not measurable in adult human plasma, whereas systemic absorption was demonstrated in the juvenile animal toxicity studies. Animal and human doses should not be compared directly for evaluating relative exposure. ### Geriatic Use Chronic Idiopathic Constipation (CIC) - Of 2601 subjects in placebo-controlled clinical trials of Plecanatide, 273 (10%) were 65 years of age and over, and 47 (2%) were 75 years and over. Clinical studies of Plecanatide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from patients 18 years to less than 65 years of age. Irritable Bowel Syndrome with Constipation (IBS-C) - Of 1621 subjects in the placebo-controlled clinical studies of Plecanatide, 134 (8.3%) were 65 years of age and over, and 25 (1.5%) were 75 years and over. Clinical studies of Plecanatide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from patients 18 years to less than 65 years of age. ### Gender There is no FDA guidance on the use of Plecanatide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Plecanatide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Plecanatide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Plecanatide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Plecanatide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Plecanatide in patients who are immunocompromised. # Administration and Monitoring ### Administration - In a clean container, crush the Plecanatide tablet to a powder and mix with 1 teaspoonful of room temperature applesauce. - Consume the entire tablet-applesauce mixture immediately. Do not store the mixture for later use. - Place the Plecanatide tablet in a clean cup. - Pour approximately 30 mL of room temperature water into the cup. - Mix by gently swirling the tablet and water mixture for at least 10 seconds. The Plecanatide tablet will fall apart in the water. - Swallow the entire contents of the tablet water mixture immediately. - If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 10 seconds, and swallow immediately. - Do not store the tablet-water mixture for later use. - Place the Plecanatide tablet in a clean cup with 30 mL of room temperature water. - Mix by gently swirling the tablet and water mixture for at least 15 seconds. The Plecanatide tablet will fall apart in the water. - Flush the nasogastric or gastric feeding tube with 30 mL of water using a catheter tip syringe. - Draw up the mixture using the syringe and immediately administer via the nasogastric or gastric feeding tube. Do not reserve for future use. - If any portion of the tablet is left in the cup, add another 30 mL of water to the cup, swirl for at least 15 seconds, and using the same syringe, administer via the nasogastric or gastric feeding tube. - Using the same or a fresh syringe, flush the nasogastric or gastric feeding tube with at least 10 mL of water. ### Monitoring - Improvement in signs or symptoms of chronic idiopathic constipation is indicative of efficacy. # IV Compatibility There is limited information regarding the compatibility of Plecanatide and IV administrations. # Overdosage There is limited information regarding Plecanatide overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Plecanatide is a structural analog of human uroguanylin, and similarly to uroguanylin, Plecanatide functions as a guanylate cyclase-C (GC-C) agonist. Both Plecanatide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation of extracellular cGMP has been associated with a decrease in the activity of pain-sensing nerves in animal models of visceral pain. Elevation of intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, Plecanatide has been shown to increase fluid secretion into the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool consistency. - In an animal model of visceral pain, Plecanatide reduced abdominal muscle contractions, a measure of intestinal pain. ## Structure ## Pharmacodynamics Food Effect - Subjects who received either a low-fat, low calorie (LF-LC) meal or a high fat, high calorie (HF-HC) meal reported looser stools than fasted subjects up to 24 hours after a single dose of Plecanatide 9 mg (3 times the recommended dose). In clinical studies, Plecanatide was administered with or without food. ## Pharmacokinetics Absorption - Plecanatide was minimally absorbed with negligible systemic availability following oral administration. Concentrations of Plecanatide and its active metabolite in plasma were below the limit of quantitation in the majority of analyzed plasma samples after an oral Plecanatide dose of 3 mg. Therefore, standard pharmacokinetic parameters such as AUC, maximum concentration (Cmax), and half-life (t½) could not be calculated. Food Effect - In a crossover study, 24 healthy subjects were given a single dose of Plecanatide 9 mg (3 times the recommended dose) in 3 different states: fasted; following a low-fat, low-calorie meal (LF-LC; approximately 350 calories: 17% from fat, 66% from carbohydrate, and 17% from protein); and following a high-fat, high-calorie meal (HF-HC; approximately 1000 calories: 60% from fat, 25% from carbohydrate, and 15% from protein). Plecanatide was detected in 1 subject (fasted state) at 0.5 and 1 hour post dose. Plecanatide concentrations were below the limit of quantitation for all other time points and for all other subjects. The active metabolite was not detected in any subject. Distribution - Given that Plecanatide concentrations following clinically relevant oral doses were not measurable, Plecanatide is expected to be minimally distributed in tissues. Oral Plecanatide was localized to the GI tract where it exerted its effects as a GC-C agonist with negligible systemic exposure. Plecanatide exhibited little to no binding to human serum albumin or human α-1-acid glycoprotein. Elimination Metabolism - Plecanatide was metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both Plecanatide and the metabolite were proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids. Excretion - No excretion studies have been conducted in humans. Plecanatide and its active metabolite were not measurable in plasma following administration of the recommended clinical doses. Drug Interaction Studies - Neither Plecanatide nor its active metabolite inhibited the cytochrome P450 (CYP) enzymes 2C9 and 3A4, and they did not induce CYP3A4 in vitro. - Plecanatide and its active metabolite were neither substrates nor inhibitors of the transporters P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro. ## Nonclinical Toxicology Carcinogenesis - The carcinogenic potential of Plecanatide was assessed in 2-year carcinogenicity studies in mice and rats. Plecanatide was not tumorigenic in mice at oral doses up to 90 mg/kg/day or in rats at oral doses up to 100 mg/kg/day. Limited systemic exposure to Plecanatide was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. Mutagenesis - Plecanatide was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, in vitro mouse lymphoma mutation assay, or the in vivo mouse bone marrow micronucleus assay. Impairment of Fertility - Plecanatide had no effect on fertility or reproductive function in male or female mice at oral doses of up to 600 mg/kg/day. # Clinical Studies - The efficacy of Plecanatide for the management of symptoms of CIC was established in two 12-week, double-blind, placebo-controlled, randomized, multicenter clinical studies in adult patients (Study 1 and Study 2). In the Intention-to-Treat (ITT) population, a total of 905 patients (Study 1) and 870 patients (Study 2) were randomized 1:1 to either placebo or Plecanatide 3 mg, once daily. In clinical studies, study medication was administered without respect to food intake. Demographics for these studies included an overall mean age of 45 years (range 18 to 80 years), 80% female, 72% white, and 24% black. - To be eligible for the studies, patients were required to meet modified Rome III criteria for at least 3 months prior to the screening visit, with symptom onset for at least 6 months prior to diagnosis. Rome III criteria were modified to require that patients report less than 3 defecations per week, rarely have a loose stool without the use of laxatives, not use manual maneuvers to facilitate defecations, and not meet criteria for IBS-C. In addition, patients were required to report at least two of the following symptoms: - Straining during at least 25% of defecations. - Lumpy or hard stool in at least 25% of defecations. - Sensation of incomplete evacuations for at least 25% of defecations. - Sensation of anorectal obstruction/blockage for at least 25% of defecations. - Patients who met these criteria were also required to demonstrate the following during the last 2 weeks of the screening period: - Less than 3 complete spontaneous bowel movements (CSBMs) (a CSBM is an SBM that is associated with a sense of complete evacuation) in each of the two weeks. - Bristol Stool Form Scale (BSFS) of 6 or 7 in less than 25% of spontaneous bowel movements (SBMs) (an SBM is a bowel movement occurring in the absence of laxative use). - One out of the following three: - BSFS of 1 or 2 in at least 25% of defecations. - A straining value recorded on at least 25% of days when a BM was reported. - At least 25% of BMs result in a sense of incomplete evacuation. - The efficacy of Plecanatide was assessed using a responder analysis and change-from-baseline in CSBM and SBM endpoints. Efficacy was assessed using information provided by patients on a daily basis in an electronic diary. - A responder was defined as a patient who had at least 3 CSBMs in a given week and an increase of at least 1 CSBM from baseline in the same week for at least 9 weeks out of the 12 week treatment period and at least 3 of the last 4 weeks of the study. The responder rates are shown in Table 3. - In both studies, improvements in the frequency of CSBMs/week were seen as early as week 1 with improvement maintained through week 12. The difference between the Plecanatide group and the placebo group in the mean change of CSBMs/week frequency from baseline to week 12 was approximately 1.1 CSBMs/week. - Over the 12 week treatment period, improvements were observed in stool frequency (number of CSBMs/week and SBMs/week) and/or stool consistency (as measured by the BSFS), and/or in the amount of straining with bowel movements (amount of time pushing or physical effort to pass stool) in the Plecanatide group as compared to placebo. - Following completion of the study drug treatment period, patients continued to record data in the daily diary for a 2 week Post-Treatment Period. During this time, Plecanatide-treated patients generally returned to baseline for these study endpoints. - In Studies 1 and 2, a third randomized treatment arm of Plecanatide 6 mg once daily did not demonstrate additional treatment benefit and had a greater incidence of adverse reactions than Plecanatide 3 mg once daily. Therefore, Plecanatide 6 mg once daily is not recommended. - The efficacy of Plecanatide for the management of symptoms of IBS-C was established in two 12-week, double-blind, placebo-controlled, randomized, multicenter clinical studies in adult patients (Study 3 and Study 4). In the Intention-to-Treat (ITT) population, a total of 699 patients (Study 3) and 754 patients (Study 4) received treatment with placebo or Plecanatide 3 mg once daily. In clinical studies, study medication was administered without respect to food intake. Demographics for these studies included an overall mean age of 44 years (range 18 to 83 years), 74% female, 73% white, and 22% black. - To be eligible, patients were required to meet the Rome III criteria for IBS for at least 3 months prior to the screening visit, with symptom onset for at least 6 months prior to diagnosis. Diagnosis required recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 or more of 1) improvement with defecation, 2) onset associated with a change in frequency of stool, and 3) onset associated with a change in form (appearance) of stool. Patients also met the IBS-C differentiation criteria for constipation, characterized by a stool pattern such that at least 25% of defecations are hard or lumpy stools and no more than 25% of defecations are loose or watery stool. - Patients who met these criteria were excluded if they demonstrated the following during the last 2 weeks of the screening period: - Worst abdominal pain intensity (WAPI) score of 0 on an 11-point scale for more than 2 days during each week. - An average WAPI of less than 3 for either week. - More than 3 complete spontaneous bowel movements (CSBMs) or more than six spontaneous bowel movements (SBMs) per week in either week. - Bristol Stool Form Scale (BSFS) of 7 for any SBM recorded. - More than 1 day in either week with a BSFS of 6 for any SBM recorded. - No use of rescue laxative (bisacodyl) within 72 hours before randomization. - The efficacy of Plecanatide was assessed using a responder analysis based on abdominal pain intensity and a stool frequency responder (CSBM) endpoint. Efficacy was assessed using information provided by patients on a daily basis through an electronic phone diary system. - A responder was defined as a patient who met both the abdominal pain intensity and stool frequency responder criteria in the same week for at least 6 of the 12 treatment weeks. The abdominal pain intensity and stool frequency responder criteria assessed each week were defined as: - Abdominal pain intensity responder: a patient who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours score (measured daily) of at least 30% compared with baseline weekly average. - Stool frequency responder: a patient who experienced an increase of at least 1 CSBM per week from baseline. - The responder rates are shown in Table 4. - In both studies, the proportion of responders who were also weekly responders for at least 2 of the 4 treatment weeks in month 3, the last month of treatment was greater in the Plecanatide groups compared to placebo. - Over the 12 week treatment period, improvements were observed in both stool consistency (as measured by the BSFS) and in the amount of straining with bowel movements (amount of time pushing or physical effort to pass stool) in the 3 mg Plecanatide group as compared to placebo. - Following completion of the study drug treatment period, patients continued to record data in the daily diary for a 2-week Post-Treatment Period. During this time, Plecanatide-treated patients generally returned to baseline for these study endpoints. - In Studies 3 and 4, a third randomized treatment arm of Plecanatide 6 mg once daily did not demonstrate additional treatment benefit over the 3 mg dose. Therefore, Plecanatide 6 mg once daily is not recommended. # How Supplied - Plecanatide tablets are packaged in an aluminum foil unit dose blister pack of 30 in a child-resistant pack or in a white, opaque, high-density polyethylene round bottle with a screw-top polypropylene child-resistant cap and heat-activated induction seal. Each bottle container-closure system also contains a desiccant and a polyester coil. - Plecanatide 3 mg tablets are white to off-white, plain and round, debossed with "SP" on one side and "3" for 3 mg on the other side and supplied as: ## Storage - Store at room temperature, 20 to 25°C (68 to 77°F); excursions permitted to 15 to 30°C (59 to 86°F). - Keep Plecanatide in a dry place. Protect from moisture. For bottles, keep Plecanatide in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Diarrhea - To stop Plecanatide and contact their healthcare provider if they experience severe diarrhea. Accidental Ingestion - Accidental ingestion of Plecanatide in children, especially in children less than 6 years of age, may result in severe diarrhea and dehydration. Instruct patients to take steps to store Plecanatide securely and out of reach of children and to dispose of unused Plecanatide. Administration and Handling Instructions - To take Plecanatide once daily with or without food. - If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take two doses at the same time. - To swallow Plecanatide tablets whole. - If adult patients have swallowing difficulties, Plecanatide tablets can be crushed and administered orally in either applesauce or with water, or administered with water via a nasogastric or gastric feeding tube, as described in the Medication Guide. - To keep Plecanatide in a dry place. Protect from moisture. For bottles, keep Plecanatide in the original bottle. Do not remove desiccant from the bottle. Do not subdivide or repackage. Remove and discard polyester coil after opening. Keep bottles closed tightly. # Precautions with Alcohol Alcohol-Plecanatide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Trulance # Look-Alike Drug Names There is limited information regarding Plecanatide Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Plecanatide
563801c874c027563449c7fc294bc67786d9c9ac	wikidoc	Pleurodesis	Pleurodesis Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview Pleurodesis is the artificial obliteration of the pleural space. It is done to prevent recurrence of pneumothorax or pleural effusion. It can be done chemically or surgically. Chemicals such as bleomycin, tetracycline, povidone iodine, or a slurry of talc can be introduced into the pleural space through a chest drain. The instilled chemicals cause irritation between the parietal and the visceral layers of the pleura which closes off the space between them and prevents further fluid from accumulating. Chemical pleurodesis is a painful procedure, so patients are often premedicated with a sedative and analgesics.. A local anesthetic may be instilled into the pleural space, or an epidural catheter may be placed for anesthesia. Surgical pleurodesis is performed via thoracotomy or thoracoscopy. This involves mechanically irritating the parietal pleura, often with a rough pad. Moreover surgical removal of parietal pleura is an effective way of achieving stable pleurodesis	Pleurodesis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview Pleurodesis is the artificial obliteration of the pleural space. It is done to prevent recurrence of pneumothorax or pleural effusion. It can be done chemically or surgically. Chemicals such as bleomycin, tetracycline, povidone iodine, or a slurry of talc can be introduced into the pleural space through a chest drain. The instilled chemicals cause irritation between the parietal and the visceral layers of the pleura which closes off the space between them and prevents further fluid from accumulating. Chemical pleurodesis is a painful procedure, so patients are often premedicated with a sedative and analgesics.. A local anesthetic may be instilled into the pleural space, or an epidural catheter may be placed for anesthesia. Surgical pleurodesis is performed via thoracotomy or thoracoscopy. This involves mechanically irritating the parietal pleura, often with a rough pad. Moreover surgical removal of parietal pleura is an effective way of achieving stable pleurodesis Template:Respiratory system surgeries and other procedures Template:SIB Template:WH Template:WS	https://www.wikidoc.org/index.php/Pleurodesis
848b4805b982bbe5bc8d74f44db2f2520165cb1e	wikidoc	Pneumonitis	Pneumonitis # Overview Pneumonitis or pulmonitis is a general term that refers to inflammation of lung tissue. Many factors can cause pneumonitis, including breathing in animal dander, aspiration (inhaling small food particles or vomit "down the wrong pipe"), and receiving radiation therapy to the chest. Pneumonitis was listed as the one of the top 15 leading causes of death (at number 15) in the United States as of 2010, overtaking homicide, which dropped off the list. This was due to a number of factors, including an increase in the population of people over 75, for whom pneumonitis is a common cause of death. Pneumonia is pneumonitis combined with consolidation and exudation due to infection. # Classification It can be classified into acute interstitial pneumonitis, blood pneumonitis, lymphocytic interstitial pneumonitis, radiation pneumonitis, and uremic pneumonitis. # Causes - Viral infection. As one example, measles can cause severe pneumonitis, and ribavirin has been proposed as a possible treatment. - Pneumonia - Radiation therapy - Inhaling chemicals, such as Sodium hydroxide - Sepsis - Adverse reaction to medications - Ado-trastuzumab emtansine - Azacitidine - Ceritinib - Crizotinib - Cyclophosphamide - Dactinomycin - Hydrochlorothiazide - Idelalisib - Ixabepilone - Pembrolizumab - Sorafenib - Sulfasalazine - Sirolimus - Vandetanib - Hypersensitivity to inhaled agents - Inhalation of spores of some species of mushroom (Bronchoalveolar allergic syndrome) - Mercury exposure - Smoking - Overexposure to Chlorine - Drugs such as Afatinib, Crizotinib, Everolimus, Minocycline hydrochloride, Olaparib , Trametinib	Pneumonitis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Pneumonitis or pulmonitis is a general term that refers to inflammation of lung tissue.[1][2] Many factors can cause pneumonitis, including breathing in animal dander, aspiration (inhaling small food particles or vomit "down the wrong pipe"), and receiving radiation therapy to the chest.[3] Pneumonitis was listed as the one of the top 15 leading causes of death (at number 15) in the United States as of 2010, overtaking homicide, which dropped off the list. This was due to a number of factors, including an increase in the population of people over 75, for whom pneumonitis is a common cause of death.[4] Pneumonia is pneumonitis combined with consolidation and exudation due to infection.[5] # Classification It can be classified into acute interstitial pneumonitis, blood pneumonitis, lymphocytic interstitial pneumonitis, radiation pneumonitis, and uremic pneumonitis.[2] # Causes - Viral infection. As one example, measles can cause severe pneumonitis, and ribavirin has been proposed as a possible treatment. - Pneumonia - Radiation therapy - Inhaling chemicals, such as Sodium hydroxide [6] - Sepsis - Adverse reaction to medications - Ado-trastuzumab emtansine - Azacitidine - Ceritinib - Crizotinib - Cyclophosphamide - Dactinomycin - Hydrochlorothiazide - Idelalisib - Ixabepilone - Pembrolizumab - Sorafenib - Sulfasalazine - Sirolimus - Vandetanib - Hypersensitivity to inhaled agents[7] - Inhalation of spores of some species of mushroom (Bronchoalveolar allergic syndrome)[8] - Mercury exposure - Smoking - Overexposure to Chlorine - Drugs such as Afatinib, Crizotinib, Everolimus, Minocycline hydrochloride, Olaparib , Trametinib	https://www.wikidoc.org/index.php/Pleuropneumonitis
9fcc04d70f01e8f1cdc5f7216b120d0aa5566dc6	wikidoc	Pluto Water	Pluto Water Pluto Water was a trademark for a strongly laxative natural water product which was very popular in the United States in the early 20th century. The water's high native content of mineral salts generally made it effective within one hour of ingestion, a fact the company played up in their promotional literature. Pluto Water was bottled in French Lick, Indiana. It was advertised "America's Laxative" with the slogan "When Nature Won't, PLUTO Will". The bottle and many advertisements featured an image of the devil. Louis Armstrong reported favoring Pluto Water until he switched to Swiss Kriss.	Pluto Water Pluto Water was a trademark for a strongly laxative natural water product which was very popular in the United States in the early 20th century. The water's high native content of mineral salts generally made it effective within one hour of ingestion, a fact the company played up in their promotional literature. Pluto Water was bottled in French Lick, Indiana. It was advertised "America's Laxative" with the slogan "When Nature Won't, PLUTO Will". The bottle and many advertisements featured an image of the devil. Louis Armstrong reported favoring Pluto Water until he switched to Swiss Kriss. # External links - old Pluto Water ads reproduced on gono.com museum Template:Pharma-stub Redd Foxx mentioned Pluto Water in his show Sanford and Son	https://www.wikidoc.org/index.php/Pluto_Water
104224c6d61e103ba9f34a202ae06d1a1543b958	wikidoc	Pneumolysin	Pneumolysin # Overview Pneumolysin is a putative virulence factor of the gram-positive bacteria Streptococcus pneumoniae. It is a pore-forming toxin of 53 kDa composed of 471 amino acids. It has a range of biological activities including the ability to lyse and interfere with the function of cells and soluble molecules of the immune system. Released pneumolysin will aid the bacteria during colonization, by facilitating adherence to the host, during invasion by damaging host cells, and during infection by interfering with the host immune response. The presence of pneumolysin in sputum, urine, CSF and blood can be indicative of an S. pneumoniae infection.	Pneumolysin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Pneumolysin is a putative virulence factor of the gram-positive bacteria Streptococcus pneumoniae.[1] It is a pore-forming toxin of 53 kDa composed of 471 amino acids.[2] It has a range of biological activities including the ability to lyse[3] and interfere with the function of cells and soluble molecules of the immune system.[4] Released pneumolysin will aid the bacteria during colonization, by facilitating adherence to the host,[5] during invasion by damaging host cells,[6] and during infection by interfering with the host immune response.[7] The presence of pneumolysin in sputum,[8] urine,[9] CSF[10] and blood[11] can be indicative of an S. pneumoniae infection.	https://www.wikidoc.org/index.php/Pneumolysin
5d88697c2afdfefda769c59296e64e0de40eec89	wikidoc	Pocket mask	Pocket mask A pocket mask, or pocket face mask or CPR mask, is a device used to safely deliver rescue breaths during a cardiac arrest or respiratory arrest. # Design The pocket mask is a small device that can be carried on one's person. Air is administered to the patient when the emergency responder exhales through a one-way filter valve. Modern pocket masks have either a built in one-way valve or an attachable, disposable filter to protect the emergency responder from the patient's potentially infectious bodily substances, such as vomit or blood. Many masks also have a built-in oxygen intake tube, allowing for administration of 50-60% oxygen. Without being hooked up to an external line, exhaled air from the provider can still provide sufficient oxygen to live, up to 16%. Earth's atmosphere consists of approximately 21% oxygen. # Usage While a pocket mask is not as efficient as a bag valve mask, it does have advantages, besides portability, when only one rescuer is available. Because the bag valve mask requires two hands to operate, one to form a seal and the other to squeeze the bag, the pocket mask allows for both of the rescuer's hands to be on the patients head. This allows the responder to perform a jaw thrust on patient's suspected of a spinal injury.	Pocket mask A pocket mask, or pocket face mask or CPR mask, is a device used to safely deliver rescue breaths during a cardiac arrest or respiratory arrest. # Design The pocket mask is a small device that can be carried on one's person. Air is administered to the patient when the emergency responder exhales through a one-way filter valve. Modern pocket masks have either a built in one-way valve or an attachable, disposable filter to protect the emergency responder from the patient's potentially infectious bodily substances, such as vomit or blood.[1] Many masks also have a built-in oxygen intake tube, allowing for administration of 50-60% oxygen. Without being hooked up to an external line, exhaled air from the provider can still provide sufficient oxygen to live, up to 16%. Earth's atmosphere consists of approximately 21% oxygen. # Usage While a pocket mask is not as efficient as a bag valve mask, it does have advantages, besides portability, when only one rescuer is available. Because the bag valve mask requires two hands to operate, one to form a seal and the other to squeeze the bag, the pocket mask allows for both of the rescuer's hands to be on the patients head. This allows the responder to perform a jaw thrust on patient's suspected of a spinal injury.	https://www.wikidoc.org/index.php/Pocket_mask
e141c26ea467fdaf119f54d9bab88d60b6175590	wikidoc	Podophyllin	Podophyllin Podophyllin is a resinous powder obtained by precipitating an alcoholic tincture of the rhizome of American Mayapple (Podophyllum peltatum) by means of water acidified with hydrochloric acid. It varies in color from grayish to bright yellow or greenish-brown, the first-named being the purest. The powder is soluble in alcohol and strong solutions of alkalis, such as ammonia. Its composition is somewhat complex. There are certainly at least two resins in the powder (which is known officially as Podophylli resina), one of them being soluble and the other insoluble in ether. Each of these contains an active substance, which can be obtained in crystalline form, and is known as podophyllotoxin. It is soluble in alcohol, ether, chloroform and boiling water. # Reactivity Alkalis decompose it into picro-podophyllic acid and picro-podophyllin, minute traces of both of which occur in a free state in the rhizome. The acid is inert, but picro-podophyllin is the active principle. It is a crystalline body, soluble only in concentrated alcohol. Hence the inutility of the pharmacopeial tinctura podophylli, which cannot be diluted before administration. The properties of podophyllin resin vary with the reaction of the tissue with which it is in contact; where this is acid the drug is inert, the picro-podophyllin being precipitated. The resin does not affect the unbroken skin, but may be absorbed from a raw surface, and will then cause purging. When taken internally it is both a secretory and an excretory cholagogue, but so irritant and powerful that its use in cases of jaundice is generally undesirable. Its value, however, in certain cases of constipation of hepatic origin is undeniable. It is largely used in patent medicines, usually as an auxiliary to aloes. The best method of prescribing podophyllin is in pill form. # Toxicity In toxic doses podophyllin causes intense enteritis, with all its characteristic symptoms, and severe depression, which may end in death. The treatment is symptomatic, there being no specific antidote. # Medical Applications Podophyllin is also used to remove genital warts. This requires several applications of podophyllin toxin to the warts over a period of time. Podophyllin resin and podofilox lotion or gel remove genital warts by stopping cell growth. A health professional applies podophyllin resin to the warts. Petroleum jelly, such as Vaseline, to protect normal tissue near the warts from irritation. Resin is washed off within 4 hours to reduce side effects. Your health professional usually applies the resin once a week for at least 6 weeks or until warts disappear. You can apply podofilox in lotion or gel at home. The usual schedule is twice a day for 3 days, followed by 4 days without any lotion. You repeat this schedule for 4 weeks. Podofilox lotion or gel has been found to be effective in clearing warts. It has mild side effects and is well-suited for treatment at home. Neither podophyllin resin nor podofilox lotion or gel is used during pregnancy because these medications can be harmful to the fetus. The most common side effects near the application site are skin reactions, including: - Burning - Redness - Pain - Itching - Swelling Complications from podophyllin resin application are rare. Complications are more likely when podophyllin resin is: - Applied to large areas. - Applied to areas that are already swollen and irritated. - Left on longer than 12 hours so that more of the medication is absorbed into the body (systemic toxicity). *Podofilox lotion or gel has milder side effects at the application area than podophyllum resin. Podophyllin resin must be applied by a health professional so that the amount used can be carefully monitored to avoid more serious side effects. Because podofilox lotion or gel can be applied at home, you need fewer visits to a health professional. This reduces the cost of treatment. Neither podophyllin resin nor podofilox lotion or gel is used during pregnancy because these medications can be harmful to the fetus. Genital warts often go away on their own. Also, treating genital warts does not cure infection with human papillomavirus (HPV), the virus that causes genital warts. The virus remains in the body in an inactive state after warts are removed. A person treated for genital warts may still be able to spread the infection. Condoms may help reduce the risk of HPV infection, but it is not known how much protection they provide. The benefits and effectiveness of each type of treatment need to be compared with the side effects and cost. Discuss this with your health professional.	Podophyllin Podophyllin is a resinous powder obtained by precipitating an alcoholic tincture of the rhizome of American Mayapple (Podophyllum peltatum) by means of water acidified with hydrochloric acid. It varies in color from grayish to bright yellow or greenish-brown, the first-named being the purest. The powder is soluble in alcohol and strong solutions of alkalis, such as ammonia. Its composition is somewhat complex. There are certainly at least two resins in the powder (which is known officially as Podophylli resina), one of them being soluble and the other insoluble in ether. Each of these contains an active substance, which can be obtained in crystalline form, and is known as podophyllotoxin. It is soluble in alcohol, ether, chloroform and boiling water. # Reactivity Alkalis decompose it into picro-podophyllic acid and picro-podophyllin, minute traces of both of which occur in a free state in the rhizome. The acid is inert, but picro-podophyllin is the active principle. It is a crystalline body, soluble only in concentrated alcohol. Hence the inutility of the pharmacopeial tinctura podophylli, which cannot be diluted before administration. The properties of podophyllin resin vary with the reaction of the tissue with which it is in contact; where this is acid the drug is inert, the picro-podophyllin being precipitated. The resin does not affect the unbroken skin, but may be absorbed from a raw surface, and will then cause purging. When taken internally it is both a secretory and an excretory cholagogue, but so irritant and powerful that its use in cases of jaundice is generally undesirable. Its value, however, in certain cases of constipation of hepatic origin is undeniable. It is largely used in patent medicines, usually as an auxiliary to aloes. The best method of prescribing podophyllin is in pill form. # Toxicity In toxic doses podophyllin causes intense enteritis, with all its characteristic symptoms, and severe depression, which may end in death. The treatment is symptomatic, there being no specific antidote. # Medical Applications Podophyllin is also used to remove genital warts. This requires several applications of podophyllin toxin to the warts over a period of time. Podophyllin resin and podofilox lotion or gel remove genital warts by stopping cell growth. A health professional applies podophyllin resin to the warts. Petroleum jelly, such as Vaseline, to protect normal tissue near the warts from irritation. Resin is washed off within 4 hours to reduce side effects. Your health professional usually applies the resin once a week for at least 6 weeks or until warts disappear. You can apply podofilox in lotion or gel at home. The usual schedule is twice a day for 3 days, followed by 4 days without any lotion. You repeat this schedule for 4 weeks. Podofilox lotion or gel has been found to be effective in clearing warts. It has mild side effects and is well-suited for treatment at home. Neither podophyllin resin nor podofilox lotion or gel is used during pregnancy because these medications can be harmful to the fetus. The most common side effects near the application site are skin reactions, including: - Burning - Redness - Pain - Itching - Swelling Complications from podophyllin resin application are rare. Complications are more likely when podophyllin resin is: - Applied to large areas. - Applied to areas that are already swollen and irritated. - Left on longer than 12 hours so that more of the medication is absorbed into the body (systemic toxicity). *Podofilox lotion or gel has milder side effects at the application area than podophyllum resin. Podophyllin resin must be applied by a health professional so that the amount used can be carefully monitored to avoid more serious side effects. Because podofilox lotion or gel can be applied at home, you need fewer visits to a health professional. This reduces the cost of treatment. Neither podophyllin resin nor podofilox lotion or gel is used during pregnancy because these medications can be harmful to the fetus. Genital warts often go away on their own. Also, treating genital warts does not cure infection with human papillomavirus (HPV), the virus that causes genital warts. The virus remains in the body in an inactive state after warts are removed. A person treated for genital warts may still be able to spread the infection. Condoms may help reduce the risk of HPV infection, but it is not known how much protection they provide. The benefits and effectiveness of each type of treatment need to be compared with the side effects and cost. Discuss this with your health professional.	https://www.wikidoc.org/index.php/Podophyllin
62c5f908a28bbb78f0cce5de24bf5271ffadc1ee	wikidoc	Policosanol	Policosanol # Overview PolicosanolTemplate:Pronunciation-needed (or polycosanol) is the generic term for a natural mixture of long chain alcohols extracted from plant waxes. It is used as a nutritional supplement intended to lower LDL cholesterol ("bad" cholesterol) and increase HDL cholesterol ("good" or "healthy" cholesterol) and to help prevent atherosclerosis, though some studies have raised questions about the effectiveness of policosanol. # Physical properties Policosanol is a mixture of a few fatty alcohols derived from the waxes of such plants as sugar cane and yams, as well as beeswax. The most prevalent alcohol in policosanol is octacosanol, followed by triacontanol. There is a much lower concentration of several other fatty alcohols: behenyl alcohol, lignoceryl alcohol, ceryl alcohol, 1-heptacosanol, 1-nonacosanol, 1-dotriacontanol, and geddyl alcohol. Modulation of HMG-CoA reductase and bile acid absorption inhibition have been proposed as mechanisms. # Studies Published studies have come to conflicting conclusions regarding the efficacy of policosanol in lowering LDL (i.e., "bad cholesterol") or raising HDL (i.e., "good cholesterol")., despite a number of studies funded by the Cuban government, which produces and markets the drug. Older independent clinical trials found no evidence of the efficacy of policosanol, while more recent studies have found effect.	Policosanol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview PolicosanolTemplate:Pronunciation-needed (or polycosanol) is the generic term for a natural mixture of long chain alcohols extracted from plant waxes. It is used as a nutritional supplement intended to lower LDL cholesterol ("bad" cholesterol) and increase HDL cholesterol ("good" or "healthy" cholesterol) and to help prevent atherosclerosis, though some studies have raised questions about the effectiveness of policosanol. # Physical properties Policosanol is a mixture of a few fatty alcohols derived from the waxes of such plants as sugar cane[1] and yams, as well as beeswax. The most prevalent alcohol in policosanol is octacosanol,[2] followed by triacontanol. There is a much lower concentration of several other fatty alcohols: behenyl alcohol, lignoceryl alcohol, ceryl alcohol, 1-heptacosanol, 1-nonacosanol, 1-dotriacontanol, and geddyl alcohol. Modulation of HMG-CoA reductase[3] and bile acid absorption inhibition[4] have been proposed as mechanisms. # Studies Published studies have come to conflicting conclusions regarding the efficacy of policosanol in lowering LDL (i.e., "bad cholesterol") or raising HDL (i.e., "good cholesterol").,[5][6][7] despite a number of studies funded by the Cuban government, which produces and markets the drug.[8] Older independent clinical trials found no evidence of the efficacy of policosanol,[5] while more recent studies have found effect. # External Links - Policosanol at PDRHealth.com - U.S. Patent 6,225,354	https://www.wikidoc.org/index.php/Policosanol
9ff824b7f55d6f9baea6364b3f0a4e75748307fc	wikidoc	Polidocanol	Polidocanol # 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 Polidocanol is a sclerosing agent that is FDA approved for the treatment of uncomplicated spider veins (varicose veins ≤1 mm in diameter) and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower extremity. Common adverse reactions include mild local reactions at the site of injection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Asclera® (polidocanol) is indicated to sclerose uncomplicated spider veins (varicose veins ≤1 mm in diameter) and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower extremity. Asclera has not been studied in varicose veins more than 3 mm in diameter. ### Dosage - For intravenous use only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter is seen or if the contents of the vial are discolored or if the vial is damaged in any way. - For spider veins (varicose veins ≤1 mm in diameter), use Asclera 0.5%. For reticular veins (varicose veins 1 to 3 mm in diameter), use Asclera 1%. Use 0.1 to 0.3 mL per injection and no more than 10 mL per session. - Use a syringe (glass or plastic) with a fine needle (typically, 26- or 30-gauge). Insert the needle tangentially into the vein and inject the solution slowly while the needle is still in the vein. Apply only gentle pressure during injection to prevent vein rupture. After the needle has been removed and the injection site has been covered, apply compression in the form of a stocking or bandage. After the treatment session, encourage the patient to walk for 15 to 20 minutes. Keep the patient under observation to detect any anaphylactic or allergic reaction. - Maintain compression for 2 to 3 days after treatment of spider veins and for 5 to 7 days for reticular veins. For extensive varicosities, longer compression treatment with compression bandages or a gradient compression stocking of a higher compression class is recommended. Post-treatment compression is necessary to reduce the risk of deep vein thrombosis. - Repeat treatments may be necessary if the extent of the varicose veins requires more than 10 mL. These treatments should be separated by 1 to 2 weeks. - Small intravaricose blood clots (thrombi) that develop may be removed by stab incision and thrombus expression (microthrombectomy). ### DOSAGE FORMS AND STRENGTHS - Asclera is available as a 0.5% and 1% solution in 2 mL glass ampules. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Polidocanol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Polidocanol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Polidocanol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Polidocanol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Polidocanol in pediatric patients. # Contraindications - Asclera is contraindicated for patients with known allergy (anaphylaxis) to polidocanol and patients with acute thromboembolic diseases. # Warnings - Severe allergic reactions have been reported following polidocanol use, including anaphylactic reactions, some of them fatal. Severe reactions are more frequent with use of larger volumes (> 3 mL). The dose of polidocanol should therefore be minimized. Be prepared to treat anaphylaxis appropriately. - Severe adverse local effects, including tissue necrosis, may occur following extravasation; therefore, care should be taken in intravenous needle placement and the smallest effective volume at each injection site should be used. - After the injection session is completed, apply compression with a stocking or bandage, and have the patient walk for 15-20 minutes. Keep the patient under supervision during this period to treat any anaphylactic or allergic reaction. - Intra-arterial injection can cause severe necrosis, ischemia or gangrene. If this occurs consult a vascular surgeon immediately. - Inadvertent perivascular injection of Asclera can cause pain. If pain is severe, a local anesthetic (without adrenaline) may be injected. # Adverse Reactions ## Clinical Trials Experience ### Clinical Study Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - In 5 controlled randomized clinical trials, Asclera has been administered to 401 patients with small or very small varicose veins (reticular and spider veins) and compared with another sclerosing agent and with placebo. Patients were 18 to 70 years old. The patient population was predominately female and consisted of Caucasian and Asian patients. - Table 1 shows adverse events more common with Asclera or sodium tetradecyl sulfate (STS) 1% than with placebo by at least 3% in the placebo- controlled EASI study. All of these were injection site reactions and most were mild. - Ultrasound examinations at one week (±3 days) and 12 weeks (±2 weeks) after treatment did not reveal deep vein thrombosis in any treatment group. ## Postmarketing Experience ### Post-marketing Safety Experience - The following adverse reactions have been reported during use of polidocanol in world-wide experience; in some of these cases these adverse events have been serious or troublesome. Because these reactions are reported voluntarily from a population of uncertain size and without a control group, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. - Anaphylactic shock, angioedema, urticaria generalized, asthma - Cerebrovascular accident, migraine, paresthesia (local), loss of consciousness, confusional state, dizziness - Cardiac arrest, palpitations - Deep vein thrombosis, pulmonary embolism, syncope vasovagal, circulatory collapse, vasculitis - Dyspnea - Skin hyperpigmentation, allergic dermatitis, hypertrichosis (in the area of sclerotherapy) - Injection site necrosis, pyrexia, hot flush - Nerve injury # Drug Interactions - No drug-drug interactions have been studied with Asclera. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Polidocanol has been shown to have an embryocidal effect in rabbits when given in doses approximately equal (on the basis of body surface area) to the human dose. This effect may have been secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Asclera should not be used during pregnancy. - Developmental reproductive toxicity testing was performed in rats and rabbits with intravenous administration. Polidocanol induced maternal and fetal toxicity in rabbits, including reduced mean fetal weight and reduced fetal survival, when administered during gestation days 6-20 at doses of 4 and 10 mg/kg, but it did not cause skeletal or visceral abnormalities. No adverse maternal or fetal effects were observed in rabbits at a dose of 2 mg/kg. No evidence of teratogenicity or fetal toxicity was observed in rats dosed during gestation days 6-17 with doses up to 10 mg/kg. Polidocanol did not affect the ability of rats to deliver and rear pups when administered intermittently by intravenous injection from gestation day 17 to post-partum day 21 at doses up to 10 mg/kg. - There are no adequate and well-controlled studies on the use of Asclera in pregnant women. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Polidocanol in women who are pregnant. ### Labor and Delivery - The effects of Asclera on labor and delivery in pregnant women are unknown. ### Nursing Mothers - It is not known whether polidocanol 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, avoid administering to a nursing woman. ### Pediatric Use - The safety and effectiveness of Asclera in pediatric patients have not been established. ### Geriatic Use - Clinical studies of Asclera did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Polidocanol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Polidocanol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Polidocanol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Polidocanol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Polidocanol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Polidocanol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Polidocanol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Polidocanol in the drug label. # Overdosage - Overdose may result in a higher incidence of localized reactions such as necrosis. # Pharmacology ## Mechanism of Action - The active ingredient of Asclera is polidocanol. - Polidocanol is a sclerosing agent that locally damages the endothelium of blood vessels. When injected intravenously, polidocanol induces endothelial damage. Platelets then aggregate at the site of damage and attach to the venous wall. Eventually, a dense network of platelets, cellular debris, and fibrin occludes the vessel. Finally, the occluded vein is replaced with connective fibrous tissue. ## Structure - Asclera is a sterile, nonpyrogenic, and colorless to faintly greenish-yellow solution of polidocanol for intravenous use as a sclerosing agent. - The active ingredient, polidocanol is a non-ionic detergent, consisting of two components, a polar hydrophilic (dodecyl alcohol) and an apolar hydrophobic (polyethylene oxide) chain. Polidocanol has the following structural formula: - C12H25(OCH2CH2)nOH Polyethylene glycol monododecyl ether Mean extent of polymerization (n) : Approximately 9 Mean molecular weight : Approximately 600 - Each mL contains 5 mg (0.5%) or 10 mg (1.0%) polidocanol in water for injection with 5% (v/v) ethanol at pH 6.5-8.0; disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate are added for pH adjustment. ## Pharmacodynamics - Polidocanol has a concentration- and volume-dependent damaging effect on the endothelium of blood vessels. ## Pharmacokinetics - During the major effectiveness study (EASI-trial), scheduled blood samples were taken from a sub-group of 22 patients to measure plasma levels of polidocanol after Asclera treatment of spider and reticular veins. Low systemic blood levels of polidocanol were seen in some patients. - The mean t1/2 of polidocanol in 4 patients with evaluable data receiving 4.5 -18.0 mg was 1.5 h. ## Nonclinical Toxicology - Long-term studies to evaluate carcinogenic potential have not been conducted with polidocanol. Polidocanol was negative in bacterial reverse mutation assays in Salmonella and E. coli, and in a micronucleus assay conducted in mice. Polidocanol induced numerical chromosomal aberrations in cultured newborn Chinese hamster lung fibroblasts in the absence of metabolic activation. - Polidocanol did not affect reproductive performance (fertility) of rats when administered intermittently at dosages up to 10 mg/kg (approximately equal to the maximum human dose on the basis of body surface area). # Clinical Studies - Asclera was evaluated in a multicenter, randomized, double-blind, placebo- and comparator-controlled trial (EASI-study) in patients with spider or reticular varicose veins. A total of 338 patients were treated with Asclera , sodium tetradecyl sulfate (STS) 1% (n=105), or placebo (0.9% isotonic saline solution) (n=53) for either spider or reticular veins. Patients were predominately female, ranging in age from 19 to 70 years. All of them received an intravenous injection in the first treatment session; repeat injections were given three and six weeks later if the previous injection was evaluated as unsuccessful (defined as 1, 2 or 3 on a 5-point scale, see below). Patients returned at 12 and 26 weeks after the last injection for final assessments. - The primary effectiveness endpoint was improvement of veins judged by a blinded panel. Digital images of the selected treatment area were taken prior to injection, compared with those taken at 12 weeks post-treatment, and rated on a 5-point scale (1 = worse than before, 2 = same as before, 3 = moderate improvement, 4 = good improvement, 5 = complete treatment success); results are shown in Table 2. - The secondary efficacy criterion was the rate of treatment success, pre-defined as a score of 4 or 5 with patients scoring 1, 2, or 3 considered treatment failures; results are shown in Table 3. - At 12 and 26 weeks, patients' judgement of the results was assessed by showing them the digital images of their treatment area taken at baseline and asking them to rate their satisfaction with their treatment using a verbal rating scale (1 = very unsatisfied; 2 = somewhat unsatisfied; 3 = slightly satisfied; 4 = satisfied and 5 = very satisfied); results are shown in Table 4. # How Supplied - Asclera is supplied in single-use, preservative free ampules in the following packages: - Each ampule is intended for immediate use in a single patient. Each unopened ampule is stable up to three years. ## Storage - Store at 15-30°C; (59-86°F). # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL - 20 MG AMPULE CARTON NDC 46783-221-52 ASCLERA® (polidocanol) Injection 20 mg per 2 mL (10 mg per mL) For Intravenous Use Only Rx Only Single use: Discard unused portion Contains: 5 ampules each containing 20 mg per 2 mL ### PRINCIPAL DISPLAY PANEL - 10 MG AMPULE CARTON NDC 46783-121-52 ASCLERA® (polidocanol) Injection 10 mg per 2 mL (5 mg per mL) For Intravenous Use Only Rx Only Single use: Discard unused portion Contains: 5 ampules each containing 10 mg per 2 mL ### Ingredients and Appearance # Patient Counseling Information - Advise the patient to wear compression stockings or support hose on the treated legs continuously for 2 to 3 days and for 2 to 3 weeks during the daytime. Compression stockings or support hose should be thigh or knee high depending upon the area treated in order to provide adequate coverage. - Advise the patient to walk for 15 to 20 minutes immediately after the procedure and daily for the next few days. - For two to three days following treatment, advise the patient to avoid heavy exercise, sunbathing, long plane flights, and hot baths or sauna. # Precautions with Alcohol - Alcohol-Polidocanol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ASCLERA® # Look-Alike Drug Names There is limited information regarding Polidocanol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Polidocanol 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 Polidocanol is a sclerosing agent that is FDA approved for the treatment of uncomplicated spider veins (varicose veins ≤1 mm in diameter) and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower extremity. Common adverse reactions include mild local reactions at the site of injection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Asclera® (polidocanol) is indicated to sclerose uncomplicated spider veins (varicose veins ≤1 mm in diameter) and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower extremity. Asclera has not been studied in varicose veins more than 3 mm in diameter. ### Dosage - For intravenous use only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if particulate matter is seen or if the contents of the vial are discolored or if the vial is damaged in any way. - For spider veins (varicose veins ≤1 mm in diameter), use Asclera 0.5%. For reticular veins (varicose veins 1 to 3 mm in diameter), use Asclera 1%. Use 0.1 to 0.3 mL per injection and no more than 10 mL per session. - Use a syringe (glass or plastic) with a fine needle (typically, 26- or 30-gauge). Insert the needle tangentially into the vein and inject the solution slowly while the needle is still in the vein. Apply only gentle pressure during injection to prevent vein rupture. After the needle has been removed and the injection site has been covered, apply compression in the form of a stocking or bandage. After the treatment session, encourage the patient to walk for 15 to 20 minutes. Keep the patient under observation to detect any anaphylactic or allergic reaction. - Maintain compression for 2 to 3 days after treatment of spider veins and for 5 to 7 days for reticular veins. For extensive varicosities, longer compression treatment with compression bandages or a gradient compression stocking of a higher compression class is recommended. Post-treatment compression is necessary to reduce the risk of deep vein thrombosis. - Repeat treatments may be necessary if the extent of the varicose veins requires more than 10 mL. These treatments should be separated by 1 to 2 weeks. - Small intravaricose blood clots (thrombi) that develop may be removed by stab incision and thrombus expression (microthrombectomy). ### DOSAGE FORMS AND STRENGTHS - Asclera is available as a 0.5% and 1% solution in 2 mL glass ampules. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Polidocanol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Polidocanol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Polidocanol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Polidocanol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Polidocanol in pediatric patients. # Contraindications - Asclera is contraindicated for patients with known allergy (anaphylaxis) to polidocanol and patients with acute thromboembolic diseases. # Warnings - Severe allergic reactions have been reported following polidocanol use, including anaphylactic reactions, some of them fatal. Severe reactions are more frequent with use of larger volumes (> 3 mL). The dose of polidocanol should therefore be minimized. Be prepared to treat anaphylaxis appropriately. - Severe adverse local effects, including tissue necrosis, may occur following extravasation; therefore, care should be taken in intravenous needle placement and the smallest effective volume at each injection site should be used. - After the injection session is completed, apply compression with a stocking or bandage, and have the patient walk for 15-20 minutes. Keep the patient under supervision during this period to treat any anaphylactic or allergic reaction. - Intra-arterial injection can cause severe necrosis, ischemia or gangrene. If this occurs consult a vascular surgeon immediately. - Inadvertent perivascular injection of Asclera can cause pain. If pain is severe, a local anesthetic (without adrenaline) may be injected. # Adverse Reactions ## Clinical Trials Experience ### Clinical Study Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - In 5 controlled randomized clinical trials, Asclera has been administered to 401 patients with small or very small varicose veins (reticular and spider veins) and compared with another sclerosing agent and with placebo. Patients were 18 to 70 years old. The patient population was predominately female and consisted of Caucasian and Asian patients. - Table 1 shows adverse events more common with Asclera or sodium tetradecyl sulfate (STS) 1% than with placebo by at least 3% in the placebo- controlled EASI study. All of these were injection site reactions and most were mild. - Ultrasound examinations at one week (±3 days) and 12 weeks (±2 weeks) after treatment did not reveal deep vein thrombosis in any treatment group. ## Postmarketing Experience ### Post-marketing Safety Experience - The following adverse reactions have been reported during use of polidocanol in world-wide experience; in some of these cases these adverse events have been serious or troublesome. Because these reactions are reported voluntarily from a population of uncertain size and without a control group, it is not possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. - Anaphylactic shock, angioedema, urticaria generalized, asthma - Cerebrovascular accident, migraine, paresthesia (local), loss of consciousness, confusional state, dizziness - Cardiac arrest, palpitations - Deep vein thrombosis, pulmonary embolism, syncope vasovagal, circulatory collapse, vasculitis - Dyspnea - Skin hyperpigmentation, allergic dermatitis, hypertrichosis (in the area of sclerotherapy) - Injection site necrosis, pyrexia, hot flush - Nerve injury # Drug Interactions - No drug-drug interactions have been studied with Asclera. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Polidocanol has been shown to have an embryocidal effect in rabbits when given in doses approximately equal (on the basis of body surface area) to the human dose. This effect may have been secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Asclera should not be used during pregnancy. - Developmental reproductive toxicity testing was performed in rats and rabbits with intravenous administration. Polidocanol induced maternal and fetal toxicity in rabbits, including reduced mean fetal weight and reduced fetal survival, when administered during gestation days 6-20 at doses of 4 and 10 mg/kg, but it did not cause skeletal or visceral abnormalities. No adverse maternal or fetal effects were observed in rabbits at a dose of 2 mg/kg. No evidence of teratogenicity or fetal toxicity was observed in rats dosed during gestation days 6-17 with doses up to 10 mg/kg. Polidocanol did not affect the ability of rats to deliver and rear pups when administered intermittently by intravenous injection from gestation day 17 to post-partum day 21 at doses up to 10 mg/kg. - There are no adequate and well-controlled studies on the use of Asclera in pregnant women. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Polidocanol in women who are pregnant. ### Labor and Delivery - The effects of Asclera on labor and delivery in pregnant women are unknown. ### Nursing Mothers - It is not known whether polidocanol 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, avoid administering to a nursing woman. ### Pediatric Use - The safety and effectiveness of Asclera in pediatric patients have not been established. ### Geriatic Use - Clinical studies of Asclera did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Polidocanol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Polidocanol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Polidocanol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Polidocanol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Polidocanol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Polidocanol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Polidocanol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Polidocanol in the drug label. # Overdosage - Overdose may result in a higher incidence of localized reactions such as necrosis. # Pharmacology ## Mechanism of Action - The active ingredient of Asclera is polidocanol. - Polidocanol is a sclerosing agent that locally damages the endothelium of blood vessels. When injected intravenously, polidocanol induces endothelial damage. Platelets then aggregate at the site of damage and attach to the venous wall. Eventually, a dense network of platelets, cellular debris, and fibrin occludes the vessel. Finally, the occluded vein is replaced with connective fibrous tissue. ## Structure - Asclera is a sterile, nonpyrogenic, and colorless to faintly greenish-yellow solution of polidocanol for intravenous use as a sclerosing agent. - The active ingredient, polidocanol is a non-ionic detergent, consisting of two components, a polar hydrophilic (dodecyl alcohol) and an apolar hydrophobic (polyethylene oxide) chain. Polidocanol has the following structural formula: - C12H25(OCH2CH2)nOH Polyethylene glycol monododecyl ether Mean extent of polymerization (n) : Approximately 9 Mean molecular weight : Approximately 600 - Each mL contains 5 mg (0.5%) or 10 mg (1.0%) polidocanol in water for injection with 5% (v/v) ethanol at pH 6.5-8.0; disodium hydrogen phosphate dihydrate, potassium dihydrogen phosphate are added for pH adjustment. ## Pharmacodynamics - Polidocanol has a concentration- and volume-dependent damaging effect on the endothelium of blood vessels. ## Pharmacokinetics - During the major effectiveness study (EASI-trial), scheduled blood samples were taken from a sub-group of 22 patients to measure plasma levels of polidocanol after Asclera treatment of spider and reticular veins. Low systemic blood levels of polidocanol were seen in some patients. - The mean t1/2 of polidocanol in 4 patients with evaluable data receiving 4.5 -18.0 mg was 1.5 h. ## Nonclinical Toxicology - Long-term studies to evaluate carcinogenic potential have not been conducted with polidocanol. Polidocanol was negative in bacterial reverse mutation assays in Salmonella and E. coli, and in a micronucleus assay conducted in mice. Polidocanol induced numerical chromosomal aberrations in cultured newborn Chinese hamster lung fibroblasts in the absence of metabolic activation. - Polidocanol did not affect reproductive performance (fertility) of rats when administered intermittently at dosages up to 10 mg/kg (approximately equal to the maximum human dose on the basis of body surface area). # Clinical Studies - Asclera was evaluated in a multicenter, randomized, double-blind, placebo- and comparator-controlled trial (EASI-study) in patients with spider or reticular varicose veins. A total of 338 patients were treated with Asclera [0.5% for spider veins (n=94), 1% for reticular veins (n=86)], sodium tetradecyl sulfate (STS) 1% (n=105), or placebo (0.9% isotonic saline solution) (n=53) for either spider or reticular veins. Patients were predominately female, ranging in age from 19 to 70 years. All of them received an intravenous injection in the first treatment session; repeat injections were given three and six weeks later if the previous injection was evaluated as unsuccessful (defined as 1, 2 or 3 on a 5-point scale, see below). Patients returned at 12 and 26 weeks after the last injection for final assessments. - The primary effectiveness endpoint was improvement of veins judged by a blinded panel. Digital images of the selected treatment area were taken prior to injection, compared with those taken at 12 weeks post-treatment, and rated on a 5-point scale (1 = worse than before, 2 = same as before, 3 = moderate improvement, 4 = good improvement, 5 = complete treatment success); results are shown in Table 2. - The secondary efficacy criterion was the rate of treatment success, pre-defined as a score of 4 or 5 with patients scoring 1, 2, or 3 considered treatment failures; results are shown in Table 3. - At 12 and 26 weeks, patients' judgement of the results was assessed by showing them the digital images of their treatment area taken at baseline and asking them to rate their satisfaction with their treatment using a verbal rating scale (1 = very unsatisfied; 2 = somewhat unsatisfied; 3 = slightly satisfied; 4 = satisfied and 5 = very satisfied); results are shown in Table 4. # How Supplied - Asclera is supplied in single-use, preservative free ampules in the following packages: - Each ampule is intended for immediate use in a single patient. Each unopened ampule is stable up to three years. ## Storage - Store at 15-30°C; (59-86°F). # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL - 20 MG AMPULE CARTON NDC 46783-221-52 ASCLERA® (polidocanol) Injection 20 mg per 2 mL (10 mg per mL) 1% For Intravenous Use Only Rx Only Single use: Discard unused portion Contains: 5 ampules each containing 20 mg per 2 mL ### PRINCIPAL DISPLAY PANEL - 10 MG AMPULE CARTON NDC 46783-121-52 ASCLERA® (polidocanol) Injection 10 mg per 2 mL (5 mg per mL) 0.5% For Intravenous Use Only Rx Only Single use: Discard unused portion Contains: 5 ampules each containing 10 mg per 2 mL ### Ingredients and Appearance # Patient Counseling Information - Advise the patient to wear compression stockings or support hose on the treated legs continuously for 2 to 3 days and for 2 to 3 weeks during the daytime. Compression stockings or support hose should be thigh or knee high depending upon the area treated in order to provide adequate coverage. - Advise the patient to walk for 15 to 20 minutes immediately after the procedure and daily for the next few days. - For two to three days following treatment, advise the patient to avoid heavy exercise, sunbathing, long plane flights, and hot baths or sauna. # Precautions with Alcohol - Alcohol-Polidocanol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ASCLERA®[1] # Look-Alike Drug Names There is limited information regarding Polidocanol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Polidocanol
0ff4e1de4fee366a3f29f1cb1eedf8fa5af27d3e	wikidoc	Polyaniline	Polyaniline Polyaniline (PANI) is a conducting polymer of the semi-flexible rod polymer family. It was discovered in 1934 as anilin black. Polyaniline also exists naturally as part of a mixed copolymer with polyacetylene and polypyrrole in some melanins. # Oxidation states Polymerized from the aniline monomer, polyaniline can be found in one of five distinct oxidation states : - leucoemeraldine - protoemeralsine - emeraldine - nigraniline - pernigraniline In figure 1 x equals half the degree of polymerization (DP). Leucoemeraldine with n = 1, m = 0 is the fully reduced state. Pernigraniline is the fully oxidized state (n = 0, m = 1) with imine links instead of amine links. The emeraldine (n = m = 0.5) form of polyaniline, often referred to as emeraldine base (EB), is either neutral or only partially reduced or oxidized. Emeraldine base is regarded as the most useful form of polyaniline due to its high stability at room temperature, compared to the easily oxidized leucoemeraldine and the easily degraded pernigraniline. Additionally, the emeraldine base polyaniline can function as a semiconductor when doped by a protic acid. # Synthesis A tried and tested method for the synthesis of polyaniline is by oxidative polymerization with ammonium peroxydisulfate as an oxidant. The components are both dissolved in 1 M hydrochloric acid and slowly (the reaction is very exothermic) added to each other. The polymer precipitates as small particles and the reaction product is a dispersion. The electrochemical method was discovered in 1862 as a test for the determination of small quantities of aniline. A two stage model for the formation of emeraldine base is proposed. In the first stage of the reaction the pernigraniline PS salt oxidation state is formed. In the second stage pernigraniline is reduced to the emeraldine salt as aniline monomer gets oxidized to the radical cation. In the third stage this radical cation couples with ES salt. This process can be followed by light scattering analysis which allows the determination of the absolute molar mass. According to one study in the first step a DP of 265 is reached with the DP of the final polymer at 319. 19% of the final polymer is made up of in situ form aniline radical cation. # Properties Polyaniline exists as bulk films or as dispersions. A recurring problem with these dispersions is particle aggregation which limits possible applications. A 2006 study proposes a strategy to prevent aggregation based on a model for nucleation and aggregate formation. The model identifies two nucleation modes for particle formation, one by so-called homogeneous nucleation forming long elongated nanofibers and very stable dispersions that can last for months. The other nucleation mode is by heterogeneous nucleation taking place on any alien body available in the reactor such as the surface of the reactor wall forming not elongated fiber but granular coral-like material. With polyaniline, formation by secondary nucleation also takes place on the nanofibers itself. In the study, heterogeneous nucleation is predominant when the reaction medium is stirred or when the reaction temperature is lowered. With both reaction conditions SEM imagery display nanofibers covered in a layer of coral like granules. The granules act as contact points for a nanoscale glue to link the particles together, causing aggregation. The explanation offered for the suppression of homogeneous nucleation is that this requires a local concentration gradient prior to the onset of nucleation which is destroyed by stirring or by low temperature. An important property of polyaniline is its electric conductivity, which makes is suitable, e.g., for manufacture of electrically conducting yarns.	Polyaniline Polyaniline (PANI) is a conducting polymer of the semi-flexible rod polymer family. It was discovered in 1934 as anilin black. Polyaniline also exists naturally as part of a mixed copolymer with polyacetylene and polypyrrole in some melanins. # Oxidation states Polymerized from the aniline monomer, polyaniline can be found in one of five distinct oxidation states [1]: - leucoemeraldine - protoemeralsine - emeraldine - nigraniline - pernigraniline In figure 1 x equals half the degree of polymerization (DP). Leucoemeraldine with n = 1, m = 0 is the fully reduced state. Pernigraniline is the fully oxidized state (n = 0, m = 1) with imine links instead of amine links. The emeraldine (n = m = 0.5) form of polyaniline, often referred to as emeraldine base (EB), is either neutral or only partially reduced or oxidized. Emeraldine base is regarded as the most useful form of polyaniline due to its high stability at room temperature, compared to the easily oxidized leucoemeraldine and the easily degraded pernigraniline. Additionally, the emeraldine base polyaniline can function as a semiconductor when doped by a protic acid. # Synthesis A tried and tested method for the synthesis of polyaniline is by oxidative polymerization with ammonium peroxydisulfate as an oxidant. The components are both dissolved in 1 M hydrochloric acid and slowly (the reaction is very exothermic) added to each other. The polymer precipitates as small particles and the reaction product is a dispersion. The electrochemical method was discovered in 1862 as a test for the determination of small quantities of aniline. A two stage model for the formation of emeraldine base is proposed. In the first stage of the reaction the pernigraniline PS salt oxidation state is formed. In the second stage pernigraniline is reduced to the emeraldine salt as aniline monomer gets oxidized to the radical cation. In the third stage this radical cation couples with ES salt. This process can be followed by light scattering analysis which allows the determination of the absolute molar mass. According to one study [2] in the first step a DP of 265 is reached with the DP of the final polymer at 319. 19% of the final polymer is made up of in situ form aniline radical cation. # Properties Polyaniline exists as bulk films or as dispersions. A recurring problem with these dispersions is particle aggregation which limits possible applications. A 2006 study [3] proposes a strategy to prevent aggregation based on a model for nucleation and aggregate formation. The model identifies two nucleation modes for particle formation, one by so-called homogeneous nucleation forming long elongated nanofibers and very stable dispersions that can last for months. The other nucleation mode is by heterogeneous nucleation taking place on any alien body available in the reactor such as the surface of the reactor wall forming not elongated fiber but granular coral-like material. With polyaniline, formation by secondary nucleation also takes place on the nanofibers itself. In the study, heterogeneous nucleation is predominant when the reaction medium is stirred or when the reaction temperature is lowered. With both reaction conditions SEM imagery display nanofibers covered in a layer of coral like granules. The granules act as contact points for a nanoscale glue to link the particles together, causing aggregation. The explanation offered for the suppression of homogeneous nucleation is that this requires a local concentration gradient prior to the onset of nucleation which is destroyed by stirring or by low temperature. An important property of polyaniline is its electric conductivity, which makes is suitable, e.g., for manufacture of electrically conducting yarns.	https://www.wikidoc.org/index.php/Polyaniline
b6c189dafa9e36872884035d96ee892e1c1eae06	wikidoc	Polycephaly	Polycephaly Polycephaly is the condition of having more than one head. By far the most common use is in relation to the anatomical head, though the word has also been used for other meanings of "head". The term is derived from the stems poly- meaning 'many' and kephal- meaning "head", and encompasses bicephaly and dicephaly (both referring to two-headedness). A variation is an animal born with two faces on a single head, a condition known as diprosopus. In medical terms these are all congenital cephalic disorders. There are many occurrences of multi-headed animals, in real life as well as in mythology. In heraldry and vexillology, the double-headed eagle is a common symbol, though no such animal is known to have ever existed. Bicephalic or tricephalic animals are the only type of multi-headed creatures seen in the real world and form by the same process as conjoined twins: the zygote begins to split but fails to completely separate. One extreme example of this is the condition of craniopagus parasiticus, whereby a fully developed body has a parasitic twin head joined at the skull. # Occurrences Two-headed people and animals, though rare, have long been known to exist and documented. The "Scottish brothers" were conjoined twins, allegedly dicephalic, born 1460 (dates vary). (Human conjoined twins, not all of the dicephalic type, have been documented since the year 945.) ## Novelty and study Polycephalic animals often make local news headlines when found. The most commonly observed two-headed animals are tortoises and snakes. Other species with known two-headed occurrences include cattle, sheep, pigs, cats, dogs, and fish. In 1894, a two-headed partridge was reported in Boston, Massachusetts. It was notable as a dicephalic animal for surviving into adulthood with two perfect heads. Scientists have published in modern journals about dissecting such animals since at least the 1930s. A 1929 paper studied the anatomy of a two-headed kitten. Polycephalic animals, due to their rarity, are a subject of novelty. "We", a two-headed albino rat snake born in captivity in 2000, was scheduled to be auctioned on eBay with an expected price tag of $150,000 (£87,000), though their policy of not trading in live animals prevented the sale. On 2006-10-31, the World Aquarium announced that "We" was adopted by Nutra Pharma Corporation, a biotechnology company developing treatments using modified cobra venom and cobratoxin. "We" died of natural causes at age eight in June 2007. Two-headed farm animals sometimes travel with animal side shows to county fairs. Many museums of natural history contain preserved two-headed animals. The Museum of Lausanne in Lausanne, Switzerland, and the Ripley's Believe It Or Not! museum in Gatlinburg, Tennessee, have collections of preserved two-headed animals. ## Anatomy and fitness Each head of a polycephalic animal has its own brain, and they somehow share control of the organs and limbs, though the specific structure of the connections varies. Animals often move in a disoriented and dizzy fashion, with the brains "arguing" with each other; some animals simply zig-zag without getting anywhere Snake heads may attack and even attempt to swallow each other. Thus, polycephalic animals survive poorly in the wild compared to normal monocephalic animals. Most two-headed snakes only live for a few months, though some have been reported to live a full life and even reproduced with the offspring born normal. A two-headed black rat snake with separate throats and stomachs survived for 20 years. "We", the two-headed albino rat snake, survived in captivity for 8 years before passing away. There is some speculation that the inbreeding of snakes in captivity increases the chances of a two-headed birth. A famous successful modern case is that of the human dicephalic twins Abigail and Brittany Hensel, born in 1990. The twins have two heads, two hearts, four lungs, and two spinal cords, and share the other organs. Each twin controls the limbs on her "side", and with coordination can walk, run, and play piano. ## One or two animals? It is difficult to draw the line between what is considered "one animal with two heads" or "two animals that share a body." With humans, dicephalic conjoined twins such as Abigail and Brittany Hensel are considered "twins", i.e. two individuals .This makes sense as there is a range of conjoinedness, and non-dicephalic conjoined twins may be barely-conjoined and separable by surgery, as is the case with Chang and Eng Bunker. Although the Hensel twins only have one pair of arms and legs total, each head controls one "side" of the body's limbs. On the other hand, Syafitri, born 2006 in Indonesia, was given one name by her parents because she only had one heart. With other animals, polycephaly is usually described as "one animal with two heads." One of the heads, especially in three-headed animals, may be poorly developed and malformed, and not "participate" much. # Oldest occurrence The February 22, 2007 isue of the journal Biology Letters detailed the discovery of a 120 million-year-old fossil of a 2-headed Hyphalosaurus lingyuanensis, marking the earliest known occurrence of axial bifurcation. # List of recent occurrences ## Humans Dicephalic conjoined twins (dicephalus dipus): - In 1990, Abigail and Brittany Hensel were born in Minnesota, United States - In 2003, Sohna and Mohna were born in India - In 2004, Rebeca Martinez was born in the Dominican Republic with an extra head but died 7 hours after surgery. - In 2005, Egyptian Naglaa Mohamed gave birth to Manar who had the head and a remnant of a torso of another child attached. Surgery was performed for separation. Naglaa Mohamed made an appearance on the Oprah Winfrey show with her surviving child. - In 2006, Syafitri was born in Indonesia - In 2007, Mary Grace and Mary Divine Asis was born in the Philippines having only one heart. ## Non-human animals ### Cats There have been numerous reports of two-faced cats; most die soon after birth. Reports of two-headed kittens are common, relative to other animals, because of their status as household pets. Recent two-headed kittens include: - On 2000-06-07, Image, a two-faced kitten, was born on and died later that year in Philadelphia, Pennsylvania. - On 2005-03-08, Deuce, a two-faced kitten, was born in Lake City, Florida, and was euthanased shortly thereafter, having come down with pneumonia. - On 2006-06-12, Gemini, a two-faced kitten was born in Glide, Oregon. - On 2006-07-12, Tiger, a two-faced kitten was born in Grove City, Ohio. Polycephalic cats in museums include: - The Museum of Lausanne in Lausanne, Switzerland, preserves a two-headed kitten (pictured). - The Laing Museum in the small town of Newburgh, Fife, Scotland, preserves the stuffed body of a two-headed kitten born in the 19th century on Mugdrum Island. - The Georgia State Capitol in Atlanta, Georgia, has a full body taxidermy of a two-faced kitten. ### Cattle - A head mount of a two-headed calf is on display in the Museum at the Georgia State Capitol Building in Atlanta, Georgia. - A two-faced calf is preserved at the Douglas County Museum in Waterville, Washington. The calf lived for ten days after birth. - The Ripley's Believe It or Not! museum in Gatlinburg, Tennessee, has full body taxidermy of a two-headed calf. - The Dalton Gang Museum, located in Meade, Kansas, also displays a full body taxidermy of a two-headed calf. - A two-headed calf mount can be found at the Old State House in Hartford, CT - A full taxidermy of a two headed calf can be found in Melton Mowbray museum, Leicestershire, Uk - A full taxidermy of a two headed calf can be found in the Museum of Marxell (in the Northern Black Forest in Germany). The calf was born by a local cow and died shortly after birth by natural causes. ### Pigs - In 1998, Rudy, a two-headed pig was born in Iowa. ### Goats and sheep - In 2006, a two-headed lamb was born in Shandong, China. - The Ripley's Believe It Or Not! museum in Gatlinburg, Tennessee, has a mount. ### Reptiles - A two-headed black rat snake with separate throats and stomachs survived for 20 years. - There are several preserved two-headed snakes on display in the Museum at the Georgia State Capitol Building in Atlanta. Two-headed turtles and tortoises are rare but not unknown. Recent discoveries include: - In 1999, a three-headed turtle was discovered in Tainan, Taiwan, by a villager named Lin Chi-fa. - In 2003, a two-headed angulate tortoise was discovered in South Africa, with the only other known case in the region reported in the early 1980s. - In 2004, Solomon and Sheba, a two-headed Mediterranean spur-thighed tortoise was born in Dorchester, England. - In 2005, a two-headed olive ridley sea turtle was found in Costa Rica by the World Wildlife Fund. - In 2005, a baby turtle of unknown species was also reported in Havana, Cuba, in 2005. - In 2006, a two-headed, five-limbed soft-shell tortoise in Singapore was also featured on a local television program, and again on another program in late 2006. - As of 2006, a living two-headed tortoise named Janus is being displayed in the Museum of Natural History of Geneva. - There is a full body mount of a crocodile with two heads located at the Georgia State Capital on the top level. # Mythological occurrences ## Greek mythology Greek mythology contains a number of multi-headed creatures. Typhon, a vast grisly monster with a hundred heads and a hundred serpents issuing from his thighs, is often described as having several offspring with Echidna, a creature with the body of a serpent but the face of a beautiful woman. Their offspring account for all the major monsters of Greek mythos, including: - The Nemean Lion – a lion often depicted with multiple heads - Cerberus – a monstrous three-headed dog that guards the gate to Hades - Ladon – a sometimes hundred-headed serpentlike dragon that guards the garden of the Hesperides and is overcome by Heracles - Chimera – sometimes depicted with the heads of a goat and a lion - The Lernaean Hydra – an ancient nameless serpent-like chthonic water beast that possessed numerous heads - Orthrus – a two-headed dog owned by Geryon - The Hecatonchires were giants with fifty heads and one hundred arms. The word "Hecatonchire" means "hundred arms". They were the sons of Gaia, and Uranus. Other accounts state that some of these creatures were the offspring of Phorcys and Ceto. Phorcys is also said to have fathered Scylla, a giant monster with six dogs' heads, which terrorises Odysseus and his crew. ## Other mythologies - Balaur, a dragon with three, seven or twelve heads, in Romanian mythology - Bune, a dragon with the heads of a dog, a griffin, and a man, in Christian demonology - Janus, a two- or four-faced god in Roman mythology - Kaliya, a multi-headed snake vanquished by Krishna in Indian mythology - Nehebkau, a two-headed snake in Egyptian mythology - Orochi, an eight-headed snake in Japanese mythology - Ravana, the ten-headed King of Lanka from the Hindu smriti Ramayana - Svantevit, four-headed god of war and divination in Slavic mythology - Triglav (meaning "three headed") is a god or complex of gods in Slavic mythology - Zmey Gorynych, a dragon in Slavic mythology # Modern Fiction Modern fiction does not like anatomical variation as much as mythology, perhaps because of the need to give specific detais, which is difficult to do if the thing one is describing is impossible. There is one obvious example: the character - Zaphod Beeblebrox, in the Hitchhiker's Guide to the Galaxy	Polycephaly Polycephaly is the condition of having more than one head. By far the most common use is in relation to the anatomical head, though the word has also been used for other meanings of "head". The term is derived from the stems poly- meaning 'many' and kephal- meaning "head", and encompasses bicephaly and dicephaly (both referring to two-headedness). A variation is an animal born with two faces on a single head, a condition known as diprosopus. In medical terms these are all congenital cephalic disorders. There are many occurrences of multi-headed animals, in real life as well as in mythology. In heraldry and vexillology, the double-headed eagle is a common symbol, though no such animal is known to have ever existed. Bicephalic or tricephalic animals are the only type of multi-headed creatures seen in the real world and form by the same process as conjoined twins: the zygote begins to split but fails to completely separate. One extreme example of this is the condition of craniopagus parasiticus, whereby a fully developed body has a parasitic twin head joined at the skull. # Occurrences Two-headed people and animals, though rare, have long been known to exist and documented. The "Scottish brothers" were conjoined twins, allegedly dicephalic, born 1460 (dates vary). (Human conjoined twins, not all of the dicephalic type, have been documented since the year 945.) ## Novelty and study Polycephalic animals often make local news headlines when found. The most commonly observed two-headed animals are tortoises and snakes.[1] Other species with known two-headed occurrences include cattle, sheep, pigs, cats, dogs, and fish. In 1894, a two-headed partridge was reported in Boston, Massachusetts.[2] It was notable as a dicephalic animal for surviving into adulthood with two perfect heads. Scientists have published in modern journals about dissecting such animals since at least the 1930s.[1] A 1929 paper studied the anatomy of a two-headed kitten.[1] Polycephalic animals, due to their rarity, are a subject of novelty. "We", a two-headed albino rat snake born in captivity in 2000, was scheduled to be auctioned on eBay with an expected price tag of $150,000 (£87,000), though their policy of not trading in live animals prevented the sale.[3] On 2006-10-31, the World Aquarium[4] announced that "We" was adopted by Nutra Pharma Corporation, a biotechnology company developing treatments using modified cobra venom and cobratoxin.[5] "We" died of natural causes at age eight in June 2007.[6] Two-headed farm animals sometimes travel with animal side shows to county fairs. Many museums of natural history contain preserved two-headed animals. The Museum of Lausanne[7] in Lausanne, Switzerland, and the Ripley's Believe It Or Not! museum in Gatlinburg, Tennessee, have collections of preserved two-headed animals. ## Anatomy and fitness Each head of a polycephalic animal has its own brain, and they somehow share control of the organs and limbs, though the specific structure of the connections varies. Animals often move in a disoriented and dizzy fashion, with the brains "arguing" with each other; some animals simply zig-zag without getting anywhere[8] Snake heads may attack and even attempt to swallow each other. Thus, polycephalic animals survive poorly in the wild compared to normal monocephalic animals.[1] Most two-headed snakes only live for a few months, though some have been reported to live a full life and even reproduced with the offspring born normal. A two-headed black rat snake with separate throats and stomachs survived for 20 years. "We", the two-headed albino rat snake, survived in captivity for 8 years before passing away. [9] There is some speculation that the inbreeding of snakes in captivity increases the chances of a two-headed birth.[10] A famous successful modern case is that of the human dicephalic twins Abigail and Brittany Hensel, born in 1990. The twins have two heads, two hearts, four lungs, and two spinal cords, and share the other organs. Each twin controls the limbs on her "side", and with coordination can walk, run, and play piano.[11] ## One or two animals? It is difficult to draw the line between what is considered "one animal with two heads" or "two animals that share a body." With humans, dicephalic conjoined twins such as Abigail and Brittany Hensel are considered "twins", i.e. two individuals[12] .This makes sense as there is a range of conjoinedness, and non-dicephalic conjoined twins may be barely-conjoined and separable by surgery, as is the case with Chang and Eng Bunker. Although the Hensel twins only have one pair of arms and legs total, each head controls one "side" of the body's limbs. On the other hand, Syafitri, born 2006 in Indonesia, was given one name by her parents because she only had one heart.[13] With other animals, polycephaly is usually described as "one animal with two heads."[3][14] One of the heads, especially in three-headed animals, may be poorly developed and malformed, and not "participate" much.[8] # Oldest occurrence The February 22, 2007 isue of the journal Biology Letters detailed the discovery of a 120 million-year-old fossil of a 2-headed Hyphalosaurus lingyuanensis, marking the earliest known occurrence of axial bifurcation.[15] # List of recent occurrences ## Humans Dicephalic conjoined twins (dicephalus dipus): - In 1990, Abigail and Brittany Hensel were born in Minnesota, United States[11] - In 2003, Sohna and Mohna were born in India[16] - In 2004, Rebeca Martinez was born in the Dominican Republic with an extra head but died 7 hours after surgery.[17] - In 2005, Egyptian Naglaa Mohamed gave birth to Manar who had the head and a remnant of a torso of another child attached. Surgery was performed for separation. Naglaa Mohamed made an appearance on the Oprah Winfrey show with her surviving child.[18] - In 2006, Syafitri was born in Indonesia[13] - In 2007, Mary Grace and Mary Divine Asis was born in the Philippines having only one heart. [19] ## Non-human animals ### Cats There have been numerous reports of two-faced cats; most die soon after birth. Reports of two-headed kittens are common, relative to other animals, because of their status as household pets. Recent two-headed kittens include: - On 2000-06-07, Image, a two-faced kitten, was born on and died later that year in Philadelphia, Pennsylvania.[20][21] - On 2005-03-08, Deuce, a two-faced kitten, was born in Lake City, Florida, and was euthanased shortly thereafter, having come down with pneumonia.[22] - On 2006-06-12, Gemini, a two-faced kitten was born in Glide, Oregon.[23] - On 2006-07-12, Tiger, a two-faced kitten was born in Grove City, Ohio.[24] Polycephalic cats in museums include: - The Museum of Lausanne in Lausanne, Switzerland, preserves a two-headed kitten (pictured). - The Laing Museum in the small town of Newburgh, Fife, Scotland, preserves the stuffed body of a two-headed kitten born in the 19th century on Mugdrum Island. - The Georgia State Capitol in Atlanta, Georgia, has a full body taxidermy of a two-faced kitten. ### Cattle - A head mount of a two-headed calf is on display in the Museum at the Georgia State Capitol Building in Atlanta, Georgia. - A two-faced calf is preserved at the Douglas County Museum in Waterville, Washington.[25] The calf lived for ten days after birth. - The Ripley's Believe It or Not! museum in Gatlinburg, Tennessee, has full body taxidermy of a two-headed calf. - The Dalton Gang Museum, located in Meade, Kansas, also displays a full body taxidermy of a two-headed calf. - A two-headed calf mount can be found at the Old State House in Hartford, CT - A full taxidermy of a two headed calf can be found in Melton Mowbray museum, Leicestershire, Uk - A full taxidermy of a two headed calf can be found in the Museum of Marxell (in the Northern Black Forest in Germany). The calf was born by a local cow and died shortly after birth by natural causes. ### Pigs - In 1998, Rudy, a two-headed pig was born in Iowa.[1] ### Goats and sheep - In 2006, a two-headed lamb was born in Shandong, China. - The Ripley's Believe It Or Not! museum in Gatlinburg, Tennessee, has a mount. ### Reptiles - A two-headed black rat snake with separate throats and stomachs survived for 20 years. - There are several preserved two-headed snakes on display in the Museum at the Georgia State Capitol Building in Atlanta.[26] Two-headed turtles and tortoises are rare but not unknown. Recent discoveries include: - In 1999, a three-headed turtle was discovered in Tainan, Taiwan, by a villager named Lin Chi-fa.[8][1] - In 2003, a two-headed angulate tortoise was discovered in South Africa, with the only other known case in the region reported in the early 1980s.[14] - In 2004, Solomon and Sheba, a two-headed Mediterranean spur-thighed tortoise was born in Dorchester, England.[27] - In 2005, a two-headed olive ridley sea turtle was found in Costa Rica by the World Wildlife Fund.[28] - In 2005, a baby turtle of unknown species was also reported in Havana, Cuba, in 2005.[29] - In 2006, a two-headed, five-limbed soft-shell tortoise in Singapore was also featured on a local television program, and again on another program in late 2006.[30] - As of 2006, a living two-headed tortoise named Janus is being displayed in the Museum of Natural History of Geneva.[31] - There is a full body mount of a crocodile with two heads located at the Georgia State Capital on the top level. # Mythological occurrences ## Greek mythology Greek mythology contains a number of multi-headed creatures. Typhon, a vast grisly monster with a hundred heads and a hundred serpents issuing from his thighs, is often described as having several offspring with Echidna, a creature with the body of a serpent but the face of a beautiful woman. Their offspring account for all the major monsters of Greek mythos, including: - The Nemean Lion – a lion often depicted with multiple heads - Cerberus – a monstrous three-headed dog that guards the gate to Hades - Ladon – a sometimes hundred-headed serpentlike dragon that guards the garden of the Hesperides and is overcome by Heracles - Chimera – sometimes depicted with the heads of a goat and a lion - The Lernaean Hydra – an ancient nameless serpent-like chthonic water beast that possessed numerous heads - Orthrus – a two-headed dog owned by Geryon - The Hecatonchires were giants with fifty heads and one hundred arms. The word "Hecatonchire" means "hundred arms". They were the sons of Gaia, and Uranus. Other accounts state that some of these creatures were the offspring of Phorcys and Ceto. Phorcys is also said to have fathered Scylla, a giant monster with six dogs' heads, which terrorises Odysseus and his crew. ## Other mythologies - Balaur, a dragon with three, seven or twelve heads, in Romanian mythology - Bune, a dragon with the heads of a dog, a griffin, and a man, in Christian demonology - Janus, a two- or four-faced god in Roman mythology - Kaliya, a multi-headed snake vanquished by Krishna in Indian mythology - Nehebkau, a two-headed snake in Egyptian mythology - Orochi, an eight-headed snake in Japanese mythology - Ravana, the ten-headed King of Lanka from the Hindu smriti Ramayana - Svantevit, four-headed god of war and divination in Slavic mythology - Triglav (meaning "three headed") is a god or complex of gods in Slavic mythology - Zmey Gorynych, a dragon in Slavic mythology # Modern Fiction Modern fiction does not like anatomical variation as much as mythology, perhaps because of the need to give specific detais, which is difficult to do if the thing one is describing is impossible. There is one obvious example: the character - Zaphod Beeblebrox, in the Hitchhiker's Guide to the Galaxy	https://www.wikidoc.org/index.php/Polycephaly
af87f58b0c75ca1cfe6ec3adbfeb8edbc42ddc29	wikidoc	Polygonatum	Polygonatum Polygonatum (King Solomon's-seal, Solomon's Seal) is a genus of about 50 species of flowering plants within the family Ruscaceae, formerly classified in the lily family Liliaceae. Some species of this genus have medicinal properties, and some (in particular P. sibiricum) are used as an tisane in traditional Chinese medicine, which is called Duong Gul Le in Korea. Some Polygonatum shoots are edible, cooked like asparagus, as are the roots - after appropriate treatment - being a good source of starch . # Selected species # Medicinal uses Revolving primarily around the root, "Solomon's Seal" are traditionally used in a range of afflictions from menopause to broken bones. As a topical application, the root are said to expedite the healing of cuts and bruises, skin irritations and inflammations, and as a face wash is good for acne, blemishes and all kinds of imperfections of the skin. When consumed as a tea, it is said to alleviate a range of symptoms associated with menopause, indigestion, diabetes, broken bones, insomnia, kidney pains, and even infertility. Its use to fight diabetes was first observed in 1930 by Langecker. After experiments, he concluded that it was effective in fighting nutricional hyperglycemia, though not that caused by adrenaline release, probably due to its content in glucokinin. - ↑ Altnature.com article on Solomon's Seal description and uses - ↑ Polygonatum odoratum in ibiblio.org - ↑ Source:Quer, Pío Font "Plantas Medicinales - El Dioscórides renovado". 1961/2005 Barcelona: Ediciones Península cs:Kokořík de:Weißwurze hsb:Kwětkata kokorička lt:Baltašaknė nl:Salomonszegel nds-nl:Salemonszegel wa:Foye di coixheure	Polygonatum Polygonatum (King Solomon's-seal, Solomon's Seal) is a genus of about 50 species of flowering plants within the family Ruscaceae, formerly classified in the lily family Liliaceae. Some species of this genus have medicinal properties, and some (in particular P. sibiricum) are used as an tisane in traditional Chinese medicine, which is called Duong Gul Le in Korea. Some Polygonatum shoots are edible, cooked like asparagus, as are the roots - after appropriate treatment [1] - being a good source of starch [2]. # Selected species # Medicinal uses Revolving primarily around the root, "Solomon's Seal" are traditionally used in a range of afflictions from menopause to broken bones. As a topical application, the root are said to expedite the healing of cuts and bruises, skin irritations and inflammations, and as a face wash is good for acne, blemishes and all kinds of imperfections of the skin. When consumed as a tea, it is said to alleviate a range of symptoms associated with menopause, indigestion, diabetes, broken bones, insomnia, kidney pains, and even infertility.[citation needed] Its use to fight diabetes was first observed in 1930 by Langecker. After experiments, he concluded that it was effective in fighting nutricional hyperglycemia, though not that caused by adrenaline release, probably due to its content in glucokinin.[3] - ↑ Altnature.com article on Solomon's Seal description and uses - ↑ Polygonatum odoratum in ibiblio.org - ↑ Source:Quer, Pío Font "Plantas Medicinales - El Dioscórides renovado". 1961/2005 Barcelona: Ediciones Península Template:Monocot-stub cs:Kokořík de:Weißwurze hsb:Kwětkata kokorička lt:Baltašaknė nl:Salomonszegel nds-nl:Salemonszegel wa:Foye di coixheure	https://www.wikidoc.org/index.php/Polygonatum
ced28d2e73e6f0cd260da493fdcd856c100d5c00	wikidoc	Polymyxin B	Polymyxin B # 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 Polymyxin B is an anti-bacterial agent that is FDA approved for the treatment of infections of the urinary tract, meninges, and bloodstream and used subconjunctivally in the treatment of infections of the eye caused by susceptible strains of P. aeruginosa. There is a Black Box Warning for this drug as shown here. Common adverse reactions include facial flushing, dizziness progressing to ataxia, drowsiness, peripheral paresthesias. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Polymyxin B sulfate is a drug of choice in the treatment of infections of the urinary tract, meninges, and bloodstream caused by susceptible strains of P. aeruginosa. It may also be used topically and subconjunctivally in the treatment of infections of the eye caused by susceptible strains of P. aeruginosa. - It may be indicated in serious infections caused by susceptible strains of the following organisms, when less potentially toxic drugs are ineffective or contraindicated: - H influenzae, specifically meningeal infections. - Escherichia coli, specifically urinary tract infections. - Aerobacter aerogenes, specifically bacteremia. - Klebsiella pneumoniae, specifically bacteremia. NOTE: IN MENINGEAL INFECTIONS, POLYMYXIN B SULFATE SHOULD BE ADMINISTERED ONLY BY THE INTRATHECAL ROUTE - To reduce the development of drug-resistant bacteria and maintain the effectiveness of polymyxin B and other antibacterial drugs, polymyxin B should be used only to treat or prevent infections that are proven or strongly suspected to be caused by 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. - Intravenous - Dissolve 500,000 polymyxin B units in 300 to 500 mL solutions for parenteral dextrose injection 5% for continuous drip. - 15,000 to 25,000 units/kg body weight/day in individuals with normal kidney function. This amount should be reduced from 15,000 units/kg downward for individuals with kidney impairment. :*Infusions may be given every 12 hours; however, the total daily dose must not exceed 25,000 units/kg/day. - Intramuscular - Not recommended routinely because of severe pain at injection sites, particularly in infants and children. Dissolve 500,000 polymyxin B units in 2 mL sterile water for injection or sodium chloride injection or procaine hydrochloride injection 1%. - 25,000 to 30,000 units/kg/day. This should be reduced in the presence of renal impairment. The dosage may be divided and given at either 4 or 6 hour intervals. - Intrathecal - A treatment of choice for P. aeruginosa meningitis. Dissolve 500,000 polymyxin B units in 10 mL sodium chloride injection, USP for 50,000 units per mL dosage unit. - Dosage is 50,000 units once daily intrathecally for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal. - IN THE INTEREST OF SAFETY, SOLUTIONS OF PARENTERAL USE SHOULD BE STORED UNDER REFRIGERATION, AND ANY UNUSED PORTIONS SHOULD BE DISCARDED AFTER 72 HOURS. - Topical - Ophthalmic: Dissolve 500,000 polymyxin B units in 20 to 50 mL sterile water for injection or sodium chloride injection USP for a 10,000 to 25,000 units per mL concentration. - For the treatment of P. aeruginosa infections of the eye, a concentration of 0.1 percent to 0.25 percent (10,000 units to 25,000 units per mL) is administered 1 to 3 drops every hour, increasing the intervals as response indicates. - Subconjunctival injection of up to 100,000 units/day may be used for the treatment of P. aeruginosa infections of the cornea and conjunctiva. - Note: Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Polymyxin B in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Polymyxin B in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Intravenous - Dissolve 500,000 polymyxin B units in 300 to 500 mL solutions for parenteral dextrose injection 5% for continuous drip. - 15,000 to 25,000 units/kg body weight/day in individuals with normal kidney function. This amount should be reduced from 15,000 units/kg downward for individuals with kidney impairment. - Infusions may be given every 12 hours; however, the total daily dose must not exceed 25,000 units/kg/day. - Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects. - Intramuscular - Not recommended routinely because of severe pain at injection sites, particularly in infants and children. Dissolve 500,000 polymyxin B units in 2 mL sterile water for injection or sodium chloride injection or procaine hydrochloride injection 1%. - 25,000 to 30,000 units/kg/day. This should be reduced in the presence of renal impairment. The dosage may be divided and given at either 4 or 6 hour intervals. - Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects. - Note: Doses as high as 45,000 units/kg/day have been used in limited clinical studies in treating prematures and newborn infants for sepsis caused by P aeruginosa. - Intrathecal - A treatment of choice for P. aeruginosa meningitis. Dissolve 500,000 polymyxin B units in 10 mL sodium chloride injection, USP for 50,000 units per mL dosage unit. - children over 2 years of age: Dosage is 50,000 units once daily intrathecally for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal. - Children under 2 years of age: 20,000 units once daily, intrathecally for 3 to 4 days or 25,000 units once every other day. Continue with a dose of 25,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal. - IN THE INTEREST OF SAFETY, SOLUTIONS OF PARENTERAL USE SHOULD BE STORED UNDER REFRIGERATION, AND ANY UNUSED PORTIONS SHOULD BE DISCARDED AFTER 72 HOURS. - Topical - Ophthalmic: Dissolve 500,000 polymyxin B units in 20 to 50 mL sterile water for injection or sodium chloride injection USP for a 10,000 to 25,000 units per mL concentration. - For the treatment of P. aeruginosa infections of the eye, a concentration of 0.1 percent to 0.25 percent (10,000 units to 25,000 units per mL) is administered 1 to 3 drops every hour, increasing the intervals as response indicates. - Subconjunctival injection of up to 100,000 units/day may be used for the treatment of P. aeruginosa infections of the cornea and conjunctiva. - Note: Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day. ## Off-Label Use and Dosage (Pediatric) # Contraindications - This drug is contraindicated in persons with a prior history of hypersensitivity reactions to polymyxins. # Warnings - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Polymyxin B for Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD.Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. ### Precautions - Prescribing polymyxin B 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 - Albuminuria, cylinduria, azotemia, and rising blood levels without any increase in dosage. - Facial flushing, dizziness progressing to ataxia, drowsiness, peripheral paresthesias (circumoral and stocking glove), apnea due to concurrent use of curariform muscle relaxants, other neurotoxic drugs or inadvertent overdosage, and signs of meningeal irritation with intrathecal administration, e.g., fever, headache, stiff neck and increased cell count and protein cerebrospinal fluid. - Other reactions occasionally reported: Drug fever, urticarial rash, pain (severe) at intramuscular injection sites, and thrombophlebitis at intravenous injection sites. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Polymyxin B in the drug label. # Drug Interactions - Avoid concurrent use of a curariform muscle relaxant and other neurotoxic drugs (ether, tubocurarine, succinylcholine, gallamine, decamethonium and sodium citrate) which may precipitate respiratory depression. If signs of respiratory paralysis appear, respiration should be assisted as required, and the drug discontinued. - As with other antibiotics, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. - If superinfection occurs, appropriate therapy should be instituted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): THE SAFETY OF THIS DRUG IN HUMAN PREGNANCY HAS NOT BEEN ESTABLISHED. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Polymyxin B in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Polymyxin B during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Polymyxin B with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Polymyxin B with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Polymyxin B with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Polymyxin B with respect to specific gender populations. ### Race There is no FDA guidance on the use of Polymyxin B with respect to specific racial populations. ### Renal Impairment PATIENTS WITH RENAL DAMAGE AND NITROGEN RETENTION SHOULD HAVE REDUCED DOSAGE. NEUROTOXIC REACTIONS MAY BE MANIFESTED BY IRRITABILITY, WEAKNESS, DROWSINESS, ATAXIA, PERIORAL PARESTHESIA, NUMBNESS OF THE EXTREMITIES, AND BLURRING OF VISION. THESE ARE USUALLY ASSOCIATED WITH HIGH SERUM LEVELS FOUND IN PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR NEPHROTOXICITY. ### Hepatic Impairment There is no FDA guidance on the use of Polymyxin B in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Polymyxin B in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Polymyxin B in patients who are immunocompromised. # Administration and Monitoring ### Administration - Parenteral - Intravenous - Intramuscular - Intrathecal - Topical - Ophthalmic ### Monitoring Baseline renal function should be done prior to therapy, with frequent monitoring of renal function and blood levels of the drug during parenteral therapy. # IV Compatibility There is limited information regarding IV Compatibility of Polymyxin B in the drug label. # Overdosage Inadvertent overdosage can cause Neurotoxic reactions: Facial flushing, dizziness progressing to ataxia, drowsiness, peripheral paresthesias (circumoral and stocking glove), apnea # Pharmacology ## Mechanism of Action - Polymyxin B sulfate has a bactericidal action against almost all gram-negative bacilli except the Proteus group. Polymyxins increase the permeability of the bacterial cell membrane leading to death of the cell. All gram-positive bacteria, fungi, and the gram-negative cocci, are resistant to polymyxin B. Appropriate methods should be used when performing in vitro susceptibility testing of polymyxin B 1,2,3. The following in vitro susceptibility test criteria should only be used for interpreting the results of polymyxin B susceptibility testing against P. aeruginosa when the indicated quality control parameters are met during testing. ## Structure - Polymyxin B for Injection, USP is one of a group of basic polypeptide antibiotics derived from B polymyxa (B aerosporous). Polymyxin B sulfate is the sulfate salt of Polymyxins B1 and B2, which are produced by the growth of Bacillus polymyxa (Prazmowski) Migula (Fam. Bacillacea). It has a potency of not less than 6,000 polymyxin B units per mg, calculated on the anhydrous basis. The structural formulae are: Each vial contains 500,000 polymyxin B units for parenteral or ophthalmic administration. Polymyxin B for Injection, USP is in powder form suitable for preparation of sterile solutions for intramuscular, intravenous drip, intrathecal, or ophthalmic use. In the medical literature, dosages have frequently been given in terms of equivalent weights of pure polymyxin B base. Each milligram of pure polymyxin B base is equivalent to 10,000 units of polymyxin B and each microgram of pure polymyxin B base is equivalent to 10 units of polymyxin B. Aqueous solutions of polymyxin B sulfate may be stored up to 12 months without significant loss of potency if kept under refrigeration. In the interest of safety, solutions for parenteral use should be stored under refrigeration and any unused portion should be discarded after 72 hours. Polymyxin B sulfate should not be stored in alkaline solutions since they are less stable. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Polymyxin B in the drug label. ## Pharmacokinetics Polymyxin B sulfate is not absorbed from the normal alimentary tract. Since the drug loses 50 percent of its activity in the presence of serum, active blood levels are low. Repeated injections may give a cumulative effect. Levels tend to be higher in infants and children. The drug is excreted slowly by the kidneys. Tissue diffusion is poor and the drug does not pass the blood brain barrier into the cerebrospinal fluid. In therapeutic dosage, polymyxin B sulfate causes some nephrotoxicity with tubule damage to a slight degree. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Polymyxin B in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Polymyxin B in the drug label. # How Supplied - Polymyxin B for Injection, USP, 500,000 polymyxin B units per vial is supplied as follows. ## Storage - Store at 20° to 25°C (68° to 77°F). - Retain in carton until time of use. - Product must be stored under refrigeration, between 2° to 8°C (36° to 46°F) and any unused portion should be discarded after 72 hours. - This container closure is not made with natural rubber latex. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be counseled that antibacterial drugs including polymyxin B should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When polymyxin B 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 polymyxin B or other antibacterial drugs in the future. - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. # Precautions with Alcohol - Alcohol-Polymyxin B interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Polymyxin B Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, 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. # Black Box Warning # Overview Polymyxin B is an anti-bacterial agent that is FDA approved for the treatment of infections of the urinary tract, meninges, and bloodstream and used subconjunctivally in the treatment of infections of the eye caused by susceptible strains of P. aeruginosa. There is a Black Box Warning for this drug as shown here. Common adverse reactions include facial flushing, dizziness progressing to ataxia, drowsiness, peripheral paresthesias. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Polymyxin B sulfate is a drug of choice in the treatment of infections of the urinary tract, meninges, and bloodstream caused by susceptible strains of P. aeruginosa. It may also be used topically and subconjunctivally in the treatment of infections of the eye caused by susceptible strains of P. aeruginosa. - It may be indicated in serious infections caused by susceptible strains of the following organisms, when less potentially toxic drugs are ineffective or contraindicated: - H influenzae, specifically meningeal infections. - Escherichia coli, specifically urinary tract infections. - Aerobacter aerogenes, specifically bacteremia. - Klebsiella pneumoniae, specifically bacteremia. NOTE: IN MENINGEAL INFECTIONS, POLYMYXIN B SULFATE SHOULD BE ADMINISTERED ONLY BY THE INTRATHECAL ROUTE - To reduce the development of drug-resistant bacteria and maintain the effectiveness of polymyxin B and other antibacterial drugs, polymyxin B should be used only to treat or prevent infections that are proven or strongly suspected to be caused by 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. - Intravenous - Dissolve 500,000 polymyxin B units in 300 to 500 mL solutions for parenteral dextrose injection 5% for continuous drip. - 15,000 to 25,000 units/kg body weight/day in individuals with normal kidney function. This amount should be reduced from 15,000 units/kg downward for individuals with kidney impairment. :*Infusions may be given every 12 hours; however, the total daily dose must not exceed 25,000 units/kg/day. - Intramuscular - Not recommended routinely because of severe pain at injection sites, particularly in infants and children. Dissolve 500,000 polymyxin B units in 2 mL sterile water for injection or sodium chloride injection or procaine hydrochloride injection 1%. - 25,000 to 30,000 units/kg/day. This should be reduced in the presence of renal impairment. The dosage may be divided and given at either 4 or 6 hour intervals. - Intrathecal - A treatment of choice for P. aeruginosa meningitis. Dissolve 500,000 polymyxin B units in 10 mL sodium chloride injection, USP for 50,000 units per mL dosage unit. - Dosage is 50,000 units once daily intrathecally for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal. - IN THE INTEREST OF SAFETY, SOLUTIONS OF PARENTERAL USE SHOULD BE STORED UNDER REFRIGERATION, AND ANY UNUSED PORTIONS SHOULD BE DISCARDED AFTER 72 HOURS. - Topical - Ophthalmic: Dissolve 500,000 polymyxin B units in 20 to 50 mL sterile water for injection or sodium chloride injection USP for a 10,000 to 25,000 units per mL concentration. - For the treatment of P. aeruginosa infections of the eye, a concentration of 0.1 percent to 0.25 percent (10,000 units to 25,000 units per mL) is administered 1 to 3 drops every hour, increasing the intervals as response indicates. - Subconjunctival injection of up to 100,000 units/day may be used for the treatment of P. aeruginosa infections of the cornea and conjunctiva. - Note: Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Polymyxin B in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Polymyxin B in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Intravenous - Dissolve 500,000 polymyxin B units in 300 to 500 mL solutions for parenteral dextrose injection 5% for continuous drip. - 15,000 to 25,000 units/kg body weight/day in individuals with normal kidney function. This amount should be reduced from 15,000 units/kg downward for individuals with kidney impairment. - Infusions may be given every 12 hours; however, the total daily dose must not exceed 25,000 units/kg/day. - Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects. - Intramuscular - Not recommended routinely because of severe pain at injection sites, particularly in infants and children. Dissolve 500,000 polymyxin B units in 2 mL sterile water for injection or sodium chloride injection or procaine hydrochloride injection 1%. - 25,000 to 30,000 units/kg/day. This should be reduced in the presence of renal impairment. The dosage may be divided and given at either 4 or 6 hour intervals. - Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects. - Note: Doses as high as 45,000 units/kg/day have been used in limited clinical studies in treating prematures and newborn infants for sepsis caused by P aeruginosa. - Intrathecal - A treatment of choice for P. aeruginosa meningitis. Dissolve 500,000 polymyxin B units in 10 mL sodium chloride injection, USP for 50,000 units per mL dosage unit. - children over 2 years of age: Dosage is 50,000 units once daily intrathecally for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal. - Children under 2 years of age: 20,000 units once daily, intrathecally for 3 to 4 days or 25,000 units once every other day. Continue with a dose of 25,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal. - IN THE INTEREST OF SAFETY, SOLUTIONS OF PARENTERAL USE SHOULD BE STORED UNDER REFRIGERATION, AND ANY UNUSED PORTIONS SHOULD BE DISCARDED AFTER 72 HOURS. - Topical - Ophthalmic: Dissolve 500,000 polymyxin B units in 20 to 50 mL sterile water for injection or sodium chloride injection USP for a 10,000 to 25,000 units per mL concentration. - For the treatment of P. aeruginosa infections of the eye, a concentration of 0.1 percent to 0.25 percent (10,000 units to 25,000 units per mL) is administered 1 to 3 drops every hour, increasing the intervals as response indicates. - Subconjunctival injection of up to 100,000 units/day may be used for the treatment of P. aeruginosa infections of the cornea and conjunctiva. - Note: Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day. ## Off-Label Use and Dosage (Pediatric) # Contraindications - This drug is contraindicated in persons with a prior history of hypersensitivity reactions to polymyxins. # Warnings - Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Polymyxin B for Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD.Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. ### Precautions - Prescribing polymyxin B 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 - Albuminuria, cylinduria, azotemia, and rising blood levels without any increase in dosage. - Facial flushing, dizziness progressing to ataxia, drowsiness, peripheral paresthesias (circumoral and stocking glove), apnea due to concurrent use of curariform muscle relaxants, other neurotoxic drugs or inadvertent overdosage, and signs of meningeal irritation with intrathecal administration, e.g., fever, headache, stiff neck and increased cell count and protein cerebrospinal fluid. - Other reactions occasionally reported: Drug fever, urticarial rash, pain (severe) at intramuscular injection sites, and thrombophlebitis at intravenous injection sites. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Polymyxin B in the drug label. # Drug Interactions - Avoid concurrent use of a curariform muscle relaxant and other neurotoxic drugs (ether, tubocurarine, succinylcholine, gallamine, decamethonium and sodium citrate) which may precipitate respiratory depression. If signs of respiratory paralysis appear, respiration should be assisted as required, and the drug discontinued. - As with other antibiotics, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. - If superinfection occurs, appropriate therapy should be instituted. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): THE SAFETY OF THIS DRUG IN HUMAN PREGNANCY HAS NOT BEEN ESTABLISHED. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Polymyxin B in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Polymyxin B during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Polymyxin B with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Polymyxin B with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Polymyxin B with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Polymyxin B with respect to specific gender populations. ### Race There is no FDA guidance on the use of Polymyxin B with respect to specific racial populations. ### Renal Impairment PATIENTS WITH RENAL DAMAGE AND NITROGEN RETENTION SHOULD HAVE REDUCED DOSAGE. NEUROTOXIC REACTIONS MAY BE MANIFESTED BY IRRITABILITY, WEAKNESS, DROWSINESS, ATAXIA, PERIORAL PARESTHESIA, NUMBNESS OF THE EXTREMITIES, AND BLURRING OF VISION. THESE ARE USUALLY ASSOCIATED WITH HIGH SERUM LEVELS FOUND IN PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR NEPHROTOXICITY. ### Hepatic Impairment There is no FDA guidance on the use of Polymyxin B in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Polymyxin B in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Polymyxin B in patients who are immunocompromised. # Administration and Monitoring ### Administration - Parenteral - Intravenous - Intramuscular - Intrathecal - Topical - Ophthalmic ### Monitoring Baseline renal function should be done prior to therapy, with frequent monitoring of renal function and blood levels of the drug during parenteral therapy. # IV Compatibility There is limited information regarding IV Compatibility of Polymyxin B in the drug label. # Overdosage Inadvertent overdosage can cause Neurotoxic reactions: Facial flushing, dizziness progressing to ataxia, drowsiness, peripheral paresthesias (circumoral and stocking glove), apnea # Pharmacology ## Mechanism of Action - Polymyxin B sulfate has a bactericidal action against almost all gram-negative bacilli except the Proteus group. Polymyxins increase the permeability of the bacterial cell membrane leading to death of the cell. All gram-positive bacteria, fungi, and the gram-negative cocci, are resistant to polymyxin B. Appropriate methods should be used when performing in vitro susceptibility testing of polymyxin B 1,2,3. The following in vitro susceptibility test criteria should only be used for interpreting the results of polymyxin B susceptibility testing against P. aeruginosa when the indicated quality control parameters are met during testing. ## Structure - Polymyxin B for Injection, USP is one of a group of basic polypeptide antibiotics derived from B polymyxa (B aerosporous). Polymyxin B sulfate is the sulfate salt of Polymyxins B1 and B2, which are produced by the growth of Bacillus polymyxa (Prazmowski) Migula (Fam. Bacillacea). It has a potency of not less than 6,000 polymyxin B units per mg, calculated on the anhydrous basis. The structural formulae are: Each vial contains 500,000 polymyxin B units for parenteral or ophthalmic administration. Polymyxin B for Injection, USP is in powder form suitable for preparation of sterile solutions for intramuscular, intravenous drip, intrathecal, or ophthalmic use. In the medical literature, dosages have frequently been given in terms of equivalent weights of pure polymyxin B base. Each milligram of pure polymyxin B base is equivalent to 10,000 units of polymyxin B and each microgram of pure polymyxin B base is equivalent to 10 units of polymyxin B. Aqueous solutions of polymyxin B sulfate may be stored up to 12 months without significant loss of potency if kept under refrigeration. In the interest of safety, solutions for parenteral use should be stored under refrigeration and any unused portion should be discarded after 72 hours. Polymyxin B sulfate should not be stored in alkaline solutions since they are less stable. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Polymyxin B in the drug label. ## Pharmacokinetics Polymyxin B sulfate is not absorbed from the normal alimentary tract. Since the drug loses 50 percent of its activity in the presence of serum, active blood levels are low. Repeated injections may give a cumulative effect. Levels tend to be higher in infants and children. The drug is excreted slowly by the kidneys. Tissue diffusion is poor and the drug does not pass the blood brain barrier into the cerebrospinal fluid. In therapeutic dosage, polymyxin B sulfate causes some nephrotoxicity with tubule damage to a slight degree. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Polymyxin B in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Polymyxin B in the drug label. # How Supplied - Polymyxin B for Injection, USP, 500,000 polymyxin B units per vial is supplied as follows. ## Storage - Store at 20° to 25°C (68° to 77°F)[see USP Controlled Room Temperature]. - Retain in carton until time of use. - Product must be stored under refrigeration, between 2° to 8°C (36° to 46°F) and any unused portion should be discarded after 72 hours. - This container closure is not made with natural rubber latex. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be counseled that antibacterial drugs including polymyxin B should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When polymyxin B 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 polymyxin B or other antibacterial drugs in the future. - Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. # Precautions with Alcohol - Alcohol-Polymyxin B interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Polymyxin_B
9b710d570052b69807c598dcda514eb2457928a1	wikidoc	Pomegranate	Pomegranate The pomegranate (Punica granatum) is a fruit-bearing deciduous shrub or small tree growing to 5–8 m tall. The pomegranate is native to the region from Afghanistan, Pakistan, and Iran to the Himalayas in northern India and has been cultivated and naturalized over the whole Mediterranean region and the Caucasus since ancient times. It is widely cultivated throughout Armenia, Azerbaijan, Iran, India, Turkey, the drier parts of southeast Asia, Peninsular Malaysia, the East Indies, and tropical Africa. Introduced into Latin America and California by Spanish settlers in 1769, pomegranate is now cultivated in parts of California and Arizona for juice production. In the functional food industry, pomegranate is included in a novel category of exotic fruits called superfruits. In the Northern Hemisphere, the fruit is typically in season from September to January. In the Southern Hemisphere, it is in season from March to May. # Foliage and fruit The leaves are opposite or sub-opposite, glossy, narrow oblong, entire, 3–7 cm long and 2 cm broad. The flowers are bright red, 3 cm in diameter, with four to five petals (often more on cultivated plants). The fruit is between a lemon and a grapefruit in size, 5–12 cm in diameter with a rounded hexagonal shape, and has thick reddish skin and around 600 seeds. The seeds and surrounding pulp, ranging in colour from white to deep red, called arils, are edible; indeed, the fruit of the pomegranate is a berry. There are some cultivars which have been introduced that have a range of pulp colours such as purple. Punica granatum nana is a dwarf variety of P. granatum popularly used as Bonsai trees and as a patio plant. The only other species in the genus Punica is the Socotran pomegranate (Punica protopunica), which is endemic to the island of Socotra. It differs in having pink (not red) flowers and smaller, less sweet fruit. Pomegranates are drought tolerant, and can be grown in dry areas with either a Mediterranean winter rainfall climate or in summer rainfall climates. In wetter areas, they are prone to root decay from fungal diseases. They are tolerant of moderate frost, down to about −10°C (14°F). # Etymology The name "pomegranate" derives from Latin pomum ("apple") and granatus ("seeded"). This has influenced the common name for pomegranate in many languages (e.g. German Granatapfel, seeded apple). The genus name Punica is named for the Phoenicians, who were active in broadening its cultivation, partly for religious reasons. In classical Latin, where "malum" was broadly applied to many apple-like fruits, the pomegranate's name was malum punicum or malum granatum, the latter giving rise to the Italian name melograno, or less commonly melagrana. A widespread root for "pomegranate" comes from the Ancient Egyptian rmn, from which derive the Hebrew rimmôn, and Arabic rummân. This root was given by Arabs to other languages, including Portuguese (romã), Kabyle rrumman and Maltese "rummien". The pomegranate ('rimmôn') is mentioned in the Bible as one of the seven fruits/plants that Israel was blessed with, and in Hebrew, 'rimmôn' is also the name of the weapon now called the grenade. According to the OED, the word grenade originated about 1532 from the French name for the pomegranate, la grenade. La grenade also gives us the word grenadine, the name of a kind of fruit syrup, originally made from pomegranates, which is widely used as a cordial and in cocktails. Even though this fruit does not originate from China, one common nickname is "Chinese apple." In German and Dutch, the term "Chinese Apple" (apfelsine in German), refers to the orange # Cultivation and uses The pomegranate originated from Persia and has been cultivated in Georgia, Armenia and the Mediterranean region for several millennia. In Georgia, Armenia and Turkey to the east of the Black Sea, there are wild pomegranate groves outside of ancient abandoned settlements. The cultivation of the pomegranate has a long history in Armenia and Turkey, where decayed remains of pomegranates dating back to 1000 BC have been found. Carbonized exocarp of the fruit has been identified in Early Bronze Age levels of Jericho, as well as Late Bronze Age levels of Hala Sultan Tekke on Cyprus and Tiryns. A large, dry pomegranate was found in the tomb of Djehuty, the butler of Queen Hatshepsut; Mesopotamian cuneiform records mention pomegranates from the mid-Third millennium BC onwards. It is also extensively grown in South China and in Southeast Asia, whether originally spread along the route of the Silk Road or brought by sea traders. The ancient city of Granada in Spain was renamed after the fruit during the Moorish period. Spanish colonists later introduced the fruit to the Caribbean and Latin America, but in the English colonies it was less at home: "Don't use the pomegranate inhospitably, a stranger that has come so far to pay his respects to thee," the English Quaker Peter Collinson wrote to the botanizing John Bartram in Philadelphia, 1762. "Plant it against the side of thy house, nail it close to the wall. In this manner it thrives wonderfully with us, and flowers beautifully, and bears fruit this hot year. I have twenty-four on one tree... Doctor Fothergill says, of all trees this is most salutiferous to mankind." The pomegranate had been introduced as an exotic to England the previous century, by John Tradescant the elder, but the disappointment that it did not set fruit there led to its repeated introduction to the American colonies, even New England. It succeeded in the South: Bartram received a barrel of pomegranates and oranges from a correspondent in Charleston, South Carolina, 1764. Thomas Jefferson planted pomegranates at Monticello in 1771: he had them from George Wythe of Williamsburg. ## Culinary use After opening the pomegranate by scoring it with a knife and breaking it open, the arils (seed casings) are separated from the peel (fruit) and internal white pulp membranes. Separating the red arils is simplified by performing this task in a bowl of water, whereby arils sink and pulp floats. The entire seed is consumed raw, though the watery, tasty aril is the part desired. The taste differs depending on subspecies of pomegranate and its ripeness. It can be very sweet or sour, but most fruits are moderate in taste, with sour notes from the acidic tannins contained in the aril juice. Having begun wide distribution in the United States and Canada in 2002, pomegranate juice has long been a popular drink in Middle Eastern and Indian cuisine where it particularly is used in preparation of curd rice (telugu) or dadhojanam of Andhra Pradesh, India. Grenadine syrup is thickened and sweetened pomegranate juice used in cocktail mixing. Before tomato arrived in the Middle East, grenadine was widely used in many Iranian foods and is still found in traditional recipes such as fesenjan, a thick sauce made from pomegranate juice and ground walnuts, usually spooned over duck or other poultry and rice, and in ash-e anar (pomegranate soup). Wild pomegranate seeds are sometimes used as a spice known as anardana (which literally means pomegranate (anar) seeds (dana) in Persian), most notably in Indian and Pakistani cuisine but also as a replacement for pomegranate syrup in Middle Eastern cuisine. As a result of this, the dried whole seeds can often be obtained in ethnic markets. The seeds are separated from the flesh, dried for 10–15 days and used as an acidic agent for chutney and curry production. Seeds may also be ground in order to avoid becoming stuck in teeth when eating dishes containing them. Seeds of the wild pomegranate daru from the Himalayas are regarded as quality sources for this spice. In Armenia and the Caucasus, pomegranate (Armenian: nur) is used mainly as juice. In Turkey, pomegranate sauce, (Turkish: nar ekşisi) is used as a salad dressing, to marinate meat, or simply to drink straight. Pomegranate seeds are also used in salads and sometimes as garnish for desserts such as güllaç. Pomegranate syrup or molasses is used in muhammara, a roasted red pepper, walnut, and garlic spread popular in Syria and Turkey. In Azerbaijan and Armenia, pomegranate is used to make high-quality wine, some of which is exported. In Greece, pomegranate (Greek: ροδι, rodi) is used in many recipes, including kollivozoumi, a creamy broth made from boiled wheat, pomegranates and raisins, legume salad with wheat and pomegranate, traditional Middle Eastern lamb kebabs with pomegranate glaze, pomegranate eggplant relish, and avocado-pomegranate dip. Pomegranate is also made into a liqueur and popular fruit confectionery used as ice cream topping or mixed with yogurt or spread as jam on toast. In Cyprus, ροδι is used to make kolliva, a mixture of wheat, pomegranate seeds, sugar, almonds and other seeds. ## Potential health benefits Pomegranate aril juice provides about 16% of an adult's daily vitamin C requirement per 100 ml serving, and is a good source of vitamin B5 (pantothenic acid), potassium and antioxidant polyphenols. The most abundant polyphenols in pomegranate juice are the hydrolyzable tannins called punicalagins which have free-radical scavenging properties. Punicalagins are absorbed into the human body and may have dietary value as antioxidants. Many food and dietary supplement makers have found advantages of using pomegranate phenolic extracts instead of the juice as ingredients in their products. Many pomegranate extracts are essentially ellagic acid which may absorb into the body only after parent molecule polyphenolic punicalagins are consumed. In preliminary laboratory research and human pilot studies, juice of the pomegranate has been found effective in reducing heart disease risk factors, including LDL oxidation, macrophage oxidative status, and foam cell formation, all of which are steps in atherosclerosis and cardiovascular disease. Tannins such as punicalagins have been identified as the primary components responsible for the reduction of oxidative stress which led to these risk factors. Pomegranate has been shown to reduce systolic blood pressure by inhibiting serum angiotensin-converting enzyme (ACE). Containing polyphenols which inhibit estrogen synthesis, pomegranate seed oil was effective against proliferation of breast cancer cells in vitro. The juice may also have antiviral and antibacterial effects against dental plaque. ### Clinical trial rationale and activity Metabolites of pomegranate juice ellagitannins localize specifically in the prostate gland, colon and intestinal tissues of mice, leading to speculation that pomegranate juice or fruit extracts may be effective against prostate cancer, lung cancer or osteoarthritis. In 2008, 10 clinical trials in the United States, Israel and Norway were underway to examine the effects of pomegranate juice consumption on various diseases, such as prostate cancer or prostatic hyperplasia, diabetes or lymphoma. Nine studies have not concluded (April 2008) but interim reports released to the public media were that pomegranate juice may slow onset or development of prostate cancer (above). Additionally, a 461 patient phase III clinical study of the potential benefits of 16 weeks of consuming pomegranate juice concentrate against the influenza virus and common cold completed in June 2007, with no results yet reported. # Pomegranates and symbolism Exodus 28:33–34 directed that images of pomegranates be woven onto the borders of Hebrew priestly robes. 1 Kings 7:13–22 describes pomegranates depicted in the temple King Solomon built in Jerusalem. Jewish tradition teaches that the pomegranate is a symbol for righteousness, because it is said to have 613 seeds which corresponds with the 613 mitzvot or commandments of the Torah. However, the actual number of seeds varies with individual fruits. For this reason and others, many Jews eat pomegranates on Rosh Hashanah. The pomegranate is one of the few images which appear on ancient coins of Judea as a holy symbol, and today many Torah scrolls are stored while not in use with a pair of decorative hollow silver "pomegranates" (rimmonim) slid down over the two upper scroll handles. Some Jewish scholars believe that it was the pomegranate, not the apple, that was the forbidden fruit of the Garden of Eden For the same reason, pomegranates are a motif found in Christian religious decoration. They are often woven into the fabric on vestments and liturgical hangings or wrought in metalwork. The wild pomegranate did not grow natively in the Aegean area in Neolithic times. It originated in eastern Iran and came to the Aegean world along the same cultural pathways that brought the goddess whom the Anatolians worshipped as Cybele and the Mesopotamians as Ishtar. The myth of Persephone, the dark goddess of the Underworld, also prominently features the pomegranate. In one version of Greek mythology, Persephone was kidnapped by Hades and taken off to live in the underworld as his wife. Her mother, Demeter (goddess of the Harvest), went into mourning for her lost daughter and thus all green things ceased to grow. Zeus, the highest ranking of the Greek gods, could not leave the Earth to die, so he commanded Hades to return Persephone. It was the rule of the Fates that anyone who consumed food or drink in the Underworld was doomed to spend eternity there. Persephone had no food, but Hades tricked her into eating four pomegranate seeds while she was still his prisoner and so, because of this, she was condemned to spend four months in the Underworld every year. During these four months, when Persephone is sitting on the throne of the Underworld next to her husband Hades, her mother Demeter mourns and no longer gives fertility to the earth. This became an ancient Greek explanation for the seasons. Dante Gabriel Rossetti's painting Persephona depicts Persephone holding the fatal fruit. It should be noted that the number of seeds that Persephone ate is varied, depending on which version of the story is told. The number of seeds she is said to have eaten ranges from three to seven, which accounts for just one barren season if it is just three or four seeds, or two barren seasons (half the year) if she ate six or seven seeds. There is no set number. The pomegranate also evoked the presence of the Aegean Triple Goddess who evolved into the Olympian Hera, who is sometimes represented offering the pomegranate, as in the Polykleitos' cult image of the Argive Heraion (see below). According to Carl A. P. Ruck and Danny Staples, the chambered pomegranate is also a surrogate for the poppy's narcotic capsule, with its comparable shape and chambered interior. On a Mycenaean seal illustrated in Joseph Campbell's Occidental Mythology 1964, figure 19, the seated Goddess of the double-headed axe (the labrys) offers three poppy pods in her right hand and supports her breast with her left. She embodies both aspects of the dual goddess, life-giving and death-dealing at once. The Titan Orion was represented as "marrying" Side, a name that in Boeotia means "pomegranate", thus consecrating the primal hunter to the Goddess. Other Greek dialects call the pomegranate rhoa; its possible connection with the name of the earth goddess Rhea, inexplicable in Greek, proved suggestive for the mythographer Karl Kerenyi, who suggested that the consonance might ultimately derive from a deeper, pre-Indo-European language layer. In the 6th century BC, Polykleitos took ivory and gold to sculpt the seated Argive Hera in her temple. She held a scepter in one hand and offered a pomegranate, like a royal orb, in the other. "About the pomegranate I must say nothing," whispered the traveller Pausanias in the 2nd century, "for its story is something of a mystery." Indeed, in the Orion story we hear that Hera cast pomegranate-Side (an ancient city in Antalya) into dim Erebus — "for daring to rival Hera's beauty", which forms the probable point of connection with the older Osiris/Isis story. Since the ancient Egyptians identified the Orion constellation in the sky as Sah the "soul of Osiris", the identification of this section of the myth seems relatively complete. Hera wears, not a wreath nor a tiara nor a diadem, but clearly the calyx of the pomegranate that has become her serrated crown. In some artistic depictions, the pomegranate is found in the hand of Mary, mother of Jesus. In modern times the pomegranate still holds strong symbolic meanings for the Greeks. On important days in the Greek Orthodox calendar, such as the Presentation of the Virgin Mary and on Christmas Day, it is traditional to have at the dinner table "polysporia", also known by their ancient name "panspermia," in some regions of Greece. In ancient times they were offered to Demeter and to the other gods for fertile land, for the spirits of the dead and in honor of compassionate Dionysus. When one buys a new home, it is conventional for a house guest to bring as a first gift a pomegranate, which is placed under/near the ikonostasi, (home altar), of the house, as it is a symbol of abundance, fertility and good luck. Pomegranates are also prominent at Greek weddings and funerals. When Greeks commemorate their dead, they make kollyva as offerings, which consist of boiled wheat, mixed with sugar and decorated with pomegranate. It is also traditional in Greece to break a pomegranate on the ground at weddings and on New Years. Pomegranate decorations for the home are very common in Greece and sold in most homegoods stores . # Other - The pomegranate is the symbol and heraldic device of the city of Granada in Andalusia, Spain. - In South Africa, the pomegranate is sometimes referred to as 'the poor man's cranberry'. - Pomegranate is one of the symbols of Armenia, representing fertility, abundance and marriage. - It is the official logo of many cities in Turkey. - The Immortals, an elite infantry unit in ancient Persia, had spears with pomegranate-shaped counterweights at the butt made of gold (for officers) and silver (for regular infantry). In modern Iran the fruit is still believed to a give long and healthy life. - The Qur'an mentions pomegranates three times (6:99, 6:141, 55:068) — twice as examples of the good things God creates, once as a fruit found in the Garden of Paradise. - Pomegranate juice is used for natural dyeing of non-synthetic fabrics. - Pomegranate juice is sold in the USA under several labels, and is available in health food stores and supermarkets across the country. - Pomegranate juice will turn blue when subjected to basic (ie alkaline) conditions (similar to litmus paper). - Although not native to China, Korea or Japan, the pomegranate is widely grown there and many cultivars have been developed. It is widely used for bonsai, because of its flowers and for the unusual twisted bark that older specimens can attain. - Balaustines are the red rose-like flowers of the pomegranate, which are very bitter to the taste. In medicine, its dried form has been used as an astringent. (The term "balaustine" (Latin: balaustinus) is also used for a pomegranate-red colour.) - The pomegranate was the personal emblem of the Holy Roman Emperor, Maximilian I, and of Catherine of Aragon. - With the rise in popularity of the pomegranate in American markets, Starbucks introduced a pomegranate frappuccino in the summer of 2006. - The pomegranate is a divine symbol in Pinto Ricardo's series, The Stone Dance of the Chameleon. - The pomegranate is also called the Food of the Dead. - In Orthodox Christian memorial services pomegranate seeds will often be put in the koliva which is blessed after the service and eaten by all of the mourners. - In the Hindu epic Caitanya-caritamrita (Adi-lila, 5.188), Sri Nityananda's teeth were described as resembling pomegranate seeds. - In Mexico, they are an essential ingredient of chiles en nogada, one of its most important national dishes, used to symbolize the red component of the national flag. - Kandahar is famous all over Afghanistan for its high quality pomegranates. - The pomegranate is also known as a Wine Apple in Ireland.	Pomegranate The pomegranate (Punica granatum) is a fruit-bearing deciduous shrub or small tree growing to 5–8 m tall. The pomegranate is native to the region from Afghanistan, Pakistan, and Iran to the Himalayas in northern India and has been cultivated and naturalized over the whole Mediterranean region and the Caucasus since ancient times. It is widely cultivated throughout Armenia, Azerbaijan, Iran, India, Turkey, the drier parts of southeast Asia, Peninsular Malaysia, the East Indies, and tropical Africa. Introduced into Latin America and California by Spanish settlers in 1769, pomegranate is now cultivated in parts of California and Arizona for juice production. [1][2] In the functional food industry, pomegranate is included in a novel category of exotic fruits called superfruits[3]. In the Northern Hemisphere, the fruit is typically in season from September to January.[4] In the Southern Hemisphere, it is in season from March to May. # Foliage and fruit The leaves are opposite or sub-opposite, glossy, narrow oblong, entire, 3–7 cm long and 2 cm broad. The flowers are bright red, 3 cm in diameter, with four to five petals (often more on cultivated plants). The fruit is between a lemon and a grapefruit in size, 5–12 cm in diameter with a rounded hexagonal shape, and has thick reddish skin and around 600 seeds.[5] The seeds and surrounding pulp, ranging in colour from white to deep red, called arils, are edible; indeed, the fruit of the pomegranate is a berry. There are some cultivars which have been introduced that have a range of pulp colours such as purple. Punica granatum nana is a dwarf variety of P. granatum popularly used as Bonsai trees and as a patio plant. The only other species in the genus Punica is the Socotran pomegranate (Punica protopunica), which is endemic to the island of Socotra. It differs in having pink (not red) flowers and smaller, less sweet fruit. Pomegranates are drought tolerant, and can be grown in dry areas with either a Mediterranean winter rainfall climate or in summer rainfall climates. In wetter areas, they are prone to root decay from fungal diseases. They are tolerant of moderate frost, down to about −10°C (14°F). # Etymology Template:Nutritionalvalue The name "pomegranate" derives from Latin pomum ("apple") and granatus ("seeded"). This has influenced the common name for pomegranate in many languages (e.g. German Granatapfel, seeded apple). The genus name Punica is named for the Phoenicians, who were active in broadening its cultivation, partly for religious reasons. In classical Latin, where "malum" was broadly applied to many apple-like fruits, the pomegranate's name was malum punicum or malum granatum, the latter giving rise to the Italian name melograno, or less commonly melagrana. A widespread root for "pomegranate" comes from the Ancient Egyptian rmn, from which derive the Hebrew rimmôn, and Arabic rummân. This root was given by Arabs to other languages, including Portuguese (romã)[6], Kabyle rrumman and Maltese "rummien". The pomegranate ('rimmôn') is mentioned in the Bible as one of the seven fruits/plants that Israel was blessed with, and in Hebrew, 'rimmôn' is also the name of the weapon now called the grenade. According to the OED, the word grenade originated about 1532 from the French name for the pomegranate, la grenade. La grenade also gives us the word grenadine, the name of a kind of fruit syrup, originally made from pomegranates, which is widely used as a cordial and in cocktails. Even though this fruit does not originate from China, one common nickname is "Chinese apple." In German and Dutch, the term "Chinese Apple" (apfelsine in German), refers to the orange # Cultivation and uses The pomegranate originated from Persia and has been cultivated in Georgia, Armenia and the Mediterranean region for several millennia.[7] In Georgia, Armenia and Turkey to the east of the Black Sea, there are wild pomegranate groves outside of ancient abandoned settlements. The cultivation of the pomegranate has a long history in Armenia and Turkey, where decayed remains of pomegranates dating back to 1000 BC have been found. [8] Carbonized exocarp of the fruit has been identified in Early Bronze Age levels of Jericho, as well as Late Bronze Age levels of Hala Sultan Tekke on Cyprus and Tiryns[citation needed]. A large, dry pomegranate was found in the tomb of Djehuty, the butler of Queen Hatshepsut; Mesopotamian cuneiform records mention pomegranates from the mid-Third millennium BC onwards.[9] It is also extensively grown in South China and in Southeast Asia, whether originally spread along the route of the Silk Road or brought by sea traders. The ancient city of Granada in Spain was renamed after the fruit during the Moorish period. Spanish colonists later introduced the fruit to the Caribbean and Latin America, but in the English colonies it was less at home: "Don't use the pomegranate inhospitably, a stranger that has come so far to pay his respects to thee," the English Quaker Peter Collinson wrote to the botanizing John Bartram in Philadelphia, 1762. "Plant it against the side of thy house, nail it close to the wall. In this manner it thrives wonderfully with us, and flowers beautifully, and bears fruit this hot year. I have twenty-four on one tree... Doctor Fothergill says, of all trees this is most salutiferous to mankind."[10] The pomegranate had been introduced as an exotic to England the previous century, by John Tradescant the elder, but the disappointment that it did not set fruit there led to its repeated introduction to the American colonies, even New England. It succeeded in the South: Bartram received a barrel of pomegranates and oranges from a correspondent in Charleston, South Carolina, 1764. Thomas Jefferson planted pomegranates at Monticello in 1771: he had them from George Wythe of Williamsburg.[11] ## Culinary use After opening the pomegranate by scoring it with a knife and breaking it open, the arils (seed casings) are separated from the peel (fruit) and internal white pulp membranes. Separating the red arils is simplified by performing this task in a bowl of water, whereby arils sink and pulp floats. The entire seed is consumed raw, though the watery, tasty aril is the part desired. The taste differs depending on subspecies of pomegranate and its ripeness. It can be very sweet or sour, but most fruits are moderate in taste, with sour notes from the acidic tannins contained in the aril juice. Having begun wide distribution in the United States and Canada in 2002, pomegranate juice has long been a popular drink in Middle Eastern and Indian cuisine[13] where it particularly is used in preparation of curd rice (telugu) or dadhojanam of Andhra Pradesh, India. Grenadine syrup is thickened and sweetened pomegranate juice used in cocktail mixing. Before tomato arrived in the Middle East, grenadine was widely used in many Iranian foods and is still found in traditional recipes such as fesenjan, a thick sauce made from pomegranate juice and ground walnuts, usually spooned over duck or other poultry and rice, and in ash-e anar (pomegranate soup). [14] Wild pomegranate seeds are sometimes used as a spice known as anardana (which literally means pomegranate (anar) seeds (dana) in Persian), most notably in Indian and Pakistani cuisine but also as a replacement for pomegranate syrup in Middle Eastern cuisine. As a result of this, the dried whole seeds can often be obtained in ethnic markets. The seeds are separated from the flesh, dried for 10–15 days and used as an acidic agent for chutney and curry production. Seeds may also be ground in order to avoid becoming stuck in teeth when eating dishes containing them. Seeds of the wild pomegranate daru from the Himalayas are regarded as quality sources for this spice. In Armenia and the Caucasus, pomegranate (Armenian: nur) is used mainly as juice.[12] In Turkey, pomegranate sauce, (Turkish: nar ekşisi) is used as a salad dressing, to marinate meat, or simply to drink straight. Pomegranate seeds are also used in salads and sometimes as garnish for desserts such as güllaç.[13] Pomegranate syrup or molasses is used in muhammara, a roasted red pepper, walnut, and garlic spread popular in Syria and Turkey.[14] In Azerbaijan and Armenia, pomegranate is used to make high-quality wine, some of which is exported. In Greece, pomegranate (Greek: ροδι, rodi) is used in many recipes, including kollivozoumi, a creamy broth made from boiled wheat, pomegranates and raisins, legume salad with wheat and pomegranate, traditional Middle Eastern lamb kebabs with pomegranate glaze, pomegranate eggplant relish, and avocado-pomegranate dip. Pomegranate is also made into a liqueur and popular fruit confectionery used as ice cream topping or mixed with yogurt or spread as jam on toast. In Cyprus, ροδι is used to make kolliva, a mixture of wheat, pomegranate seeds, sugar, almonds and other seeds. ## Potential health benefits Pomegranate aril juice provides about 16% of an adult's daily vitamin C requirement per 100 ml serving, and is a good source of vitamin B5 (pantothenic acid), potassium and antioxidant polyphenols.[15] The most abundant polyphenols in pomegranate juice are the hydrolyzable tannins called punicalagins which have free-radical scavenging properties.[16] Punicalagins are absorbed into the human body and may have dietary value as antioxidants.[17][18] Many food and dietary supplement makers have found advantages of using pomegranate phenolic extracts instead of the juice as ingredients in their products. Many pomegranate extracts are essentially ellagic acid which may absorb into the body only after parent molecule polyphenolic punicalagins are consumed. In preliminary laboratory research and human pilot studies, juice of the pomegranate has been found effective in reducing heart disease risk factors, including LDL oxidation, macrophage oxidative status, and foam cell formation,[19] all of which are steps in atherosclerosis and cardiovascular disease. Tannins such as punicalagins have been identified as the primary components responsible for the reduction of oxidative stress which led to these risk factors.[20] Pomegranate has been shown to reduce systolic blood pressure by inhibiting serum angiotensin-converting enzyme (ACE).[21] Containing polyphenols which inhibit estrogen synthesis, pomegranate seed oil was effective against proliferation of breast cancer cells in vitro.[22] The juice may also have antiviral[23] and antibacterial effects against dental plaque.[24] ### Clinical trial rationale and activity Metabolites of pomegranate juice ellagitannins localize specifically in the prostate gland, colon and intestinal tissues of mice,[25] leading to speculation that pomegranate juice or fruit extracts may be effective against prostate cancer, lung cancer[26][27] or osteoarthritis.[28][29] In 2008, 10 clinical trials in the United States, Israel and Norway were underway to examine the effects of pomegranate juice consumption on various diseases, such as prostate cancer or prostatic hyperplasia, diabetes or lymphoma.[30] Nine studies have not concluded (April 2008) but interim reports released to the public media were that pomegranate juice may slow onset or development of prostate cancer (above). Additionally, a 461 patient phase III clinical study of the potential benefits of 16 weeks of consuming pomegranate juice concentrate against the influenza virus and common cold completed in June 2007, with no results yet reported.[31] # Pomegranates and symbolism Exodus 28:33–34 directed that images of pomegranates be woven onto the borders of Hebrew priestly robes. 1 Kings 7:13–22 describes pomegranates depicted in the temple King Solomon built in Jerusalem. Jewish tradition teaches that the pomegranate is a symbol for righteousness, because it is said to have 613 seeds which corresponds with the 613 mitzvot or commandments of the Torah. However, the actual number of seeds varies with individual fruits.[32] For this reason and others, many Jews eat pomegranates on Rosh Hashanah. The pomegranate is one of the few images which appear on ancient coins of Judea as a holy symbol, and today many Torah scrolls are stored while not in use with a pair of decorative hollow silver "pomegranates" (rimmonim) slid down over the two upper scroll handles. Some Jewish scholars believe that it was the pomegranate, not the apple, that was the forbidden fruit of the Garden of Eden[15] For the same reason, pomegranates are a motif found in Christian religious decoration. They are often woven into the fabric on vestments and liturgical hangings or wrought in metalwork. The wild pomegranate did not grow natively in the Aegean area in Neolithic times. It originated in eastern Iran and came to the Aegean world along the same cultural pathways that brought the goddess whom the Anatolians worshipped as Cybele and the Mesopotamians as Ishtar. The myth of Persephone, the dark goddess of the Underworld, also prominently features the pomegranate. In one version of Greek mythology, Persephone was kidnapped by Hades and taken off to live in the underworld as his wife. Her mother, Demeter (goddess of the Harvest), went into mourning for her lost daughter and thus all green things ceased to grow. Zeus, the highest ranking of the Greek gods, could not leave the Earth to die, so he commanded Hades to return Persephone. It was the rule of the Fates that anyone who consumed food or drink in the Underworld was doomed to spend eternity there. Persephone had no food, but Hades tricked her into eating four pomegranate seeds while she was still his prisoner and so, because of this, she was condemned to spend four months in the Underworld every year. During these four months, when Persephone is sitting on the throne of the Underworld next to her husband Hades, her mother Demeter mourns and no longer gives fertility to the earth. This became an ancient Greek explanation for the seasons. Dante Gabriel Rossetti's painting Persephona depicts Persephone holding the fatal fruit. It should be noted that the number of seeds that Persephone ate is varied, depending on which version of the story is told. The number of seeds she is said to have eaten ranges from three to seven, which accounts for just one barren season if it is just three or four seeds, or two barren seasons (half the year) if she ate six or seven seeds. There is no set number. The pomegranate also evoked the presence of the Aegean Triple Goddess who evolved into the Olympian Hera, who is sometimes represented offering the pomegranate, as in the Polykleitos' cult image of the Argive Heraion (see below). According to Carl A. P. Ruck and Danny Staples, the chambered pomegranate is also a surrogate for the poppy's narcotic capsule, with its comparable shape and chambered interior.[33] On a Mycenaean seal illustrated in Joseph Campbell's Occidental Mythology 1964, figure 19, the seated Goddess of the double-headed axe (the labrys) offers three poppy pods in her right hand and supports her breast with her left. She embodies both aspects of the dual goddess, life-giving and death-dealing at once. The Titan Orion was represented as "marrying" Side, a name that in Boeotia means "pomegranate", thus consecrating the primal hunter to the Goddess. Other Greek dialects call the pomegranate rhoa; its possible connection with the name of the earth goddess Rhea, inexplicable in Greek, proved suggestive for the mythographer Karl Kerenyi, who suggested that the consonance might ultimately derive from a deeper, pre-Indo-European language layer. In the 6th century BC, Polykleitos took ivory and gold to sculpt the seated Argive Hera in her temple. She held a scepter in one hand and offered a pomegranate, like a royal orb, in the other. "About the pomegranate I must say nothing," whispered the traveller Pausanias in the 2nd century, "for its story is something of a mystery." Indeed, in the Orion story we hear that Hera cast pomegranate-Side (an ancient city in Antalya) into dim Erebus — "for daring to rival Hera's beauty", which forms the probable point of connection with the older Osiris/Isis story. Since the ancient Egyptians identified the Orion constellation in the sky as Sah the "soul of Osiris", the identification of this section of the myth seems relatively complete. Hera wears, not a wreath nor a tiara nor a diadem, but clearly the calyx of the pomegranate that has become her serrated crown.[34] In some artistic depictions, the pomegranate is found in the hand of Mary, mother of Jesus. In modern times the pomegranate still holds strong symbolic meanings for the Greeks. On important days in the Greek Orthodox calendar, such as the Presentation of the Virgin Mary and on Christmas Day, it is traditional to have at the dinner table "polysporia", also known by their ancient name "panspermia," in some regions of Greece. In ancient times they were offered to Demeter[citation needed] and to the other gods for fertile land, for the spirits of the dead and in honor of compassionate Dionysus. When one buys a new home, it is conventional for a house guest to bring as a first gift a pomegranate, which is placed under/near the ikonostasi, (home altar), of the house, as it is a symbol of abundance, fertility and good luck. Pomegranates are also prominent at Greek weddings and funerals. When Greeks commemorate their dead, they make kollyva as offerings, which consist of boiled wheat, mixed with sugar and decorated with pomegranate. It is also traditional in Greece to break a pomegranate on the ground at weddings and on New Years. Pomegranate decorations for the home are very common in Greece and sold in most homegoods stores [16]. # Other Template:Unreferencedsection - The pomegranate is the symbol and heraldic device of the city of Granada in Andalusia, Spain. - In South Africa, the pomegranate is sometimes referred to as 'the poor man's cranberry'. - Pomegranate is one of the symbols of Armenia, representing fertility, abundance and marriage. - It is the official logo of many cities in Turkey. - The Immortals, an elite infantry unit in ancient Persia, had spears with pomegranate-shaped counterweights at the butt made of gold (for officers) and silver (for regular infantry). In modern Iran the fruit is still believed to a give long and healthy life.[citation needed] - The Qur'an mentions pomegranates three times (6:99, 6:141, 55:068) — twice as examples of the good things God creates, once as a fruit found in the Garden of Paradise. - Pomegranate juice is used for natural dyeing of non-synthetic fabrics. - Pomegranate juice is sold in the USA under several labels, and is available in health food stores and supermarkets across the country. - Pomegranate juice will turn blue when subjected to basic (ie alkaline) conditions (similar to litmus paper). - Although not native to China, Korea or Japan, the pomegranate is widely grown there and many cultivars have been developed. It is widely used for bonsai, because of its flowers and for the unusual twisted bark that older specimens can attain. - Balaustines are the red rose-like flowers of the pomegranate, which are very bitter to the taste. In medicine, its dried form has been used as an astringent.[35] (The term "balaustine" (Latin: balaustinus) is also used for a pomegranate-red colour.[36]) - The pomegranate was the personal emblem of the Holy Roman Emperor, Maximilian I, and of Catherine of Aragon. - With the rise in popularity of the pomegranate in American markets, Starbucks introduced a pomegranate frappuccino in the summer of 2006. - The pomegranate is a divine symbol in Pinto Ricardo's series, The Stone Dance of the Chameleon. - The pomegranate is also called the Food of the Dead. - In Orthodox Christian memorial services pomegranate seeds will often be put in the koliva which is blessed after the service and eaten by all of the mourners. - In the Hindu epic Caitanya-caritamrita (Adi-lila, 5.188), Sri Nityananda's teeth were described as resembling pomegranate seeds. - In Mexico, they are an essential ingredient of chiles en nogada, one of its most important national dishes, used to symbolize the red component of the national flag. - Kandahar is famous all over Afghanistan for its high quality pomegranates. - The pomegranate is also known as a Wine Apple in Ireland.	https://www.wikidoc.org/index.php/Pomegranate
02663d28d5cf7695363d35575707ec464575284f	wikidoc	Portal vein	Portal vein Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Portal vein can refer to: - the hepatic portal vein, a large vein that carries blood from the digestive tract to the liver and is formed by the splenic vein and superior mesenteric vein - a vein that is part of a portal venous system and connects two systems of capillary beds	Portal vein Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. Portal vein can refer to: - the hepatic portal vein, a large vein that carries blood from the digestive tract to the liver and is formed by the splenic vein and superior mesenteric vein - a vein that is part of a portal venous system and connects two systems of capillary beds Template:SIB Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Portal_vein

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