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904ee7d69e55acc4f077c7a2ebad2eb7aae23d71 | wikidoc | Apramycin | Apramycin
# Overview
Apramycin (also Nebramycin II) is an aminoglycoside antibiotic used in veterinary medicine. It is produced by Streptomyces tenebrarius.
# Pharmacology
## Indication
Apramycin is used for the treatment of bacterial infections in animals.
## Mechanism of action
Apramycin stands out among aminoglycosides for its mechanism of action which is based on blocking translocation and its ability to bind also to the eukaryotic decoding site despite differences in key residues required for apramycin recognition by the bacterial target. The drug binds in the deep groove of the RNA which forms a continuously stacked helix comprising non-canonical C.A and G.A base pairs and a bulged-out adenine. The binding mode of apramycin at the human decoding-site RNA is distinct from aminoglycoside recognition of the bacterial target, suggesting a molecular basis for the actions of apramycin in eukaryotes and bacteria.
# Spectrum of bacterial susceptibility and resistance
Apramycin can be used to treat bacterial infections in animals caused by Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The following shows susceptibility data on medically significant organisms:
- Escherichia coli - 1 μg/mL - >512 μg/mL (this large range may be due to resistant organisms, typical MIC values are likely in the range of 2 -8 μg/mL.
- Klebsiella pneumoniae - 2 μg/mL - >256 μg/mL
- Pseudomonas aeruginosa - 4 μg/mL | Apramycin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Apramycin (also Nebramycin II) is an aminoglycoside antibiotic used in veterinary medicine. It is produced by Streptomyces tenebrarius.[1]
# Pharmacology
## Indication
Apramycin is used for the treatment of bacterial infections in animals.
## Mechanism of action
Apramycin stands out among aminoglycosides for its mechanism of action which is based on blocking translocation and its ability to bind also to the eukaryotic decoding site despite differences in key residues required for apramycin recognition by the bacterial target. The drug binds in the deep groove of the RNA which forms a continuously stacked helix comprising non-canonical C.A and G.A base pairs and a bulged-out adenine. The binding mode of apramycin at the human decoding-site RNA is distinct from aminoglycoside recognition of the bacterial target, suggesting a molecular basis for the actions of apramycin in eukaryotes and bacteria.
# Spectrum of bacterial susceptibility and resistance
Apramycin can be used to treat bacterial infections in animals caused by Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The following shows susceptibility data on medically significant organisms:
- Escherichia coli - 1 μg/mL - >512 μg/mL (this large range may be due to resistant organisms, typical MIC values are likely in the range of 2 -8 μg/mL.
- Klebsiella pneumoniae - 2 μg/mL - >256 μg/mL
- Pseudomonas aeruginosa - 4 μg/mL
[2] | https://www.wikidoc.org/index.php/Apramycin | |
735e36243864af06f854de8225c640d81be70fc8 | wikidoc | Aprotinin | Aprotinin
# 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
Aprotinin is a protease inhibitor that is FDA approved for the treatment of prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anaphylactoid reactions, sepsis, hemoperitoneum, dyspepsia, gastrointestinal hemorrhage, pulmonary hypertension, pulmonary thrombosis, hyperglycemia, arthralgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Aprotinin is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.
- Aprotinin given prophylactically in both Regimen A and Regimen B (half Regimen A) to patients undergoing CABG surgery significantly reduced the donor blood transfusion requirement relative to placebo treatment. In low risk patients there is no difference in efficacy between regimen A and B. Therefore, the dosage used (A vs. B) is at the discretion of the practitioner.
- Aprotinin is supplied as a solution containing 10,000 KIU/mL, which is equal to 1.4 mg/mL. All intravenous doses of Aprotinin should be administered through a central line. DO NOT ADMINISTER ANY OTHER DRUG USING THE SAME LINE. Both regimens include a 1 mL initial (test) dose, a loading dose, a dose to be added while recirculating the priming fluid of the cardiopulmonary bypass circuit (“pump prime” dose), and a constant infusion dose. To avoid physical incompatibility of aprotinin and heparin when adding to the pump prime solution, each agent must be added during recirculation of the pump prime to assure adequate dilution prior to admixture with the other component. Regimens A and B, both incorporating a 1 mL initial (test) dose, are described in the table below:
- The 1 ml initial (test) dose should be administered intravenously at least 10 minutes before the loading dose. With the patient in a supine position, the loading dose is given slowly over 20-30 minutes, after induction of anesthesia but prior to sternotomy. In patients with known previous exposure to aprotinin, the loading dose should be given just prior to cannulation.
- When the loading dose is complete, it is followed by the constant infusion dose, which is continued until surgery is complete and the patient leaves the operating room. The “pump prime” dose is added to the recirculating priming fluid of the cardiopulmonary bypass circuit, by replacement of an aliquot of the priming fluid, prior to the institution of cardiopulmonary bypass. Total doses of more than 7 million KIU have not been studied in controlled trials.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any unused portion.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aprotinin in adult patients.
### Non–Guideline-Supported Use
- Operation on musculoskeletal system
- Pancreatitis
- Surgical procedure on thorax
- Transplantation of liver
- Vascular surgery procedure, Peripheral
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Aprotinin 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 Aprotinin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aprotinin in pediatric patients.
# Contraindications
- Administration of aprotinin to patients with a known or suspected previous aprotinin exposure during the last 12 months is contraindicated. For patients with known or suspected history of exposure to aprotinin greater than 12 months previously. Aprotinin may also be a component of some fibrin sealant products and the use of these products should be included in the patient history.
# Warnings
- Anaphylactic or anaphylactoid reactions have occurred with aprotinin administration, including fatal reactions in association with the initial (test) dose.
- The initial (test) dose does not fully predict a patient’s risk for a hypersensitivity reaction, including a fatal reaction. Fatal hypersensitivity reactions have occurred among patients who tolerated an initial (test) dose.
- Hypersensitivity reactions often manifest as anaphylactic/anaphylactoid reactions with hypotension the most frequently reported sign of the hypersensitivity reaction. The hypersensitivity reaction can progress to anaphylactic shock with circulatory failure. If a hypersensitivity reaction occurs during injection or infusion of aprotinin, administration should be stopped immediately and emergency treatment should be initiated.
- Even when a second exposure to aprotinin has been tolerated without symptoms, a subsequent administration may result in severe hypersensitivity/anaphylactic reactions.
- Aprotinin should be administered only in operative settings where cardiopulmonary bypass can be rapidly initiated. Before initiating treatment with aprotinin, the recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction
- Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room (e.g., epinephrine, corticosteroids). 2) Administration of the initial (test) dose and loading dose should be done only when the patient is intubated and when conditions for rapid cannulation and initiation of cardiopulmonary bypass are present. 3) Delay the addition of aprotinin into the pump prime solution until after the loading dose has been safely administered.
- Re-exposure to aprotinin
- Administration of aprotinin, especially to patients who have received aprotinin in the past, requires a careful risk/benefit assessment because an allergic reaction may occur. Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also case reports of anaphylaxis occurring upon re-exposure after more than 12 months.
- In a retrospective review of 387 European patient records with documented re-exposure to aprotinin, the incidence of hypersensitivity/anaphylactic reactions was 2.7%. Two patients who experienced hypersensitivity/anaphylactic reactions subsequently died, 24 hours and 5 days after surgery, respectively. The relationship of these 2 deaths to aprotinin is unclear. This retrospective review also showed that the incidence of a hypersensitivity or anaphylactic reaction following re-exposure is increased when the re-exposure occurs within 6 months of the initial administration (5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months). Other smaller studies have shown that in case of re-exposure, the incidence of hypersensitivity/anaphylactic reactions may reach the five percent level.
- An analysis of all spontaneous reports from the Bayer Global database covering a period from 1985 to March 2006 revealed that of 291 possibly associated spontaneous cases of hypersensitivity (fatal: n=52 and non-fatal: n=239), 47% (138/291) of hypersensitivity cases had documented previous exposure to aprotinin. Of the 138 cases with documented previous exposure, 110 had information on the time of the previous exposure. Ninety-nine of the 110 cases had previous exposure within the prior 12 months.
- Aprotinin administration increases the risk for renal dysfunction and may increase the need for dialysis in the perioperative period. This risk may be especially increased for patients with pre-existing renal impairment or those who receive aminoglycoside antibiotics or drugs that alter renal function. Data from Bayer’s global pool of placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery showed that the incidence of serum creatinine elevations >0.5 mg/dL above pre-treatment levels was statistically higher at 9.0% (185/2047) in the high-dose aprotinin (Regimen A) group compared with 6.6% (129/1957) in the placebo group.
- In the majority of instances, post-operative renal dysfunction was not severe and was reversible. However, renal dysfunction may progress to renal failure and the incidence of serum creatinine elevations >2.0 mg/dL above baseline was slightly higher in the high-dose aprotinin group (1.1% vs. 0.8%). Careful consideration of the balance of benefits versus potential risks is advised before administering aprotinin to patients with impaired renal function (creatinine clearance < 60 mL/min) or those with other risk factors for renal dysfunction (such as perioperative administration of aminogylcoside or products that alter renal function).
# Adverse Reactions
## Clinical Trials Experience
- Studies of patients undergoing CABG surgery, either primary or repeat, indicate that aprotinin is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to aprotinin therapy. Adverse events reported, up to the time of hospital discharge, from patients in US placebo-controlled trials are listed in the following table. The table lists only those events that were reported in 2% or more of the aprotinin treated patients without regard to causal relationship.
## Postmarketing Experience
- Sepsis, death, multi-system organ failure, immune system disorder, hemoperitoneum.
- Ventricular fibrillation, heart arrest, bradycardia, congestive heart failure, hemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block, pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.
- Dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure.
- Although thrombosis was not reported more frequently in aprotinin versus placebo-treated patients in controlled trials, it has been reported in uncontrolled trials, compassionate use trials, and spontaneous post-marketing reporting. These reports of thrombosis encompass the following terms: thrombosis, occlusion, arterial thrombosis, pulmonary thrombosis, coronary occlusion, embolus, pulmonary embolus, thrombophlebitis, deep thrombophlebitis, cerebrovascular accident, cerebral embolism. Other hematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes disseminated intravascular coagulation), decreased prothrombin.
- Hyperglycemia, hypokalemia, hypervolemia, acidosis.
- Arthralgia.
- Agitation, dizziness, anxiety, convulsion.
- Pneumonia, apnea, increased cough, lung edema.
- Skin discoloration.
- Oliguria, kidney failure, acute kidney failure, Acute tubular necrosis.
- In the pooled analysis of all patients undergoing CABG surgery, there was no significant difference in the incidence of investigator-reported myocardial infarction (MI) in aprotinin treated patients as compared to placebo treated patients. However, because no uniform criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B and Pump Prime Regimen; one study evaluated only Regimen A), in which data were analyzed by a blinded consultant employing an algorithm for possible, probable or definite MI.
- Utilizing this method, the incidence of definite myocardial infarction was 5.9% in the aprotinin-treated patients versus 4.7% in the placebo treated patients. This difference in the incidence rates was not statistically significant. Data from these three studies are summarized below.
- Although there was a statistically significantly increased risk of graft closure for aprotinin treated patients compared to patients who received placebo (p=0.035), further analysis showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When the analysis of graft closures was repeated for U.S. centers only, there was no statistically significant difference in graft closure rates in patients who received aprotinin vs. placebo.
- These results are the same whether analyzed as the proportion of patients who experienced at least one graft closure postoperatively or as the proportion of grafts closed. There were no differences between treatment groups in the incidence of myocardial infarction as evaluated by the blinded consultant (2.9% aprotinin vs. 3.8% placebo) or of death (1.4% aprotinin vs. 1.6% placebo) in this study.
- Hypersensitivity and anaphylactic reactions during surgery were rarely reported in U.S. controlled clinical studies in patients with no prior exposure to aprotinin (1/1424 patients or <0.1% on aprotinin vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the incidence of hypersensitivity/anaphylactic reactions has been reported to reach the 5% level. A review of 387 European patient records involving re-exposure to aprotinin showed that the incidence of hypersensitivity or anaphylactic reactions was 5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months.
- Serum Creatinine: Aprotinin administration is associated with a risk for renal dysfunction.
- Serum Transaminases: Data pooled from all patients undergoing CABG surgery in U.S. placebo-controlled trials showed no evidence of an increase in the incidence of postoperative hepatic dysfunction in patients treated with aprotinin.
- The incidence of treatment-emergent increases in ALT (formerly SGPT) > 1.8 times the upper limit of normal was 14% in both the aprotinin and placebo-treated patients (p=0.687), while the incidence of increases > 3 times the upper limit of normal was 5% in both groups (p=0.847).
- The incidence of treatment-emergent elevations in plasma glucose, AST (formerly SGOT), LDH, alkaline phosphatase, and CPK-MB was not notably different between aprotinin and placebo treated patients undergoing CABG surgery. Significant elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are expected in aprotinin treated patients in the hours after surgery due to circulating concentrations of aprotinin, which are known to inhibit activation of the intrinsic clotting system by contact with a foreign material (e.g., celite), a method used in these tests.
# Drug Interactions
There is limited information regarding Aprotinin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats at intravenous doses up to 200,000 KIU/kg/day for 11 days, and in rabbits at intravenous doses up to 100,000 KIU/kg/day for 13 days, 2.4 and 1.2 times the human dose on a mg/kg basis and 0.37 and 0.36 times the human mg/m2 dose.
- They have revealed no evidence of impaired fertility or harm to the fetus due to aprotinin. 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):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aprotinin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Aprotinin during labor and delivery.
### Nursing Mothers
Not applicable
### Pediatric Use
Safety and effectiveness in pediatric patient(s) have not been established.
### Geriatic Use
- Of the total of 3083 subjects in clinical studies of aprotinin, 1100 (35.7 percent) were 65 and over, while 297 (9.6 percent) were 75 and over. Of patients 65 years and older, 479 (43.5 percent) received Regimen A and 237 (21.5 percent) received Regimen B. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either dose regimen, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Aprotinin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aprotinin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Aprotinin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Aprotinin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aprotinin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aprotinin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Aprotinin prolongs whole blood clotting times by a different mechanism than heparin. In the presence of aprotinin, prolongation is dependent on the type of whole blood clotting test employed. If an activated clotting time (ACT) is used to determine the effectiveness of heparin anticoagulation, the prolongation of the ACT by aprotinin may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation.
- During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear adequate.
- In patients undergoing CPB with aprotinin therapy, one of the following methods may be employed to maintain adequate anticoagulation
- ACT - An ACT is not a standardized coagulation test, and different formulations of the assay are affected differently by the presence of aprotinin. The test is further influenced by variable dilution effects and the temperature experienced during cardiopulmonary bypass. It has been observed that Kaolin-based ACTs are not increased to the same degree by aprotinin as are diatomaceous earth-based (celite) ACTs. While protocols vary, a minimal celite ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of hemodilution and hypothermia, is recommended in the presence of aprotinin. Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of Trasylol ®.
- Fixed Heparin Dosing where a standard loading dose of heparin, administered prior to cannulation of the heart, plus the quantity of heparin added to the prime volume of the CPB circuit, should total at least 350 IU/kg. Additional heparin should be administered in a fixed-dose regimen based on patient weight and duration of CPB.
- Heparin Titration with Protamine titration, a method that is not affected by aprotinin, can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of aprotinin to determine the heparin loading dose. Additional heparin should be administered on the basis of heparin levels measured by protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7 U/mL (2.0 mg/kg) or below the level indicated by heparin dose response testing performed prior to administration of aprotinin.
- Protamine Administration
- In patients treated with aprotinin, the amount of protamine administered to reverse heparin activity should be based on the actual amount of heparin administered, and not on the ACT values.
# IV Compatibility
There is limited information regarding the compatibility of Aprotinin and IV administrations.
# Overdosage
- The maximum amount of aprotinin that can be safely administered in single or multiple doses has not been determined. Doses up to 17.5 million KIU have been administered within a 24 hour period without any apparent toxicity.
- There is one poorly documented case, however, of a patient who received a large, but not well determined, amount of aprotinin (in excess of 15 million KIU) in 24 hours. The patient, who had pre-existing liver dysfunction, developed hepatic and renal failure postoperatively and died. Autopsy showed hepatic necrosis and extensive renal tubular and glomerular necrosis. The relationship of these findings to aprotinin therapy is unclear.
# Pharmacology
## Mechanism of Action
- Aprotinin is a broad spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation.
- Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b).
- The effects of aprotinin use in CPB involves a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding.
## Structure
- Aprotinin (aprotinin injection), C284H432N84O79S7, is a natural proteinase inhibitor obtained from bovine lung. Aprotinin (molecular weight of 6512 daltons), consists of 58 amino acid residues that are arranged in a single polypeptide chain, cross-linked by three disulfide bridges.
- It is supplied as a clear, colorless, sterile isotonic solution for intravenous administration. Each milliliter contains 10,000 KIU (Kallikrein Inhibitor Units) (1.4 mg/mL) and 9 mg sodium chloride in water for injection. Hydrochloric acid and/or sodium hydroxide is used to adjust the pH to 4.5-6.5.
## Pharmacodynamics
There is limited information regarding Aprotinin Pharmacodynamics in the drug label.
## Pharmacokinetics
- The studies comparing the pharmacokinetics of aprotinin in healthy volunteers, cardiac patients undergoing surgery with cardiopulmonary bypass, and women undergoing hysterectomy suggest linear pharmacokinetics over the dose range of 50,000 KIU to 2 million KIU. After intravenous (IV) injection, rapid distribution of aprotinin occurs into the total extracellular space, leading to a rapid initial decrease in plasma aprotinin concentration. Following this distribution phase, a plasma half-life of about 150 minutes is observed. At later time points, (i.e., beyond 5 hours after dosing) there is a terminal elimination phase with a half-life of about 10 hours.
- Average steady state intraoperative plasma concentrations were 137 KIU/mL (n=10) after administration of the following dosage regimen: 1 million KIU IV loading dose, 1 million KIU into the pump prime volume, 250,000 KIU per hour of operation as continuous intravenous infusion (Regimen B). Average steady state intraoperative plasma concentrations were 250 KIU/mL in patients (n=20) treated with aprotinin during cardiac surgery by administration of Regimen A (exactly double Regimen B): 2 million KIU IV loading dose, 2 million KIU into the pump prime volume, 500,000 KIU per hour of operation as continuous intravenous infusion.
- Following a single IV dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of the dose. Animal studies have shown that aprotinin is accumulated primarily in the kidney. Aprotinin, after being filtered by the glomeruli, is actively reabsorbed by the proximal tubules in which it is stored in phagolysosomes. Aprotinin is slowly degraded by lysosomal enzymes. The physiological renal handling of aprotinin is similar to that of other small proteins, e.g., insulin.
## Nonclinical Toxicology
There is limited information regarding Aprotinin Nonclinical Toxicology in the drug label.
# Clinical Studies
- Four placebo-controlled, double-blind studies of aprotinin were conducted in the United States; of 540 randomized patients undergoing repeat coronary artery bypass graft (CABG) surgery, 480 were valid for efficacy analysis.
- The following treatment regimens were used in the studies
- Aprotinin Regimen A (2 million KIU IV loading dose, 2 million KIU into the pump prime volume, and 500,000 KIU per hour of surgery as a continuous intravenous infusion); aprotinin Regimen B (1 million KIU IV loading dose, 1 million KIU into the pump prime volume, and 250,000 KIU per hour of surgery as a continuous intravenous infusion); a pump prime regimen (2 million KIU into the pump prime volume only); and a placebo regimen (normal saline). All patients valid for efficacy in the above studies were pooled by treatment regimen for analyses of efficacy.
- In this pooled analysis, fewer patients receiving aprotinin, either Regimen A or Regimen B, required any donor blood compared to the pump prime only or placebo regimens. The number of units of donor blood required by patients, the volume (milliliters) of donor blood transfused, the number of units of donor blood products transfused, the thoracic drainage rate, and the total thoracic drainage volumes were also reduced in patients receiving aprotinin as compared to placebo.
- Four placebo-controlled, double-blind studies of aprotinin were conducted in the United States; of 1745 randomized patients undergoing primary CABG surgery, 1599 were valid for efficacy analysis. The dosage regimens used in these studies were identical to those used in the repeat CABG studies described above (Regimens A, B, pump prime, and placebo). All patients valid for efficacy were pooled by treatment regimen.
- In this pooled analysis, fewer patients receiving aprotinin Regimens A, B, and pump prime required any donor blood in comparison to the placebo regimen. The number of units of donor blood required by patients, the volume of donor blood transfused, the number of units of donor blood products transfused, the thoracic drainage rate, and total thoracic drainage volumes were also reduced in patients receiving aprotinin as compared to placebo.
- Additional subgroup analyses showed no diminution in benefit with increasing age. Male and female patients benefited from aprotinin with a reduction in the average number of units of donor blood transfused. Although male patients did better than female patients in terms of the percentage of patients who required any donor blood transfusions, the number of female patients studied was small.
- A double-blind, randomized, Canadian study compared aprotinin Regimen A (n=28) and placebo (n=23) in primary cardiac surgery patients (mainly CABG) requiring cardiopulmonary bypass who were treated with aspirin within 48 hours of surgery. The mean total blood loss (1209.7 mL vs. 2532.3 mL) and the mean number of units of packed red blood cells transfused (1.6 units vs 4.3 units) were significantly less (p<0.008) in the aprotinin group compared to the placebo group.
- In a U.S. randomized study of aprotinin Regimen A and Regimen B versus the placebo regimen in 212 patients undergoing primary aortic and/or mitral valve replacement or repair, no benefit was found for aprotinin in terms of the need for transfusion or the number of units of blood required.
# How Supplied
## Storage
- Aprotinin should be stored between 2° and 25°C (36° - 77°F).
- Protect from freezing.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Aprotinin in the drug label.
# Precautions with Alcohol
Alcohol-Aprotinin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRASYLOL
# Look-Alike Drug Names
There is limited information regarding Aprotinin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Aprotinin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Aprotinin is a protease inhibitor that is FDA approved for the treatment of prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anaphylactoid reactions, sepsis, hemoperitoneum, dyspepsia, gastrointestinal hemorrhage, pulmonary hypertension, pulmonary thrombosis, hyperglycemia, arthralgia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Aprotinin is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery who are at an increased risk for blood loss and blood transfusion.
- Aprotinin given prophylactically in both Regimen A and Regimen B (half Regimen A) to patients undergoing CABG surgery significantly reduced the donor blood transfusion requirement relative to placebo treatment. In low risk patients there is no difference in efficacy between regimen A and B. Therefore, the dosage used (A vs. B) is at the discretion of the practitioner.
- Aprotinin is supplied as a solution containing 10,000 KIU/mL, which is equal to 1.4 mg/mL. All intravenous doses of Aprotinin should be administered through a central line. DO NOT ADMINISTER ANY OTHER DRUG USING THE SAME LINE. Both regimens include a 1 mL initial (test) dose, a loading dose, a dose to be added while recirculating the priming fluid of the cardiopulmonary bypass circuit (“pump prime” dose), and a constant infusion dose. To avoid physical incompatibility of aprotinin and heparin when adding to the pump prime solution, each agent must be added during recirculation of the pump prime to assure adequate dilution prior to admixture with the other component. Regimens A and B, both incorporating a 1 mL initial (test) dose, are described in the table below:
- The 1 ml initial (test) dose should be administered intravenously at least 10 minutes before the loading dose. With the patient in a supine position, the loading dose is given slowly over 20-30 minutes, after induction of anesthesia but prior to sternotomy. In patients with known previous exposure to aprotinin, the loading dose should be given just prior to cannulation.
- When the loading dose is complete, it is followed by the constant infusion dose, which is continued until surgery is complete and the patient leaves the operating room. The “pump prime” dose is added to the recirculating priming fluid of the cardiopulmonary bypass circuit, by replacement of an aliquot of the priming fluid, prior to the institution of cardiopulmonary bypass. Total doses of more than 7 million KIU have not been studied in controlled trials.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any unused portion.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aprotinin in adult patients.
### Non–Guideline-Supported Use
- Operation on musculoskeletal system [1]
- Pancreatitis [2]
- Surgical procedure on thorax [3]
- Transplantation of liver[4]
- Vascular surgery procedure, Peripheral [5]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Aprotinin 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 Aprotinin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aprotinin in pediatric patients.
# Contraindications
- Administration of aprotinin to patients with a known or suspected previous aprotinin exposure during the last 12 months is contraindicated. For patients with known or suspected history of exposure to aprotinin greater than 12 months previously. Aprotinin may also be a component of some fibrin sealant products and the use of these products should be included in the patient history.
# Warnings
- Anaphylactic or anaphylactoid reactions have occurred with aprotinin administration, including fatal reactions in association with the initial (test) dose.
- The initial (test) dose does not fully predict a patient’s risk for a hypersensitivity reaction, including a fatal reaction. Fatal hypersensitivity reactions have occurred among patients who tolerated an initial (test) dose.
- Hypersensitivity reactions often manifest as anaphylactic/anaphylactoid reactions with hypotension the most frequently reported sign of the hypersensitivity reaction. The hypersensitivity reaction can progress to anaphylactic shock with circulatory failure. If a hypersensitivity reaction occurs during injection or infusion of aprotinin, administration should be stopped immediately and emergency treatment should be initiated.
- Even when a second exposure to aprotinin has been tolerated without symptoms, a subsequent administration may result in severe hypersensitivity/anaphylactic reactions.
- Aprotinin should be administered only in operative settings where cardiopulmonary bypass can be rapidly initiated. Before initiating treatment with aprotinin, the recommendations below should be followed to manage a potential hypersensitivity or anaphylactic reaction
- Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room (e.g., epinephrine, corticosteroids). 2) Administration of the initial (test) dose and loading dose should be done only when the patient is intubated and when conditions for rapid cannulation and initiation of cardiopulmonary bypass are present. 3) Delay the addition of aprotinin into the pump prime solution until after the loading dose has been safely administered.
- Re-exposure to aprotinin
- Administration of aprotinin, especially to patients who have received aprotinin in the past, requires a careful risk/benefit assessment because an allergic reaction may occur. Although the majority of cases of anaphylaxis occur upon re-exposure within the first 12 months, there are also case reports of anaphylaxis occurring upon re-exposure after more than 12 months.
- In a retrospective review of 387 European patient records with documented re-exposure to aprotinin, the incidence of hypersensitivity/anaphylactic reactions was 2.7%. Two patients who experienced hypersensitivity/anaphylactic reactions subsequently died, 24 hours and 5 days after surgery, respectively. The relationship of these 2 deaths to aprotinin is unclear. This retrospective review also showed that the incidence of a hypersensitivity or anaphylactic reaction following re-exposure is increased when the re-exposure occurs within 6 months of the initial administration (5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months). Other smaller studies have shown that in case of re-exposure, the incidence of hypersensitivity/anaphylactic reactions may reach the five percent level.
- An analysis of all spontaneous reports from the Bayer Global database covering a period from 1985 to March 2006 revealed that of 291 possibly associated spontaneous cases of hypersensitivity (fatal: n=52 and non-fatal: n=239), 47% (138/291) of hypersensitivity cases had documented previous exposure to aprotinin. Of the 138 cases with documented previous exposure, 110 had information on the time of the previous exposure. Ninety-nine of the 110 cases had previous exposure within the prior 12 months.
- Aprotinin administration increases the risk for renal dysfunction and may increase the need for dialysis in the perioperative period. This risk may be especially increased for patients with pre-existing renal impairment or those who receive aminoglycoside antibiotics or drugs that alter renal function. Data from Bayer’s global pool of placebo-controlled studies in patients undergoing coronary artery bypass graft (CABG) surgery showed that the incidence of serum creatinine elevations >0.5 mg/dL above pre-treatment levels was statistically higher at 9.0% (185/2047) in the high-dose aprotinin (Regimen A) group compared with 6.6% (129/1957) in the placebo group.
- In the majority of instances, post-operative renal dysfunction was not severe and was reversible. However, renal dysfunction may progress to renal failure and the incidence of serum creatinine elevations >2.0 mg/dL above baseline was slightly higher in the high-dose aprotinin group (1.1% vs. 0.8%). Careful consideration of the balance of benefits versus potential risks is advised before administering aprotinin to patients with impaired renal function (creatinine clearance < 60 mL/min) or those with other risk factors for renal dysfunction (such as perioperative administration of aminogylcoside or products that alter renal function).
# Adverse Reactions
## Clinical Trials Experience
- Studies of patients undergoing CABG surgery, either primary or repeat, indicate that aprotinin is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to aprotinin therapy. Adverse events reported, up to the time of hospital discharge, from patients in US placebo-controlled trials are listed in the following table. The table lists only those events that were reported in 2% or more of the aprotinin treated patients without regard to causal relationship.
## Postmarketing Experience
- Sepsis, death, multi-system organ failure, immune system disorder, hemoperitoneum.
- Ventricular fibrillation, heart arrest, bradycardia, congestive heart failure, hemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block, pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.
- Dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure.
- Although thrombosis was not reported more frequently in aprotinin versus placebo-treated patients in controlled trials, it has been reported in uncontrolled trials, compassionate use trials, and spontaneous post-marketing reporting. These reports of thrombosis encompass the following terms: thrombosis, occlusion, arterial thrombosis, pulmonary thrombosis, coronary occlusion, embolus, pulmonary embolus, thrombophlebitis, deep thrombophlebitis, cerebrovascular accident, cerebral embolism. Other hematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes disseminated intravascular coagulation), decreased prothrombin.
- Hyperglycemia, hypokalemia, hypervolemia, acidosis.
- Arthralgia.
- Agitation, dizziness, anxiety, convulsion.
- Pneumonia, apnea, increased cough, lung edema.
- Skin discoloration.
- Oliguria, kidney failure, acute kidney failure, Acute tubular necrosis.
- In the pooled analysis of all patients undergoing CABG surgery, there was no significant difference in the incidence of investigator-reported myocardial infarction (MI) in aprotinin treated patients as compared to placebo treated patients. However, because no uniform criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B and Pump Prime Regimen; one study evaluated only Regimen A), in which data were analyzed by a blinded consultant employing an algorithm for possible, probable or definite MI.
- Utilizing this method, the incidence of definite myocardial infarction was 5.9% in the aprotinin-treated patients versus 4.7% in the placebo treated patients. This difference in the incidence rates was not statistically significant. Data from these three studies are summarized below.
- Although there was a statistically significantly increased risk of graft closure for aprotinin treated patients compared to patients who received placebo (p=0.035), further analysis showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When the analysis of graft closures was repeated for U.S. centers only, there was no statistically significant difference in graft closure rates in patients who received aprotinin vs. placebo.
- These results are the same whether analyzed as the proportion of patients who experienced at least one graft closure postoperatively or as the proportion of grafts closed. There were no differences between treatment groups in the incidence of myocardial infarction as evaluated by the blinded consultant (2.9% aprotinin vs. 3.8% placebo) or of death (1.4% aprotinin vs. 1.6% placebo) in this study.
- Hypersensitivity and anaphylactic reactions during surgery were rarely reported in U.S. controlled clinical studies in patients with no prior exposure to aprotinin (1/1424 patients or <0.1% on aprotinin vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the incidence of hypersensitivity/anaphylactic reactions has been reported to reach the 5% level. A review of 387 European patient records involving re-exposure to aprotinin showed that the incidence of hypersensitivity or anaphylactic reactions was 5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months.
- Serum Creatinine: Aprotinin administration is associated with a risk for renal dysfunction.
- Serum Transaminases: Data pooled from all patients undergoing CABG surgery in U.S. placebo-controlled trials showed no evidence of an increase in the incidence of postoperative hepatic dysfunction in patients treated with aprotinin.
- The incidence of treatment-emergent increases in ALT (formerly SGPT) > 1.8 times the upper limit of normal was 14% in both the aprotinin and placebo-treated patients (p=0.687), while the incidence of increases > 3 times the upper limit of normal was 5% in both groups (p=0.847).
- The incidence of treatment-emergent elevations in plasma glucose, AST (formerly SGOT), LDH, alkaline phosphatase, and CPK-MB was not notably different between aprotinin and placebo treated patients undergoing CABG surgery. Significant elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are expected in aprotinin treated patients in the hours after surgery due to circulating concentrations of aprotinin, which are known to inhibit activation of the intrinsic clotting system by contact with a foreign material (e.g., celite), a method used in these tests.
# Drug Interactions
There is limited information regarding Aprotinin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats at intravenous doses up to 200,000 KIU/kg/day for 11 days, and in rabbits at intravenous doses up to 100,000 KIU/kg/day for 13 days, 2.4 and 1.2 times the human dose on a mg/kg basis and 0.37 and 0.36 times the human mg/m2 dose.
- They have revealed no evidence of impaired fertility or harm to the fetus due to aprotinin. 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):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aprotinin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Aprotinin during labor and delivery.
### Nursing Mothers
Not applicable
### Pediatric Use
Safety and effectiveness in pediatric patient(s) have not been established.
### Geriatic Use
- Of the total of 3083 subjects in clinical studies of aprotinin, 1100 (35.7 percent) were 65 and over, while 297 (9.6 percent) were 75 and over. Of patients 65 years and older, 479 (43.5 percent) received Regimen A and 237 (21.5 percent) received Regimen B. No overall differences in safety or effectiveness were observed between these subjects and younger subjects for either dose regimen, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Aprotinin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aprotinin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Aprotinin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Aprotinin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aprotinin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aprotinin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Aprotinin prolongs whole blood clotting times by a different mechanism than heparin. In the presence of aprotinin, prolongation is dependent on the type of whole blood clotting test employed. If an activated clotting time (ACT) is used to determine the effectiveness of heparin anticoagulation, the prolongation of the ACT by aprotinin may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation.
- During extended extracorporeal circulation, patients may require additional heparin, even in the presence of ACT levels that appear adequate.
- In patients undergoing CPB with aprotinin therapy, one of the following methods may be employed to maintain adequate anticoagulation
- ACT - An ACT is not a standardized coagulation test, and different formulations of the assay are affected differently by the presence of aprotinin. The test is further influenced by variable dilution effects and the temperature experienced during cardiopulmonary bypass. It has been observed that Kaolin-based ACTs are not increased to the same degree by aprotinin as are diatomaceous earth-based (celite) ACTs. While protocols vary, a minimal celite ACT of 750 seconds or kaolin-ACT of 480 seconds, independent of the effects of hemodilution and hypothermia, is recommended in the presence of aprotinin. Consult the manufacturer of the ACT test regarding the interpretation of the assay in the presence of Trasylol ®.
- Fixed Heparin Dosing where a standard loading dose of heparin, administered prior to cannulation of the heart, plus the quantity of heparin added to the prime volume of the CPB circuit, should total at least 350 IU/kg. Additional heparin should be administered in a fixed-dose regimen based on patient weight and duration of CPB.
- Heparin Titration with Protamine titration, a method that is not affected by aprotinin, can be used to measure heparin levels. A heparin dose response, assessed by protamine titration, should be performed prior to administration of aprotinin to determine the heparin loading dose. Additional heparin should be administered on the basis of heparin levels measured by protamine titration. Heparin levels during bypass should not be allowed to drop below 2.7 U/mL (2.0 mg/kg) or below the level indicated by heparin dose response testing performed prior to administration of aprotinin.
- Protamine Administration
- In patients treated with aprotinin, the amount of protamine administered to reverse heparin activity should be based on the actual amount of heparin administered, and not on the ACT values.
# IV Compatibility
There is limited information regarding the compatibility of Aprotinin and IV administrations.
# Overdosage
- The maximum amount of aprotinin that can be safely administered in single or multiple doses has not been determined. Doses up to 17.5 million KIU have been administered within a 24 hour period without any apparent toxicity.
- There is one poorly documented case, however, of a patient who received a large, but not well determined, amount of aprotinin (in excess of 15 million KIU) in 24 hours. The patient, who had pre-existing liver dysfunction, developed hepatic and renal failure postoperatively and died. Autopsy showed hepatic necrosis and extensive renal tubular and glomerular necrosis. The relationship of these findings to aprotinin therapy is unclear.
# Pharmacology
## Mechanism of Action
- Aprotinin is a broad spectrum protease inhibitor which modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery. SIR results in the interrelated activation of the hemostatic, fibrinolytic, cellular and humoral inflammatory systems. Aprotinin, through its inhibition of multiple mediators [e.g., kallikrein, plasmin] results in the attenuation of inflammatory responses, fibrinolysis, and thrombin generation.
- Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis. In platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while in granulocytes it prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b).
- The effects of aprotinin use in CPB involves a reduction in inflammatory response which translates into a decreased need for allogeneic blood transfusions, reduced bleeding, and decreased mediastinal re-exploration for bleeding.
## Structure
- Aprotinin (aprotinin injection), C284H432N84O79S7, is a natural proteinase inhibitor obtained from bovine lung. Aprotinin (molecular weight of 6512 daltons), consists of 58 amino acid residues that are arranged in a single polypeptide chain, cross-linked by three disulfide bridges.
- It is supplied as a clear, colorless, sterile isotonic solution for intravenous administration. Each milliliter contains 10,000 KIU (Kallikrein Inhibitor Units) (1.4 mg/mL) and 9 mg sodium chloride in water for injection. Hydrochloric acid and/or sodium hydroxide is used to adjust the pH to 4.5-6.5.
## Pharmacodynamics
There is limited information regarding Aprotinin Pharmacodynamics in the drug label.
## Pharmacokinetics
- The studies comparing the pharmacokinetics of aprotinin in healthy volunteers, cardiac patients undergoing surgery with cardiopulmonary bypass, and women undergoing hysterectomy suggest linear pharmacokinetics over the dose range of 50,000 KIU to 2 million KIU. After intravenous (IV) injection, rapid distribution of aprotinin occurs into the total extracellular space, leading to a rapid initial decrease in plasma aprotinin concentration. Following this distribution phase, a plasma half-life of about 150 minutes is observed. At later time points, (i.e., beyond 5 hours after dosing) there is a terminal elimination phase with a half-life of about 10 hours.
- Average steady state intraoperative plasma concentrations were 137 KIU/mL (n=10) after administration of the following dosage regimen: 1 million KIU IV loading dose, 1 million KIU into the pump prime volume, 250,000 KIU per hour of operation as continuous intravenous infusion (Regimen B). Average steady state intraoperative plasma concentrations were 250 KIU/mL in patients (n=20) treated with aprotinin during cardiac surgery by administration of Regimen A (exactly double Regimen B): 2 million KIU IV loading dose, 2 million KIU into the pump prime volume, 500,000 KIU per hour of operation as continuous intravenous infusion.
- Following a single IV dose of radiolabelled aprotinin, approximately 25-40% of the radioactivity is excreted in the urine over 48 hours. After a 30 minute infusion of 1 million KIU, about 2% is excreted as unchanged drug. After a larger dose of 2 million KIU infused over 30 minutes, urinary excretion of unchanged aprotinin accounts for approximately 9% of the dose. Animal studies have shown that aprotinin is accumulated primarily in the kidney. Aprotinin, after being filtered by the glomeruli, is actively reabsorbed by the proximal tubules in which it is stored in phagolysosomes. Aprotinin is slowly degraded by lysosomal enzymes. The physiological renal handling of aprotinin is similar to that of other small proteins, e.g., insulin.
## Nonclinical Toxicology
There is limited information regarding Aprotinin Nonclinical Toxicology in the drug label.
# Clinical Studies
- Four placebo-controlled, double-blind studies of aprotinin were conducted in the United States; of 540 randomized patients undergoing repeat coronary artery bypass graft (CABG) surgery, 480 were valid for efficacy analysis.
- The following treatment regimens were used in the studies
- Aprotinin Regimen A (2 million KIU IV loading dose, 2 million KIU into the pump prime volume, and 500,000 KIU per hour of surgery as a continuous intravenous infusion); aprotinin Regimen B (1 million KIU IV loading dose, 1 million KIU into the pump prime volume, and 250,000 KIU per hour of surgery as a continuous intravenous infusion); a pump prime regimen (2 million KIU into the pump prime volume only); and a placebo regimen (normal saline). All patients valid for efficacy in the above studies were pooled by treatment regimen for analyses of efficacy.
- In this pooled analysis, fewer patients receiving aprotinin, either Regimen A or Regimen B, required any donor blood compared to the pump prime only or placebo regimens. The number of units of donor blood required by patients, the volume (milliliters) of donor blood transfused, the number of units of donor blood products transfused, the thoracic drainage rate, and the total thoracic drainage volumes were also reduced in patients receiving aprotinin as compared to placebo.
- Four placebo-controlled, double-blind studies of aprotinin were conducted in the United States; of 1745 randomized patients undergoing primary CABG surgery, 1599 were valid for efficacy analysis. The dosage regimens used in these studies were identical to those used in the repeat CABG studies described above (Regimens A, B, pump prime, and placebo). All patients valid for efficacy were pooled by treatment regimen.
- In this pooled analysis, fewer patients receiving aprotinin Regimens A, B, and pump prime required any donor blood in comparison to the placebo regimen. The number of units of donor blood required by patients, the volume of donor blood transfused, the number of units of donor blood products transfused, the thoracic drainage rate, and total thoracic drainage volumes were also reduced in patients receiving aprotinin as compared to placebo.
- Additional subgroup analyses showed no diminution in benefit with increasing age. Male and female patients benefited from aprotinin with a reduction in the average number of units of donor blood transfused. Although male patients did better than female patients in terms of the percentage of patients who required any donor blood transfusions, the number of female patients studied was small.
- A double-blind, randomized, Canadian study compared aprotinin Regimen A (n=28) and placebo (n=23) in primary cardiac surgery patients (mainly CABG) requiring cardiopulmonary bypass who were treated with aspirin within 48 hours of surgery. The mean total blood loss (1209.7 mL vs. 2532.3 mL) and the mean number of units of packed red blood cells transfused (1.6 units vs 4.3 units) were significantly less (p<0.008) in the aprotinin group compared to the placebo group.
- In a U.S. randomized study of aprotinin Regimen A and Regimen B versus the placebo regimen in 212 patients undergoing primary aortic and/or mitral valve replacement or repair, no benefit was found for aprotinin in terms of the need for transfusion or the number of units of blood required.
# How Supplied
## Storage
- Aprotinin should be stored between 2° and 25°C (36° - 77°F).
- Protect from freezing.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Aprotinin in the drug label.
# Precautions with Alcohol
Alcohol-Aprotinin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TRASYLOL[6]
# Look-Alike Drug Names
There is limited information regarding Aprotinin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Aprotinin | |
ebd6b91ed324d1973f35a4eff637765df87f65f0 | wikidoc | Aquaporin | Aquaporin
Aquaporin, are integral membrane proteins from a larger family of major intrinsic proteins (MIP) that form pores in the membrane of biological cells.
Genetic defects involving aquaporin genes have been associated with several human diseases. The 2003 Nobel Prize in Chemistry was awarded to Peter Agre for the discovery of aquaporins and jointly to Roderick MacKinnon for his work on the structure and mechanism of potassium channels.
# Function
Aquaporins selectively conduct water molecules in and out, while preventing the passage of ions and other solutes. Also known as water channels, aquaporins are membrane pore proteins. Aquaporins are commonly composed of four (typically) identical subunit proteins in mammals, with each monomer acting as a water channel.
Water molecules traverse through the pore of the channel in single file. The presence of water channels increases membrane permeability to water.
Many human cell types express them, as do certain bacteria and many other organisms, such as plants for which it is essential for the water transport system.
# Discovery
In most cells, water moves in and out by osmosis through the lipid component of cell membranes. Due to the relatively high water permeability of some epithelial cells it was long suspected that some additional mechanism for water transport across membranes must exist, but it was not until the discovery of the first aquaporin, ‘aquaporin-1’ (originally known as CHIP), was reported by Peter Agre, then of Johns Hopkins University and now a professor and administrator at Duke University. The discovery of this first aquaporin took place in 1992.
The pioneering discoveries and research on water channels by Agre and his colleagues resulted in the presentation of a Nobel Prize in Chemistry to Agre in 2003. In 1999, together with other research teams, Agre reported the first high-resolution images of the three-dimensional structure of an aquaporin, viz. aquaporin-1. Further studies using supercomputer simulations have identified the pathway of water as it moves through the channel and demonstrated how a pore can allow water to pass without the passage of small solutes.
However the first report of protein mediated water transport through membranes was by Gheorghe Benga in 1986. This publication which preceded Agre"s first publication on water membrane transport proteins has led to a controversy that Benga's work was neither adequately recognized by Agre nor the Nobel Prize Committee.
# Structure
Aquaporins are made up of six transmembrane α-helices arranged in a right-handed bundle, with the amino and the carboxyl termini located on the cytoplasmic surface of the membrane. The amino and carboxyl halves of the sequence show similarity to each other, in what appears to be a tandem repeat. Some researches believe that this results from an early evolution event which saw the duplication of the half sized gene. There are also five interhelical loop regions (A – E) that form the extracellular and cytoplasmic vestibules. Loops B and E are hydrophobic loops which contain the highly, although not completely conserved Asn-Pro-Ala (NPA) motif, which overlap the middle of the lipid bilayer of the membrane forming a 3-D 'hourglass' structure where the water flows through. This overlap forms one of the two well-known channel constriction sites in the peptide, the NPA motif and a second and usually narrower constriction known as 'selectivity filter' or ar/R selectivity filter.
Aquaporins form tetramers in the cell membrane, and facilitate the transport of water and, in some cases, other small uncharged solutes, such as glycerol, CO2, ammonia and urea across the membrane depending on the size of the pore. The different aquaporins contain differences in their peptide sequence which allows for the size of the pore in the protein to differ between aquaporins. The resultant size of the pore directly affects what molecules are able to pass through the pore, with small pore sizes only allowing small molecules like water to pass through the pore. However, the water pores are completely impermeable to charged species, such as protons, a property critical for the conservation of membrane's electrochemical potential.
## NPA motif
Using computer simulations, it has been suggested that the orientation of the water molecules moving through the channel assures that only water passes between cells, due to the formation of a single line of water molecules. The water molecules move through the narrow channel by orienting themselves in the local electrical field formed by the atoms of the channel wall. Upon entering, the water molecules face with their oxygen atom down the channel. Midstream, they reverse orientation, facing with the oxygen atom up. This rotation of the water molecules in the pore is caused by the interaction of hydrogen bonds between the oxygen of the water molecule and the asparagines in the two NPA motifs. While passing through the channel, the single-file chain of water molecules streams through, always entering face down and leaving face up. The strictly opposite orientations of the water molecules keep them from conducting protons via the Grotthuss mechanism, while still permitting a fast flux of water molecules.
## ar/R selectivity filter
The ar/R (aromatic/arginine) selectivity filter is a cluster of amino acids that help bind to water molecules and exclude other molecules that may try to enter the pore. It is the mechanism by which the aquaporin is able to selectively bind water molecules (hence allowing them through) and prevent other molecules from entering. The ar/P filter is a tetrad that is formed by two amino acid residues from helices 2 (H2) and 5 (H5) and two residues from loop E (LE1 and LE2), found on either side of the NPA motif. The ar/R region is usually found towards the extracellular vestibule, approximately 8 Å above the NPA motif and is often the narrowest part of the pore. The narrow pore acts to weaken the hydrogen bonds between the water molecules allowing the water to interact with the positively charged arginine, which also acts as a proton filter for the pore.
# Aquaporins in mammals
There are thirteen known types of aquaporins in mammals, and six of these are located in the kidney, but the existence of many more is suspected.
The most studied aquaporins are:
- Aquaporin 1
- Aquaporin 2
- Aquaporin 3
- Aquaporin 4
Water crosses the cell membrane by either diffusing through the phospholipid bilayer or by passing through special water channels. Most aquaporins appear to be exclusive water channels that will not allow permeation of ions or other small molecules. Some aquaporins - known as aquaglyceroporins - transport water plus glycerol and a few other small molecules.
## Comparison
# Aquaporins in plants
In plants water is taken up from the soil through the roots, where it passes from the cortex into the vascular tissues. There are two routes for water to flow in these tissues, known as the; apoplastic and symplastic pathways. The presence of aquaporins in the cell membranes seems to serve to facilitate the transcellular symplastic pathway for water transport. When plant roots are exposed to mercuric chloride, which is known to inhibit aquaporins, the flow of water is greatly reduced while the flow of ions is not, supporting the view that there exists a mechanism for water transport independent of the transport of ions; aquaporins.
Aquaporins in plants are separated into four main homologous subfamilies, or groups:
- Plasma membrane Intrinsic Protein (PIP)
- Tonoplast Intrinsic Protein (TIP)
- Nodulin-26 like Intrinsic Protein (NIP)
- Small basic Intrinsic Protein (SIP)
These four subfamilies have continued to be broken up into smaller evolutionary subgroups that are directly related to their DNA sequence specificity. PIPs cluster into two subgroups, PIP1 and PIP2, whilst TIPs cluster into 5 subgroups, TIP1, TIP2, TIP3, TIP4 and TIP5. Each subgroup is again split up into isoforms e.g. PIP1;1, PIP1;2.
The silencing of plant aquaporins has been linked to pore plant growth and even death of the plant.
## Gating of Plant Aquaporins
The gating of aquaporins is carried out to stop the flow of water through the pore of the protein. This may be carried out for a number of reasons, for example plant contains low amounts of cellular water due to drought. The gating of an aquaporin is carried out by an interaction between a gating mechanism and the aquaporin which causes a 3D change in the protein so that it blocks the pore and thus disallows the flow of water through the pore. In plants it has been seen that there are at least two forms of aquaporin gating. These are gating by the dephosphorylation of certain serine residues, which has been linked as a response to drought, and the protonation of specific histidine residues in response to flooding. The phosphorylation of an aquaporin has also been linked to the opening and closing of a plant in response to temperature.
## PIPs
Plasma membrane intrinsic proteins are found, as their name suggests in the plasma membrane of plant cells. There are two PIP subgroups, PIP1 and PIP2, due to the distinct differences in their peptide sequence. PIP1s commonly have lower water channel activity than PIP2s although it is not understood why. Also not understood, but the water channel activity of PIP1s has been seen to increase when in the tetramer form with PIP2s.
# Aquaporins and disease
There have been two clear examples of diseases identified as resulting from mutations in aquaporins:
- Mutations in the aquaporin-2 gene cause hereditary nephrogenic diabetes insipidus in humans.
- Mice homozygous for inactivating mutations in the aquaporin-0 gene develop congenital cataracts.
A small number of people have been identified with severe or total deficiency in aquaporin-1. Interestingly, they are generally healthy, but exhibit a defect in the ability to concentrate solutes in the urine and to conserve water when deprived of drinking water. Mice with targeted deletions in aquaporin-1 also exhibit a deficiency in water conservation due to an inability to concentrate solutes in the kidney medulla by countercurrent multiplication.
In addition to its role in genetically determined nephrogenic diabetes insipidus, aquaporins also play a key role in acquired forms of nephrogenic diabetes insipidus (disorders that cause increased urine production). Acquired nephrogenic diabetes insipidus can result from impaired regulation of aquaporin-2 due to administration of lithium salts (as a treatment for bipolar disorder), low potassium concentrations in the blood (hypokalemia), high calcium concentrations in the blood (hypercalcemia), or a chronically high intake of water beyond the normal requirements (e.g. due to excessive habitual intake of bottled water or coffee).
Finally, it has been found that autoimmune reactions against aquaporin 4 produce Devic's disease. | Aquaporin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Aquaporin, are integral membrane proteins from a larger family of major intrinsic proteins (MIP) that form pores in the membrane of biological cells.[1]
Genetic defects involving aquaporin genes have been associated with several human diseases.[2][3] The 2003 Nobel Prize in Chemistry was awarded to Peter Agre for the discovery of aquaporins[4] and jointly to Roderick MacKinnon for his work on the structure and mechanism of potassium channels.[5]
# Function
Aquaporins selectively conduct water molecules in and out, while preventing the passage of ions and other solutes. Also known as water channels, aquaporins are membrane pore proteins. Aquaporins are commonly composed of four (typically) identical subunit proteins in mammals, with each monomer acting as a water channel.[6]
Water molecules traverse through the pore of the channel in single file. The presence of water channels increases membrane permeability to water.
Many human cell types express them, as do certain bacteria and many other organisms, such as plants for which it is essential for the water transport system.[7]
# Discovery
In most cells, water moves in and out by osmosis through the lipid component of cell membranes. Due to the relatively high water permeability of some epithelial cells it was long suspected that some additional mechanism for water transport across membranes must exist, but it was not until the discovery of the first aquaporin, ‘aquaporin-1’ (originally known as CHIP), was reported by Peter Agre, then of Johns Hopkins University and now a professor and administrator at Duke University. The discovery of this first aquaporin took place in 1992.[8]
The pioneering discoveries and research on water channels by Agre and his colleagues resulted in the presentation of a Nobel Prize in Chemistry to Agre in 2003.[5] In 1999, together with other research teams, Agre reported the first high-resolution images of the three-dimensional structure of an aquaporin, viz. aquaporin-1.[9] Further studies using supercomputer simulations have identified the pathway of water as it moves through the channel and demonstrated how a pore can allow water to pass without the passage of small solutes.[10]
However the first report of protein mediated water transport through membranes was by Gheorghe Benga in 1986.[11][12] This publication which preceded Agre"s first publication on water membrane transport proteins has led to a controversy that Benga's work was neither adequately recognized by Agre nor the Nobel Prize Committee.[13]
# Structure
Aquaporins are made up of six transmembrane α-helices arranged in a right-handed bundle, with the amino and the carboxyl termini located on the cytoplasmic surface of the membrane.[6][14] The amino and carboxyl halves of the sequence show similarity to each other, in what appears to be a tandem repeat. Some researches believe that this results from an early evolution event which saw the duplication of the half sized gene. There are also five interhelical loop regions (A – E) that form the extracellular and cytoplasmic vestibules. Loops B and E are hydrophobic loops which contain the highly, although not completely conserved Asn-Pro-Ala (NPA) motif, which overlap the middle of the lipid bilayer of the membrane forming a 3-D 'hourglass' structure where the water flows through. This overlap forms one of the two well-known channel constriction sites in the peptide, the NPA motif and a second and usually narrower constriction known as 'selectivity filter' or ar/R selectivity filter.
Aquaporins form tetramers in the cell membrane, and facilitate the transport of water and, in some cases, other small uncharged solutes, such as glycerol, CO2, ammonia and urea across the membrane depending on the size of the pore. The different aquaporins contain differences in their peptide sequence which allows for the size of the pore in the protein to differ between aquaporins. The resultant size of the pore directly affects what molecules are able to pass through the pore, with small pore sizes only allowing small molecules like water to pass through the pore. However, the water pores are completely impermeable to charged species, such as protons, a property critical for the conservation of membrane's electrochemical potential.
## NPA motif
Using computer simulations, it has been suggested that the orientation of the water molecules moving through the channel assures that only water passes between cells, due to the formation of a single line of water molecules. The water molecules move through the narrow channel by orienting themselves in the local electrical field formed by the atoms of the channel wall. Upon entering, the water molecules face with their oxygen atom down the channel. Midstream, they reverse orientation, facing with the oxygen atom up. This rotation of the water molecules in the pore is caused by the interaction of hydrogen bonds between the oxygen of the water molecule and the asparagines in the two NPA motifs. While passing through the channel, the single-file chain of water molecules streams through, always entering face down and leaving face up. The strictly opposite orientations of the water molecules keep them from conducting protons via the Grotthuss mechanism, while still permitting a fast flux of water molecules.[15]
## ar/R selectivity filter
The ar/R (aromatic/arginine) selectivity filter is a cluster of amino acids that help bind to water molecules and exclude other molecules that may try to enter the pore. It is the mechanism by which the aquaporin is able to selectively bind water molecules (hence allowing them through) and prevent other molecules from entering. The ar/P filter is a tetrad that is formed by two amino acid residues from helices 2 (H2) and 5 (H5) and two residues from loop E (LE1 and LE2), found on either side of the NPA motif. The ar/R region is usually found towards the extracellular vestibule, approximately 8 Å above the NPA motif and is often the narrowest part of the pore. The narrow pore acts to weaken the hydrogen bonds between the water molecules allowing the water to interact with the positively charged arginine, which also acts as a proton filter for the pore.
# Aquaporins in mammals
There are thirteen known types of aquaporins in mammals, and six of these are located in the kidney,[16] but the existence of many more is suspected.
The most studied aquaporins are:
- Aquaporin 1
- Aquaporin 2
- Aquaporin 3
- Aquaporin 4
Water crosses the cell membrane by either diffusing through the phospholipid bilayer or by passing through special water channels. Most aquaporins appear to be exclusive water channels that will not allow permeation of ions or other small molecules. Some aquaporins - known as aquaglyceroporins - transport water plus glycerol and a few other small molecules.
## Comparison
# Aquaporins in plants
In plants water is taken up from the soil through the roots, where it passes from the cortex into the vascular tissues. There are two routes for water to flow in these tissues, known as the; apoplastic and symplastic pathways. The presence of aquaporins in the cell membranes seems to serve to facilitate the transcellular symplastic pathway for water transport. When plant roots are exposed to mercuric chloride, which is known to inhibit aquaporins, the flow of water is greatly reduced while the flow of ions is not, supporting the view that there exists a mechanism for water transport independent of the transport of ions; aquaporins.
Aquaporins in plants are separated into four main homologous subfamilies, or groups:[18]
- Plasma membrane Intrinsic Protein (PIP)
- Tonoplast Intrinsic Protein (TIP)[19]
- Nodulin-26 like Intrinsic Protein (NIP)[20]
- Small basic Intrinsic Protein (SIP)[21]
These four subfamilies have continued to be broken up into smaller evolutionary subgroups that are directly related to their DNA sequence specificity. PIPs cluster into two subgroups, PIP1 and PIP2, whilst TIPs cluster into 5 subgroups, TIP1, TIP2, TIP3, TIP4 and TIP5. Each subgroup is again split up into isoforms e.g. PIP1;1, PIP1;2.
The silencing of plant aquaporins has been linked to pore plant growth and even death of the plant.
## Gating of Plant Aquaporins
The gating of aquaporins is carried out to stop the flow of water through the pore of the protein. This may be carried out for a number of reasons, for example plant contains low amounts of cellular water due to drought.[22] The gating of an aquaporin is carried out by an interaction between a gating mechanism and the aquaporin which causes a 3D change in the protein so that it blocks the pore and thus disallows the flow of water through the pore. In plants it has been seen that there are at least two forms of aquaporin gating. These are gating by the dephosphorylation of certain serine residues, which has been linked as a response to drought, and the protonation of specific histidine residues in response to flooding. The phosphorylation of an aquaporin has also been linked to the opening and closing of a plant in response to temperature.
## PIPs
Plasma membrane intrinsic proteins are found, as their name suggests in the plasma membrane of plant cells.[23] There are two PIP subgroups, PIP1 and PIP2, due to the distinct differences in their peptide sequence. PIP1s commonly have lower water channel activity than PIP2s although it is not understood why. Also not understood, but the water channel activity of PIP1s has been seen to increase when in the tetramer form with PIP2s.
# Aquaporins and disease
There have been two clear examples of diseases identified as resulting from mutations in aquaporins:
- Mutations in the aquaporin-2 gene cause hereditary nephrogenic diabetes insipidus in humans.[24]
- Mice homozygous for inactivating mutations in the aquaporin-0 gene develop congenital cataracts.[25]
A small number of people have been identified with severe or total deficiency in aquaporin-1. Interestingly, they are generally healthy, but exhibit a defect in the ability to concentrate solutes in the urine and to conserve water when deprived of drinking water. Mice with targeted deletions in aquaporin-1 also exhibit a deficiency in water conservation due to an inability to concentrate solutes in the kidney medulla by countercurrent multiplication.
In addition to its role in genetically determined nephrogenic diabetes insipidus, aquaporins also play a key role in acquired forms of nephrogenic diabetes insipidus (disorders that cause increased urine production).[26] Acquired nephrogenic diabetes insipidus can result from impaired regulation of aquaporin-2 due to administration of lithium salts (as a treatment for bipolar disorder), low potassium concentrations in the blood (hypokalemia), high calcium concentrations in the blood (hypercalcemia), or a chronically high intake of water beyond the normal requirements (e.g. due to excessive habitual intake of bottled water or coffee).
Finally, it has been found that autoimmune reactions against aquaporin 4 produce Devic's disease.[27] | https://www.wikidoc.org/index.php/Aquaporin | |
886670db04659673669f9176a668f723c6791fb8 | wikidoc | Arabinose | Arabinose
Arabinose is an aldopentose — a monosaccharide containing five carbon atoms, and including an aldehyde (CHO) functional group. It has chemical formula C5H10O5 and a molar mass of 150.13 g/mol.
# Isomerism
For biosynthetic reasons, saccharides are almost always more abundant in nature as the "D" form, or structurally analogous to D-(+)-glyceraldehyde. However, L-arabinose is in fact more common than D-arabinose in nature and is found in nature as a component of biopolymers such as hemicellulose and pectin. The L-arabinose operon is a very important operon in molecular biology and bioengineering.
A classic method for the organic synthesis of arabinose from glucose is the Wohl degradation. | Arabinose
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Arabinose is an aldopentose — a monosaccharide containing five carbon atoms, and including an aldehyde (CHO) functional group. It has chemical formula C5H10O5 and a molar mass of 150.13 g/mol.
# Isomerism
For biosynthetic reasons, saccharides are almost always more abundant in nature as the "D" form, or structurally analogous to D-(+)-glyceraldehyde.[1] However, L-arabinose is in fact more common than D-arabinose in nature and is found in nature as a component of biopolymers such as hemicellulose and pectin. The L-arabinose operon is a very important operon in molecular biology and bioengineering.
A classic method for the organic synthesis of arabinose from glucose is the Wohl degradation. | https://www.wikidoc.org/index.php/Arabinose | |
28a72922cd0742cf5130a1f669d550399b4690c0 | wikidoc | Arbekacin | Arbekacin
# Overview
Arbekacin (INN) is a semisynthetic aminoglycoside antibiotic. It is primarily used for the treatment of infections caused by multi-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Arbekacin was originally synthesized from dibekacin in 1973. It has been registered and marketed in Japan since 1990 under the trade name Habekacin. Arbekacin is no longer covered by patent and generic versions of the drug are also available under such trade names as Decontasin and Blubatosine.
# Pharmacology
Arbekacin is used for the short term treatment of multi-resistant bacterial infections, such as methicillin-resistant Staphylococcus aureus (MRSA).
## Pharmacodynamics
Aminoglycosides, such as Arbekacin, work by binding to the bacterial 30S ribosomal subunit, causing misreading of t-RNA which consequently, leaves the bacterium unable to synthesize proteins vital to its growth. Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes. Aminoglycosides are useful primarily in infections involving aerobic, gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter.
## Mechanism of action
Aminoglycosides, such as 'Arbekacin, inhibit protein synthesis in susceptible bacteria by irreversibly binding to bacterial 30S and 16S ribosomal subunits. Specifically Arbekacin binds to four nucleotides of 16S rRNA and a single amino acid of protein S12. This interferes with decoding site in the vicinity of nucleotide 1400 in 16S rRNA of 30S subunit. This region interacts with the wobble base in the anticodon of tRNA. This leads to misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes.
## Absorption
Aminoglycosides are not well absorbed from the gastrointestinal tract. Their absorption is markedly improved by parenteral administration.
## Toxicity
Ototoxicity and nephrotoxicity are the most serious adverse effects of aminoglycoside therapy and are more likely to occur in patients with a history of renal impairment or who are receiving other ototoxic and/or nephrotoxic drugs. Normal duration of IM or IV aminoglycoside therapy is 7–10 days. Although a longer duration may be necessary in some cases, toxicity is more likely to occur when aminoglycoside treatment is continued for longer than 10 days.
### Affected organisms
Enteric bacteria and other eubacteria | Arbekacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Arbekacin (INN) is a semisynthetic aminoglycoside antibiotic. It is primarily used for the treatment of infections caused by multi-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA).[1][2] Arbekacin was originally synthesized from dibekacin in 1973. It has been registered and marketed in Japan since 1990 under the trade name Habekacin.[3] Arbekacin is no longer covered by patent and generic versions of the drug are also available under such trade names as Decontasin and Blubatosine.
# Pharmacology
Arbekacin is used for the short term treatment of multi-resistant bacterial infections, such as methicillin-resistant Staphylococcus aureus (MRSA).
## Pharmacodynamics
Aminoglycosides, such as Arbekacin, work by binding to the bacterial 30S ribosomal subunit, causing misreading of t-RNA which consequently, leaves the bacterium unable to synthesize proteins vital to its growth. Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes. Aminoglycosides are useful primarily in infections involving aerobic, gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter.
## Mechanism of action
Aminoglycosides, such as 'Arbekacin, inhibit protein synthesis in susceptible bacteria by irreversibly binding to bacterial 30S and 16S ribosomal subunits. Specifically Arbekacin binds to four nucleotides of 16S rRNA and a single amino acid of protein S12. This interferes with decoding site in the vicinity of nucleotide 1400 in 16S rRNA of 30S subunit. This region interacts with the wobble base in the anticodon of tRNA. This leads to misreading of mRNA so incorrect amino acids are inserted into the polypeptide leading to nonfunctional or toxic peptides and the breakup of polysomes into nonfunctional monosomes.
## Absorption
Aminoglycosides are not well absorbed from the gastrointestinal tract. Their absorption is markedly improved by parenteral administration.
## Toxicity
Ototoxicity and nephrotoxicity are the most serious adverse effects of aminoglycoside therapy and are more likely to occur in patients with a history of renal impairment or who are receiving other ototoxic and/or nephrotoxic drugs. Normal duration of IM or IV aminoglycoside therapy is 7–10 days. Although a longer duration may be necessary in some cases, toxicity is more likely to occur when aminoglycoside treatment is continued for longer than 10 days.
### Affected organisms
Enteric bacteria and other eubacteria | https://www.wikidoc.org/index.php/Arbekacin | |
3c169b61deaebab56647424c185151bfdaca2994 | wikidoc | Arbovirus | Arbovirus
# Overview
Arbovirus is a term used to refer to a group of viruses that are transmitted by arthropod vectors. The word arbovirus is an acronym (ARthropod-BOrne virus). The word tibovirus is sometimes used to describe viruses transmitted by ticks (TIck-BOrne virus). Symptoms of arbovirus infection generally occur 3–15 days after exposure to the virus and last 3 or 4 days. The most common clinical features of infection are fever, headache and malaise, but encephalitis and hemorrhagic fever may also occur.
# History
Arboviruses have existed throughout human history, but were not known to exist until fairly recently. The connection between arthropods and disease was not postulated until 1881 when Cuban doctor and scientist Carlos Finlay proposed that Yellow fever may be transmitted by mosquitoes instead of human contact, a reality that was verified by Major Walter Reed in 1901. The primary vector, Aedes aegypti, had spread globally from the 15th to the 19th centuries as a result of globalization and the slave trade. This geographic spreading caused Dengue fever epidemics throughout the 18th century, and later, in 1906, transmission by the Aedes mosquitoes was confirmed, making Yellow fever and Dengue fever the first two diseases known to be caused by viruses. The discovery of the West Nile virus came in 1937, and has since been found in Culex populations and causing epidemics throughout Africa, the Middle East and Europe. In 1999, the virus was introduced into the Western Hemisphere, sparking a series of epidemics. During the latter half of the 20th century, Dengue fever reemerged as a global disease, with the virus spreading geographically due to urbanization, population growth, increased international travel and global warming. Yellow fever, alongside malaria, was a major obstacle in the construction of the Panama Canal. French supervision of the project in the 1880s was unsuccessful because of these diseases, forcing the abandonment of the project in 1889. During the American effort to construct the canal in the early 1900s, William C. Gorgas, the Chief Sanitary Officer of Havana, was tasked with overseeing the health of the workers. He had past success in eradicating the disease in Florida and Havana by reducing mosquito populations through draining nearby pools of water, cutting grass, applying oil to the edges of ponds and swamps to kill larvae, and capturing adult mosquitoes that remained indoors during the daytime. Joseph Augustin LePrince, the Chief Sanitary Inspector of the Canal Zone, invented the first commercial larvicide, a mixture of carbolic acid, resin and caustic soda, to be used throughout the Canal Zone. The combined implementation of these sanitation measures led to a dramatic decline in the number of workers dying and the eventual eradication of Yellow fever in the Canal Zone as well as the containment of malaria during the 10-year construction period. Because of the success of these methods at preventing disease, they were adopted and improved upon in other regions of the world.
# Transmission
Arboviruses maintain themselves in nature by going through a cycle between a host, an organism that carries the virus, and a vector, an organism that carries and transmits the virus to other organisms. For arboviruses, vectors are commonly mosquitoes, ticks, sandflies and other arthropods that consume the blood of vertebrates for nutritious or developmental purposes. Vertebrates which have their blood consumed act as the hosts, with each vector generally having an affinity for the blood of specific species, making those species the hosts.
Transmission between the vector and the host occurs when the vector feeds on the blood of the vertebrate, wherein the virus that has established an infection in the salivary glands of the vector comes into contact with the host's blood. While the virus is inside the host, it undergoes a process called amplification, where the virus replicates at sufficient levels to induce viremia, a condition in which there are large numbers of viruses present in the blood. The abundance of viruses in the host's blood allows the host to transmit the virus to other organisms if its blood is consumed by them. When uninfected vectors become infected from feeding, they are then capable of transmitting the virus to uninfected hosts, resuming amplification of virus populations. If viremia is not achieved in a vertebrate, the species can be called a "dead-end host", as the virus cannot be transmitted back to the vector.
An example of this vector-host relationship can be observed in the transmission of the West Nile virus. Female mosquitoes of the genus Culex prefer to consume the blood of Passerine birds, making them the hosts of the virus. When these birds are infected, the virus amplifies, potentially infecting multiple mosquitoes that feed on its blood. These infected mosquitoes may go on to further transmit the virus to more birds. If the mosquito is unable to find its preferred food source, it will choose another. Human blood is sometimes consumed, but since the West Nile virus does not replicate that well in mammals, humans are considered a dead-end host.
## In humans
Person-to-person transmission of arboviruses is not common, but can occur. Blood transfusions, organ transplantation and the use of blood products can transmit arboviruses if the virus is present in the donor's blood or organs. Because of this, blood and organs are often screened for viruses before being administered. Rarely, vertical transmission, or mother-to-child transmission, has been observed in infected pregnant and breastfeeding women. Exposure to used needles may also transmit arboviruses if they have been used by an infected person or animal. This puts intravenous drug users and healthcare workers at risk for infection in regions where the arbovirus may be spreading in human populations.
# Structure and genome
The majority of the arboviruses are spherical in shape although a few are rod-shaped. They are 17-150 nm in diameter and most have an RNA genome (the single exception is African swine fever virus, which has a DNA genome).
# Classification
In the past, arboviruses were organized into one of four groups: A, B, C and D. Group A denoted members of the genus Alphavirus, Group B were members of the genus Flavivirus, and Group C remains as the Group C serogroup of the genus Orthobunyavirus. Group D was renamed in the mid-1950s to the Guama group and is currently the Guama serogroup in the genus Orthobunyavirus. This renaming of the group was because the number of groups would eventually exceed the length of the alphabet. Since then, the organization of arboviruses into these groups has fallen out of usage as the standard biological classification system became more preferred for classifying viruses.
- Family Togaviridae
Genus Alphavirus
Eastern equine encephalitis virus (EEE)
Ross River virus (RRV)
Venezuelan equine encephalitis virus (VEE)
Western equine encephalitis virus (WEE)
- Genus Alphavirus
Eastern equine encephalitis virus (EEE)
Ross River virus (RRV)
Venezuelan equine encephalitis virus (VEE)
Western equine encephalitis virus (WEE)
- Eastern equine encephalitis virus (EEE)
- Ross River virus (RRV)
- Venezuelan equine encephalitis virus (VEE)
- Western equine encephalitis virus (WEE)
- Family Flaviviridae
Genus Flavivirus
Tick-borne viruses
Mammalian tick-borne virus group
Kyasanur forest disease virus (KFDV)
Tick-borne encephalitis virus (TBEV)
Mosquito-borne viruses
Dengue virus group
Dengue virus (DENV)
Japanese encephalitis virus group
Japanese encephalitis virus (JEV)
Murray Valley encephalitis virus (MVEV)
St. Louis encephalitis virus (SLEV)
West Nile virus (WNV)
Yellow fever virus group
Yellow fever virus (YFV)
- Genus Flavivirus
Tick-borne viruses
Mammalian tick-borne virus group
Kyasanur forest disease virus (KFDV)
Tick-borne encephalitis virus (TBEV)
Mosquito-borne viruses
Dengue virus group
Dengue virus (DENV)
Japanese encephalitis virus group
Japanese encephalitis virus (JEV)
Murray Valley encephalitis virus (MVEV)
St. Louis encephalitis virus (SLEV)
West Nile virus (WNV)
Yellow fever virus group
Yellow fever virus (YFV)
- Tick-borne viruses
Mammalian tick-borne virus group
Kyasanur forest disease virus (KFDV)
Tick-borne encephalitis virus (TBEV)
- Mammalian tick-borne virus group
Kyasanur forest disease virus (KFDV)
Tick-borne encephalitis virus (TBEV)
- Kyasanur forest disease virus (KFDV)
- Tick-borne encephalitis virus (TBEV)
- Mosquito-borne viruses
Dengue virus group
Dengue virus (DENV)
Japanese encephalitis virus group
Japanese encephalitis virus (JEV)
Murray Valley encephalitis virus (MVEV)
St. Louis encephalitis virus (SLEV)
West Nile virus (WNV)
Yellow fever virus group
Yellow fever virus (YFV)
- Dengue virus group
Dengue virus (DENV)
- Dengue virus (DENV)
- Japanese encephalitis virus group
Japanese encephalitis virus (JEV)
Murray Valley encephalitis virus (MVEV)
St. Louis encephalitis virus (SLEV)
West Nile virus (WNV)
- Japanese encephalitis virus (JEV)
- Murray Valley encephalitis virus (MVEV)
- St. Louis encephalitis virus (SLEV)
- West Nile virus (WNV)
- Yellow fever virus group
Yellow fever virus (YFV)
- Yellow fever virus (YFV)
- Family Bunyaviridae
Genus Nairovirus
Crimean–Congo hemorrhagic fever virus (CCHF)
Genus Orthobunyavirus
California encephalitis virus
La Crosse encephalitis virus (LACV)
Bunyamwera virus
Genus Phlebovirus
Rift Valley fever virus (RVFV)
Toscana virus (TOSV)
- Genus Nairovirus
Crimean–Congo hemorrhagic fever virus (CCHF)
- Crimean–Congo hemorrhagic fever virus (CCHF)
- Genus Orthobunyavirus
California encephalitis virus
La Crosse encephalitis virus (LACV)
Bunyamwera virus
- California encephalitis virus
- La Crosse encephalitis virus (LACV)
- Bunyamwera virus
- Genus Phlebovirus
Rift Valley fever virus (RVFV)
Toscana virus (TOSV)
- Rift Valley fever virus (RVFV)
- Toscana virus (TOSV)
- Family Reoviridae
Subfamily Sedoreovirinae
Genus Orbivirus
African horse sickness virus (AHSV)
Bluetongue disease virus (BTV)
Equine encephalosis virus (EEV)
Genus Seadornavirus
Banna virus (BAV)
Subfamily Spinareovirinae
Genus Coltivirus
Colorado tick fever virus (CTFV)
- Subfamily Sedoreovirinae
Genus Orbivirus
African horse sickness virus (AHSV)
Bluetongue disease virus (BTV)
Equine encephalosis virus (EEV)
Genus Seadornavirus
Banna virus (BAV)
- Genus Orbivirus
African horse sickness virus (AHSV)
Bluetongue disease virus (BTV)
Equine encephalosis virus (EEV)
- African horse sickness virus (AHSV)
- Bluetongue disease virus (BTV)
- Equine encephalosis virus (EEV)
- Genus Seadornavirus
Banna virus (BAV)
- Banna virus (BAV)
- Subfamily Spinareovirinae
Genus Coltivirus
Colorado tick fever virus (CTFV)
- Genus Coltivirus
Colorado tick fever virus (CTFV)
- Colorado tick fever virus (CTFV)
- Family Picornaviridae
Genus Parechovirus
Sebokele virus 1
- Genus Parechovirus
Sebokele virus 1
- Sebokele virus 1
# Signs and symptoms
Many arboviruses (such as African Swine Fever virus) do not normally infect humans or if so, cause either no symptoms or mild and transient infections characterized by fever, headache and rash. Others of this group however can cause epidemic disease and severe infections such as fulminant meningitis, encephalitis, meningoencephalitis, or viral hemorrhagic fever that can be fatal.
## Immune response to infection
The immune system plays a crucial role in defense against infection. Arboviruses are generally good inducers of the production of interferons, which may partially explain why acute infection is often similar to influenza (fever, headache, fatigue, myalgia). Antibodies can be important in controlling viremia and limiting the severity of infection. Recovery typically involves the cell-mediated immune system.
# Diagnosis
Preliminary diagnosis of arbovirus infection is usually based on clinical presentations of symptoms, places and dates of travel, activities and epidemiological history of the location where infection occurred. Definitive diagnosis is typically made in a laboratory by employing some combination of blood tests, particularly immunologic, serologic and/or virologic techniques such as ELISA, complement fixation, polymerase chain reaction, neutralization test and hemagglutination-inhibition test.
# Prevention
Vector control measures, especially mosquito control, are essential to reducing the transmission of disease by arboviruses. Habitat control involves draining swamps and removal of other pools of stagnant water (such as old tires, large outdoor potted plants, empty cans, etc.) that often serve as breeding grounds for mosquitoes. Insecticides can be applied in rural and urban areas, inside houses and other buildings or in outdoor environments. They are often quite effective for controlling arthropod populations, though use of some of these chemicals is controversial, and some organophosphates and organochlorides (such as DDT) have been banned in many countries. Infertile male mosquitoes have been introduced in some areas in order to reduce the breeding rate of relevant mosquito species. Larvicides are also used worldwide in mosquito abatement programs. Temefos is a common mosquito larvicide.
People can also reduce the risk of getting bitten by arthropods by employing personal protective measures such as sleeping under mosquito nets, wearing protective clothing, applying insect repellents such as permethrin and DEET to clothing and exposed skin, and (where possible) avoiding areas known to harbor high arthropod populations. Arboviral encephalitis can be prevented in two major ways: personal protective measures and public health measures to reduce the population of infected mosquitoes. Personal measures include reducing time outdoors particularly in early evening hours, wearing long pants and long sleeved shirts and applying mosquito repellent to exposed skin areas. Public health measures often require spraying of insecticides to kill juvenile (larvae) and adult mosquitoes.
## Vaccination
Vaccines are available for the following arboviral diseases:
- Japanese encephalitis
- Yellow fever
Vaccines are in development for the following arboviral diseases:
- Dengue fever
- Eastern Equine encephalitis
- West Nile
# Treatment
Because the arboviral encephalitides are viral diseases, antibiotics are not an effective form of treatment and no effective antiviral drugs have yet been discovered. Treatment is supportive, attempting to deal with problems such as swelling of the brain, loss of the automatic breathing activity of the brain and other treatable complications like bacterial pneumonia.
# List of common arboviruses
Common arboviruses include:
# List of arboviruses (not complete)
- Chikungunya
- Dengue fever
- Ross River virus
- Vesicular stomatitis virus
- West Nile virus
- Yellow fever
- Tick-borne Encephalitis
- Japanese Encephalitis
- La Crosse Encephalitis
- Murray Valley encephalitis virus
- St. Louis Encephalitis
- Equine Encephalitis
- Epizootic Hemorrhagic Disease
- O'nyong'nyong virus | Arbovirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Arbovirus is a term used to refer to a group of viruses that are transmitted by arthropod vectors. The word arbovirus is an acronym (ARthropod-BOrne virus).[1] The word tibovirus is sometimes used to describe viruses transmitted by ticks (TIck-BOrne virus).[2] Symptoms of arbovirus infection generally occur 3–15 days after exposure to the virus and last 3 or 4 days. The most common clinical features of infection are fever, headache and malaise, but encephalitis and hemorrhagic fever may also occur.[3]
# History
Arboviruses have existed throughout human history, but were not known to exist until fairly recently. The connection between arthropods and disease was not postulated until 1881 when Cuban doctor and scientist Carlos Finlay proposed that Yellow fever may be transmitted by mosquitoes instead of human contact,[4] a reality that was verified by Major Walter Reed in 1901.[5] The primary vector, Aedes aegypti, had spread globally from the 15th to the 19th centuries as a result of globalization and the slave trade.[6] This geographic spreading caused Dengue fever epidemics throughout the 18th century,[7] and later, in 1906, transmission by the Aedes mosquitoes was confirmed, making Yellow fever and Dengue fever the first two diseases known to be caused by viruses.[8] The discovery of the West Nile virus came in 1937,[9] and has since been found in Culex populations[10] and causing epidemics throughout Africa, the Middle East and Europe. In 1999, the virus was introduced into the Western Hemisphere, sparking a series of epidemics.[11] During the latter half of the 20th century, Dengue fever reemerged as a global disease, with the virus spreading geographically due to urbanization, population growth, increased international travel and global warming.[12][13][14] Yellow fever, alongside malaria, was a major obstacle in the construction of the Panama Canal. French supervision of the project in the 1880s was unsuccessful because of these diseases, forcing the abandonment of the project in 1889.[15] During the American effort to construct the canal in the early 1900s, William C. Gorgas, the Chief Sanitary Officer of Havana, was tasked with overseeing the health of the workers. He had past success in eradicating the disease in Florida and Havana by reducing mosquito populations through draining nearby pools of water, cutting grass, applying oil to the edges of ponds and swamps to kill larvae, and capturing adult mosquitoes that remained indoors during the daytime.[16] Joseph Augustin LePrince, the Chief Sanitary Inspector of the Canal Zone, invented the first commercial larvicide, a mixture of carbolic acid, resin and caustic soda, to be used throughout the Canal Zone.[17] The combined implementation of these sanitation measures led to a dramatic decline in the number of workers dying and the eventual eradication of Yellow fever in the Canal Zone as well as the containment of malaria during the 10-year construction period. Because of the success of these methods at preventing disease, they were adopted and improved upon in other regions of the world.[15][18]
# Transmission
Arboviruses maintain themselves in nature by going through a cycle between a host, an organism that carries the virus, and a vector, an organism that carries and transmits the virus to other organisms.[19] For arboviruses, vectors are commonly mosquitoes, ticks, sandflies[20] and other arthropods that consume the blood of vertebrates for nutritious or developmental purposes.[21] Vertebrates which have their blood consumed act as the hosts, with each vector generally having an affinity for the blood of specific species, making those species the hosts.[22]
Transmission between the vector and the host occurs when the vector feeds on the blood of the vertebrate, wherein the virus that has established an infection in the salivary glands of the vector comes into contact with the host's blood.[23][24] While the virus is inside the host, it undergoes a process called amplification, where the virus replicates at sufficient levels to induce viremia, a condition in which there are large numbers of viruses present in the blood.[25] The abundance of viruses in the host's blood allows the host to transmit the virus to other organisms if its blood is consumed by them. When uninfected vectors become infected from feeding, they are then capable of transmitting the virus to uninfected hosts, resuming amplification of virus populations. If viremia is not achieved in a vertebrate, the species can be called a "dead-end host", as the virus cannot be transmitted back to the vector.[26]
An example of this vector-host relationship can be observed in the transmission of the West Nile virus. Female mosquitoes of the genus Culex prefer to consume the blood of Passerine birds, making them the hosts of the virus.[27] When these birds are infected, the virus amplifies, potentially infecting multiple mosquitoes that feed on its blood. These infected mosquitoes may go on to further transmit the virus to more birds. If the mosquito is unable to find its preferred food source, it will choose another. Human blood is sometimes consumed, but since the West Nile virus does not replicate that well in mammals, humans are considered a dead-end host.[28]
## In humans
Person-to-person transmission of arboviruses is not common, but can occur. Blood transfusions, organ transplantation and the use of blood products can transmit arboviruses if the virus is present in the donor's blood or organs.[29][30][31] Because of this, blood and organs are often screened for viruses before being administered.[32] Rarely, vertical transmission, or mother-to-child transmission, has been observed in infected pregnant[33] and breastfeeding women.[34] Exposure to used needles may also transmit arboviruses if they have been used by an infected person or animal.[35] This puts intravenous drug users and healthcare workers at risk for infection in regions where the arbovirus may be spreading in human populations.
# Structure and genome
The majority of the arboviruses are spherical in shape although a few are rod-shaped. They are 17-150 nm in diameter and most have an RNA genome (the single exception is African swine fever virus, which has a DNA genome).
# Classification
In the past, arboviruses were organized into one of four groups: A, B, C and D. Group A denoted members of the genus Alphavirus,[36][37] Group B were members of the genus Flavivirus, and Group C remains as the Group C serogroup of the genus Orthobunyavirus. Group D was renamed in the mid-1950s to the Guama group and is currently the Guama serogroup in the genus Orthobunyavirus.[38] This renaming of the group was because the number of groups would eventually exceed the length of the alphabet. Since then, the organization of arboviruses into these groups has fallen out of usage as the standard biological classification system became more preferred for classifying viruses.[38]
- Family Togaviridae
Genus Alphavirus
Eastern equine encephalitis virus (EEE)
Ross River virus (RRV)
Venezuelan equine encephalitis virus (VEE)
Western equine encephalitis virus (WEE)
- Genus Alphavirus
Eastern equine encephalitis virus (EEE)
Ross River virus (RRV)
Venezuelan equine encephalitis virus (VEE)
Western equine encephalitis virus (WEE)
- Eastern equine encephalitis virus (EEE)
- Ross River virus (RRV)
- Venezuelan equine encephalitis virus (VEE)
- Western equine encephalitis virus (WEE)
- Family Flaviviridae
Genus Flavivirus
Tick-borne viruses
Mammalian tick-borne virus group
Kyasanur forest disease virus (KFDV)
Tick-borne encephalitis virus (TBEV)
Mosquito-borne viruses
Dengue virus group
Dengue virus (DENV)
Japanese encephalitis virus group
Japanese encephalitis virus (JEV)
Murray Valley encephalitis virus (MVEV)
St. Louis encephalitis virus (SLEV)
West Nile virus (WNV)
Yellow fever virus group
Yellow fever virus (YFV)
- Genus Flavivirus
Tick-borne viruses
Mammalian tick-borne virus group
Kyasanur forest disease virus (KFDV)
Tick-borne encephalitis virus (TBEV)
Mosquito-borne viruses
Dengue virus group
Dengue virus (DENV)
Japanese encephalitis virus group
Japanese encephalitis virus (JEV)
Murray Valley encephalitis virus (MVEV)
St. Louis encephalitis virus (SLEV)
West Nile virus (WNV)
Yellow fever virus group
Yellow fever virus (YFV)
- Tick-borne viruses
Mammalian tick-borne virus group
Kyasanur forest disease virus (KFDV)
Tick-borne encephalitis virus (TBEV)
- Mammalian tick-borne virus group
Kyasanur forest disease virus (KFDV)
Tick-borne encephalitis virus (TBEV)
- Kyasanur forest disease virus (KFDV)
- Tick-borne encephalitis virus (TBEV)
- Mosquito-borne viruses
Dengue virus group
Dengue virus (DENV)
Japanese encephalitis virus group
Japanese encephalitis virus (JEV)
Murray Valley encephalitis virus (MVEV)
St. Louis encephalitis virus (SLEV)
West Nile virus (WNV)
Yellow fever virus group
Yellow fever virus (YFV)
- Dengue virus group
Dengue virus (DENV)
- Dengue virus (DENV)
- Japanese encephalitis virus group
Japanese encephalitis virus (JEV)
Murray Valley encephalitis virus (MVEV)
St. Louis encephalitis virus (SLEV)
West Nile virus (WNV)
- Japanese encephalitis virus (JEV)
- Murray Valley encephalitis virus (MVEV)
- St. Louis encephalitis virus (SLEV)
- West Nile virus (WNV)
- Yellow fever virus group
Yellow fever virus (YFV)
- Yellow fever virus (YFV)
- Family Bunyaviridae
Genus Nairovirus
Crimean–Congo hemorrhagic fever virus (CCHF)
Genus Orthobunyavirus
California encephalitis virus
La Crosse encephalitis virus (LACV)
Bunyamwera virus
Genus Phlebovirus
Rift Valley fever virus (RVFV)
Toscana virus (TOSV)
- Genus Nairovirus
Crimean–Congo hemorrhagic fever virus (CCHF)
- Crimean–Congo hemorrhagic fever virus (CCHF)
- Genus Orthobunyavirus
California encephalitis virus
La Crosse encephalitis virus (LACV)
Bunyamwera virus
- California encephalitis virus
- La Crosse encephalitis virus (LACV)
- Bunyamwera virus
- Genus Phlebovirus
Rift Valley fever virus (RVFV)
Toscana virus (TOSV)
- Rift Valley fever virus (RVFV)
- Toscana virus (TOSV)
- Family Reoviridae
Subfamily Sedoreovirinae
Genus Orbivirus
African horse sickness virus (AHSV)
Bluetongue disease virus (BTV)
Equine encephalosis virus (EEV)
Genus Seadornavirus
Banna virus (BAV)
Subfamily Spinareovirinae
Genus Coltivirus
Colorado tick fever virus (CTFV)
- Subfamily Sedoreovirinae
Genus Orbivirus
African horse sickness virus (AHSV)
Bluetongue disease virus (BTV)
Equine encephalosis virus (EEV)
Genus Seadornavirus
Banna virus (BAV)
- Genus Orbivirus
African horse sickness virus (AHSV)
Bluetongue disease virus (BTV)
Equine encephalosis virus (EEV)
- African horse sickness virus (AHSV)
- Bluetongue disease virus (BTV)
- Equine encephalosis virus (EEV)
- Genus Seadornavirus
Banna virus (BAV)
- Banna virus (BAV)
- Subfamily Spinareovirinae
Genus Coltivirus
Colorado tick fever virus (CTFV)
- Genus Coltivirus
Colorado tick fever virus (CTFV)
- Colorado tick fever virus (CTFV)
- Family Picornaviridae
Genus Parechovirus
Sebokele virus 1
- Genus Parechovirus
Sebokele virus 1
- Sebokele virus 1
# Signs and symptoms
Many arboviruses (such as African Swine Fever virus) do not normally infect humans or if so, cause either no symptoms or mild and transient infections characterized by fever, headache and rash. Others of this group however can cause epidemic disease and severe infections such as fulminant meningitis, encephalitis, meningoencephalitis, or viral hemorrhagic fever that can be fatal.
## Immune response to infection
The immune system plays a crucial role in defense against infection. Arboviruses are generally good inducers of the production of interferons, which may partially explain why acute infection is often similar to influenza (fever, headache, fatigue, myalgia). Antibodies can be important in controlling viremia and limiting the severity of infection. Recovery typically involves the cell-mediated immune system.
# Diagnosis
Preliminary diagnosis of arbovirus infection is usually based on clinical presentations of symptoms, places and dates of travel, activities and epidemiological history of the location where infection occurred.[39] Definitive diagnosis is typically made in a laboratory by employing some combination of blood tests, particularly immunologic, serologic and/or virologic techniques such as ELISA,[39][40] complement fixation,[40] polymerase chain reaction,[41] neutralization test[42] and hemagglutination-inhibition test.[43]
# Prevention
Vector control measures, especially mosquito control, are essential to reducing the transmission of disease by arboviruses. Habitat control involves draining swamps and removal of other pools of stagnant water (such as old tires, large outdoor potted plants, empty cans, etc.) that often serve as breeding grounds for mosquitoes. Insecticides can be applied in rural and urban areas, inside houses and other buildings or in outdoor environments. They are often quite effective for controlling arthropod populations, though use of some of these chemicals is controversial, and some organophosphates and organochlorides (such as DDT) have been banned in many countries. Infertile male mosquitoes have been introduced in some areas in order to reduce the breeding rate of relevant mosquito species. Larvicides are also used worldwide in mosquito abatement programs. Temefos is a common mosquito larvicide.[44]
People can also reduce the risk of getting bitten by arthropods by employing personal protective measures such as sleeping under mosquito nets, wearing protective clothing, applying insect repellents such as permethrin and DEET to clothing and exposed skin, and (where possible) avoiding areas known to harbor high arthropod populations. Arboviral encephalitis can be prevented in two major ways: personal protective measures and public health measures to reduce the population of infected mosquitoes. Personal measures include reducing time outdoors particularly in early evening hours, wearing long pants and long sleeved shirts and applying mosquito repellent to exposed skin areas. Public health measures often require spraying of insecticides to kill juvenile (larvae) and adult mosquitoes.[45]
## Vaccination
Vaccines are available for the following arboviral diseases:
- Japanese encephalitis[46]
- Yellow fever[47]
Vaccines are in development for the following arboviral diseases:
- Dengue fever[48]
- Eastern Equine encephalitis[49]
- West Nile[50]
# Treatment
Because the arboviral encephalitides are viral diseases, antibiotics are not an effective form of treatment and no effective antiviral drugs have yet been discovered. Treatment is supportive, attempting to deal with problems such as swelling of the brain, loss of the automatic breathing activity of the brain and other treatable complications like bacterial pneumonia.[1]
# List of common arboviruses
Common arboviruses include:
# List of arboviruses (not complete)
- Chikungunya
- Dengue fever
- Ross River virus
- Vesicular stomatitis virus
- West Nile virus
- Yellow fever
- Tick-borne Encephalitis
- Japanese Encephalitis
- La Crosse Encephalitis
- Murray Valley encephalitis virus
- St. Louis Encephalitis
- Equine Encephalitis
- Epizootic Hemorrhagic Disease
- O'nyong'nyong virus | https://www.wikidoc.org/index.php/Arbovirosis | |
797650c52602c944317a7e3edf01f1b779470e7c | wikidoc | Argan oil | Argan oil
Argan oil is an oil produced from the kernels of the endemic argan tree, that is valued for its nutritive, cosmetic and number medicinal properties. The tree, a relict species from the Tertiary age, is extremely well adapted to drought and other environmentally difficult conditions of the southwestern Moroccos. The species Argania once covered entire North Africa and now is endangered and under protection of UNESCO, the Argan tree grows wild in semi-desert soil, its deep root system helping to protect against soil erosion and the northern advance of the Sahara. This biosphere reserve, the Arganeraie Biosphere Reserve, covers a vast intramontane plain of more than 2,560,000 hectares, bordered by the High Atlas and Anti-Atlas Mountains and open to the Atlantic in the west. Argan oil remains one of the rarest oils in the world due the small and very specific growing area.
Argan tree was first reported by the explorer Leo Africanus in 1510, an early specimen was taken to Amsterdam and then cultivated by Lady Beaufort at Badminton c1711.
# Extraction of the argan oil
## Traditional method
The production of argan oil, which is still mostly done by traditional methods, is a lengthy process done by women. The most labour intensive part of oil-extraction is removal of the soft pulp (afiash in Berber) and dry them in the sun, and then the cracking by hand, between two stones, of the very hard nut. The seeds are then removed and gently roasted. This roasting accounts for part of the oil's distinctive, nutty flavour. The traditional technique for oil extraction is to grind the roasted seeds to dough, with a little water, in a stone rotary quern. The paste is then squeezed between hands to extract the oil. The extracted paste, amlou, is still oil-rich. Oil produced by this method will keep 3-6 months, and will be produced as needed in a family, from a store of the kernels, which will keep for 20 years unopened.
## Press-extraction
Now increasingly important for oil produced for sale, as the oil will keep 12-18 months and extraction is much faster. Using mechanical presses, mixing of the dough and water is unnecessary and the dough can be directly pressed. All other steps remaining unchanged, the oil is obtained in about 43% yield (calculated from the kernels) and only two hours are needed to get one litre of oil that preserves correctly.
## Solvent-extraction
For industrial or laboratory purposes, argan oil can be extracted from ground kernels using any volatile lipophilic solvent. After evaporation of this latter, and one or two cycles of extraction, the oil is obtained in 50 to 55% yield. This type of extraction furnishes an oil with unsatisfactory organoleptic properties compared to the traditional or press extraction, which is exclusively reserved to prepare argan oil for cosmetic purposes.
# Properties and Use of the argan oil
Argan oil is exceptionally rich in natural tocopherols (vitamin E), rich in phenols and phenolic acid, rich in carotenes, rich in squalene, rich in essential fatty acids, 80% unsaturated fatty acids and depending on extraction method more resistant to oxidation than olive oil.
Argan oil is used for dipping bread, on couscous, salads and similar uses. The residue from traditional oil extraction is a thick chocolate-coloured paste called "amlou" which is sweetened and served as a dip for bread at breakfast time. It flavour is similar to that of peanut butter.
The unroasted oil is traditionally used as a treatment for skin diseases, and has found favour with cosmetics industrie.
# Medicinal uses
There has been research into argan oil's viability in the treatment of psoriasis with promising results.
Argan oil is sold in Morocco, sometimes to tourists as a £10 per 250 ml luxury item (although difficult to find outside the region of production), sometimes in ordinary shops and supermarkets for £10 per litre, and is of increasing interest to cosmetics companies. It was very difficult to buy the oil outside Morocco, but in 2001-2002 argan oil suddenly became a fashionable food in Europe and North America. It is now widely available in specialist shops and, sometimes, in supermarkets. Its price ($20-30 for 250 ml) reflects its status as a fashionable superfood.
Goats like the pulp of argan fruits and often try to climb the trees to get at them. They will digest the pulp, but shed the undigested seeds in their feces. As these have shells that are somewhat softened and easier to crack, they are occasionally used to produce oil for non-culinary purposes. An urban legend has it that all argan oil is produced this way. This myth seems to be based on the fact that occasionally, shrewd traders would have sold (and may still try to sell) such "non-food grade" argan oil to ignorant travellers or tourists. The fact that the nuts acquire a foul aroma in passing through the animal's digestive tract makes it easy to tell this oil apart from food-grade produce with its rich, walnut oil-like flavor (Nouaim 2005).
# Images
- Artisanal manufacture of argan oil
- File:Maroc Essaouira argane oil Luc Viatour 1.JPG
- File:Maroc Essaouira argane oil Luc Viatour 2.JPG
- File:Maroc Essaouira argane oil Luc Viatour 3.JPG | Argan oil
Argan oil is an oil produced from the kernels of the endemic argan tree, that is valued for its nutritive, cosmetic and number medicinal properties. The tree, a relict species from the Tertiary age, is extremely well adapted to drought and other environmentally difficult conditions of the southwestern Moroccos. The species Argania once covered entire North Africa and now is endangered and under protection of UNESCO,[1] the Argan tree grows wild in semi-desert soil, its deep root system helping to protect against soil erosion and the northern advance of the Sahara.[2] This biosphere reserve, the Arganeraie Biosphere Reserve, covers a vast intramontane plain of more than 2,560,000 hectares, bordered by the High Atlas and Anti-Atlas Mountains and open to the Atlantic in the west. Argan oil remains one of the rarest oils in the world due the small and very specific growing area.
Argan tree was first reported by the explorer Leo Africanus in 1510, an early specimen was taken to Amsterdam and then cultivated by Lady Beaufort at Badminton c1711[citation needed].
# Extraction of the argan oil
## Traditional method
The production of argan oil, which is still mostly done by traditional methods, is a lengthy process done by women. The most labour intensive part of oil-extraction is removal of the soft pulp (afiash in Berber) and dry them in the sun, and then the cracking by hand, between two stones, of the very hard nut. The seeds are then removed and gently roasted. This roasting accounts for part of the oil's distinctive, nutty flavour. The traditional technique for oil extraction is to grind the roasted seeds to dough, with a little water, in a stone rotary quern. The paste is then squeezed between hands to extract the oil. The extracted paste, amlou, is still oil-rich. Oil produced by this method will keep 3-6 months, and will be produced as needed in a family, from a store of the kernels, which will keep for 20 years unopened.
## Press-extraction
Now increasingly important for oil produced for sale, as the oil will keep 12-18 months and extraction is much faster. Using mechanical presses, mixing of the dough and water is unnecessary and the dough can be directly pressed. All other steps remaining unchanged, the oil is obtained in about 43% yield (calculated from the kernels) and only two hours are needed to get one litre of oil that preserves correctly.
## Solvent-extraction
For industrial or laboratory purposes, argan oil can be extracted from ground kernels using any volatile lipophilic solvent. After evaporation of this latter, and one or two cycles of extraction, the oil is obtained in 50 to 55% yield. This type of extraction furnishes an oil with unsatisfactory organoleptic properties compared to the traditional or press extraction, which is exclusively reserved to prepare argan oil for cosmetic purposes.
# Properties and Use of the argan oil
Argan oil is exceptionally rich in natural tocopherols (vitamin E), rich in phenols and phenolic acid, rich in carotenes, rich in squalene, rich in essential fatty acids, 80% unsaturated fatty acids[3] and depending on extraction method more resistant to oxidation than olive oil.
Argan oil is used for dipping bread, on couscous, salads and similar uses. The residue from traditional oil extraction is a thick chocolate-coloured paste called "amlou" which is sweetened and served as a dip for bread at breakfast time. It flavour is similar to that of peanut butter.
The unroasted oil is traditionally used as a treatment for skin diseases, and has found favour with cosmetics industrie.
# Medicinal uses
There has been research into argan oil's viability in the treatment of psoriasis with promising results. [4]
Argan oil is sold in Morocco, sometimes to tourists as a £10 per 250 ml luxury item (although difficult to find outside the region of production), sometimes in ordinary shops and supermarkets for £10 per litre, and is of increasing interest to cosmetics companies. It was very difficult to buy the oil outside Morocco, but in 2001-2002 argan oil suddenly became a fashionable food in Europe and North America. It is now widely available in specialist shops and, sometimes, in supermarkets. Its price ($20-30 for 250 ml) reflects its status as a fashionable superfood.
Goats like the pulp of argan fruits and often try to climb the trees to get at them. They will digest the pulp, but shed the undigested seeds in their feces.[2] As these have shells that are somewhat softened and easier to crack, they are occasionally used to produce oil for non-culinary purposes. An urban legend has it that all argan oil is produced this way. This myth seems to be based on the fact that occasionally, shrewd traders would have sold (and may still try to sell) such "non-food grade" argan oil to ignorant travellers or tourists. The fact that the nuts acquire a foul aroma in passing through the animal's digestive tract makes it easy to tell this oil apart from food-grade produce with its rich, walnut oil-like flavor (Nouaim 2005).
# Images
- Artisanal manufacture of argan oil
- File:Maroc Essaouira argane oil Luc Viatour 1.JPG
- File:Maroc Essaouira argane oil Luc Viatour 2.JPG
- File:Maroc Essaouira argane oil Luc Viatour 3.JPG | https://www.wikidoc.org/index.php/Argan_oil | |
af7b20820ebd121c01ac3fd70359b6ea11645c98 | wikidoc | Arginemia | Arginemia
Arginemia (also called arginase deficiency) is a congenital disorder where arginase deficiency causes a high level of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.
Arginase deficiency usually becomes evident by about the age of 3. It most often appears as stiffness, especially in the legs, caused by abnormal tensing of the muscles (spasticity). Other symptoms may include slower than normal growth, developmental delay and eventual loss of developmental milestones, mental retardation, seizures, tremor, and difficulty with balance and coordination (ataxia). Occasionally, high protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting.
In some affected individuals, signs and symptoms of arginase deficiency may be less severe, and may not appear until later in life.
Mutations in the ARG1 gene cause arginase deficiency. Arginase deficiency belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys.
The ARG1 gene provides instructions for making an enzyme called arginase. This enzyme controls the final step of the urea cycle, which produces urea by removing nitrogen from arginine. In people with arginase deficiency, arginase is damaged or missing, and arginine is not broken down properly. As a result, urea cannot be produced normally, and excess nitrogen accumulates in the blood in the form of ammonia. The accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency.
This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.
# Differential diagnosis
Arginase deficiency must be differentiated from other diseases that cause neurological manifestations in infants. | Arginemia
Arginemia (also called arginase deficiency) is a congenital disorder where arginase deficiency causes a high level of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.
Arginase deficiency usually becomes evident by about the age of 3. It most often appears as stiffness, especially in the legs, caused by abnormal tensing of the muscles (spasticity). Other symptoms may include slower than normal growth, developmental delay and eventual loss of developmental milestones, mental retardation, seizures, tremor, and difficulty with balance and coordination (ataxia). Occasionally, high protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting.
In some affected individuals, signs and symptoms of arginase deficiency may be less severe, and may not appear until later in life.
Mutations in the ARG1 gene cause arginase deficiency. Arginase deficiency belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys.
The ARG1 gene provides instructions for making an enzyme called arginase. This enzyme controls the final step of the urea cycle, which produces urea by removing nitrogen from arginine. In people with arginase deficiency, arginase is damaged or missing, and arginine is not broken down properly. As a result, urea cannot be produced normally, and excess nitrogen accumulates in the blood in the form of ammonia. The accumulation of ammonia and arginine are believed to cause the neurological problems and other signs and symptoms of arginase deficiency.
This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.
# Differential diagnosis
Arginase deficiency must be differentiated from other diseases that cause neurological manifestations in infants. | https://www.wikidoc.org/index.php/Arginase_deficiency | |
5b00165ca70d33ad689cd0525876d259b1fc38ac | wikidoc | Argonaute | Argonaute
Argonaute proteins are the catalytic components of the RNA-induced silencing complex (RISC), the protein complex responsible for the gene silencing phenomenon known as RNA interference (RNAi). Argonaute proteins bind small interfering RNA (siRNA) fragments and have endonuclease activity directed against messenger RNA (mRNA) strands that are complementary to their bound siRNA fragment. The proteins are also partially responsible for selection of the guide strand and destruction of the passenger strand of the siRNA substrate.
The structural basis for binding of RNA to the argonaute protein has been examined by X-ray crystallography of the binding domain of an RNA-bound argonaute protein. The phosphorylated 5' end of the RNA strand enters a conserved basic surface pocket and makes contacts through a divalent cation such as magnesium and by aromatic stacking between the 5' nucleotide in the siRNA and a conserved tyrosine residue. This site is thought to form a nucleation site for the binding of the siRNA to its mRNA target.
In eukaryotes, argonaute proteins have been identified in high concentrations in regions of the cell's cytoplasm known as cytoplasmic bodies, to which mRNA decay is also localized. The argonaute protein family is shared among not only eukaryotes, but also archaea and certain bacteria such as Aquifex aeolicus. Based on comparative genomics studies, the argonaute family is thought to have evolved from components of the translation initiation system.
Argonaute proteins are named after the argonaute (AGO) phenotype of Arabidopsis mutants, which itself was named after its resemblance to argonauts. | Argonaute
Argonaute proteins are the catalytic components of the RNA-induced silencing complex (RISC), the protein complex responsible for the gene silencing phenomenon known as RNA interference (RNAi). Argonaute proteins bind small interfering RNA (siRNA) fragments and have endonuclease activity directed against messenger RNA (mRNA) strands that are complementary to their bound siRNA fragment. The proteins are also partially responsible for selection of the guide strand and destruction of the passenger strand of the siRNA substrate.[1]
The structural basis for binding of RNA to the argonaute protein has been examined by X-ray crystallography of the binding domain of an RNA-bound argonaute protein. The phosphorylated 5' end of the RNA strand enters a conserved basic surface pocket and makes contacts through a divalent cation such as magnesium and by aromatic stacking between the 5' nucleotide in the siRNA and a conserved tyrosine residue. This site is thought to form a nucleation site for the binding of the siRNA to its mRNA target.[2]
In eukaryotes, argonaute proteins have been identified in high concentrations in regions of the cell's cytoplasm known as cytoplasmic bodies, to which mRNA decay is also localized.[3] The argonaute protein family is shared among not only eukaryotes, but also archaea and certain bacteria such as Aquifex aeolicus. Based on comparative genomics studies, the argonaute family is thought to have evolved from components of the translation initiation system.[4]
Argonaute proteins are named after the argonaute (AGO) phenotype of Arabidopsis mutants, which itself was named after its resemblance to argonauts. [5] | https://www.wikidoc.org/index.php/Argonaute | |
33e9047c0c3a211f031e8d51f0a1c77d19ac5fde | wikidoc | Donepezil | Donepezil
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# Overview
Donepezil is a reversible inhibitor of the enzyme acetylcholinesterase that is FDA approved for the {{{indicationType}}} of dementia of the Alzheimer's type. Common adverse reactions include hypertension, syncope, weight decreased, diarrhea, loss of appetite, nausea, vomiting, contusion, asthenia, depression and urinary incontinence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The dosages of ARICEPT® shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.
- The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of ARICEPT® might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.
- Evidence from the controlled trials indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events than the 5 mg dose. In open label trials using a 6 week titration, the frequency of these same adverse events was similar between the 5 mg and 10 mg dose groups. Therefore, because steady state is not achieved for 15 days and because the incidence of untoward effects may be influenced by the rate of dose escalation, treatment with a dose of 10 mg should not be contemplated until patients have been on a daily dose of 5 mg for 4 to 6 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Donepezil in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Donepezil 5 to 10 mg daily for 24 weeks.
- Dosing Information
- Donepezil 10 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Donepezil in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Donepezil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Donepezil in pediatric patients.
# Contraindications
- ARICEPT® is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.
# Warnings
### Precautions
- Anesthesia
- ARICEPT®, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
- Cardiovascular Conditions
- Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of ARICEPT®.
- Gastrointestinal Conditions
- Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDS). Clinical studies of ARICEPT® have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
- ARICEPT®, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea and vomiting. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose. In most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of ARICEPT®.
- Genitourinary
- Although not observed in clinical trials of ARICEPT®, cholinomimetics may cause bladder outflow obstruction.
- Neurological Conditions
- Seizures: Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's Disease.
- Pulmonary Conditions
- Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.
- Sulfites
- ARICEPT® Oral Solution contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than nonasthmatic people.
# Adverse Reactions
## Clinical Trials Experience
- Adverse Events Leading to Discontinuation
- The rates of discontinuation from controlled clinical trials of ARICEPT® due to adverse events for the ARICEPT® 5 mg/day treatment groups were comparable to those of placebo-treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5 mg/day to 10 mg/day, was higher at 13%.
- The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of patients and at twice the incidence seen in placebo patients, are shown in Table 1.
- Most Frequent Adverse Clinical Events Seen in Association with the Use of ARICEPT®
- The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by ARICEPT®'s cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT® treatment without the need for dose modification.
- There is evidence to suggest that the frequency of these common adverse events may be affected by the rate of titration. An open-label study was conducted with 269 patients who received placebo in the 15 and 30-week studies. These patients were titrated to a dose of 10 mg/day over a 6-week period. The rates of common adverse events were lower than those seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day.
- See Table 2 for a comparison of the most common adverse events following one and six week titration regimens.
- Adverse Events Reported in Controlled Trials
- The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 3 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT® and for which the rate of occurrence was greater for ARICEPT® assigned than placebo assigned patients. In general, adverse events occurred more frequently in female patients and with advancing age.
- Other Adverse Events Observed During Clinical Trials
- ARICEPT® has been administered to over 1700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months and 116 patients treated for over 1 year. The range of patient exposure is from 1 to 1214 days.
- Treatment emergent signs and symptoms that occurred during 3 controlled clinical trials and two open-label trials in the United States were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 900 patients from these trials who experienced that event while receiving ARICEPT®. All adverse events occurring at least twice are included, except for those already listed in Tables 2 or 3, COSTART terms too general to be informative, or events less likely to be drug caused. Events are classified by body system and listed using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to ARICEPT® treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. No important additional adverse events were seen in studies conducted outside the United States.
- Body as a Whole:Frequent: influenza, chest pain, toothache; Infrequent: fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, listlessness.
- Cardiovascular System:Frequent: hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; Infrequent: angina pectoris,postural hypotension, myocardial infarction, AV block (first degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thrombosis.
- Digestive System:Frequent: fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; Infrequent: eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue edema, epigastric distress, gastroenteritis, increased transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena, polydipsia, duodenal ulcer, stomach ulcer.
- Endocrine System:Infrequent: diabetes mellitus, goiter.
- Hemic and Lymphatic System:Infrequent: anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia.
- Metabolic and Nutritional Disorders:Frequent: dehydration; Infrequent: gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase.
- Musculoskeletal System:Frequent: bone fracture; Infrequent: muscle weakness, muscle fasciculation.
- Nervous System:Frequent: delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia; Infrequent: cerebrovascular accident, intracranial hemorrhage, transient ischemic attack, emotional lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing.
- Respiratory System:Frequent: dyspnea, sore throat, bronchitis; Infrequent: epistaxis, post nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring.
- Skin and Appendages:Frequent: pruritus, diaphoresis, urticaria; Infrequent: dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer.
- Special Senses:Frequent: cataract, eye irritation, vision blurred; Infrequent: dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots before eyes.
- Urogenital System:Frequent: urinary incontinence, nocturia; Infrequent: dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis.
- Adverse Events Leading to Discontinuation
- The rates of discontinuation from controlled clinical trials of ARICEPT® due to adverse events for the ARICEPT® patients were approximately 12% compared to 7% for placebo patients.
- The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of ARICEPT® patients and at twice the incidence seen in placebo patients, were anorexia (2% vs 1% placebo), nausea (2% vs <1% placebo), diarrhea (2% vs 0% placebo) and urinary tract infection (2% vs 1% placebo).
- Most Frequent Adverse Clinical Events Seen in Association with the Use of ARICEPT®
- The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving ARICEPT® and twice the placebo rate, are largely predicted by ARICEPT®'s cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT® treatment without the need for dose modification.
- Adverse Events Reported in Controlled Trials
- Table 4 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT® and for which the rate of occurrence was greater for ARICEPT® assigned than placebo assigned patients.
- Other Adverse Events Observed During Clinical Trials
- ARICEPT® has been administered to over 600 patients with severe Alzheimer's Disease during clinical trials of at least 6 months duration, including 3 double blind placebo controlled trials, one of which had an open label extension. All adverse events occurring at least twice are included, except for those already listed in Table 4, COSTART terms too general to be informative, or events less likely to be drug caused. Events are classified by body system using the COSTART dictionary and listed using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to ARICEPT® treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.
- Body as a Whole:Frequent: abdominal pain, asthenia, fungal infection, flu syndrome; Infrequent: allergic reaction, cellulitis, malaise, sepsis, face edema, hernia.
- Cardiovascular System:Frequent: hypotension, bradycardia, ECG abnormal, heart failure; Infrequent: myocardial infarction, angina pectoris, atrial fibrillation, congestive heart failure, peripheral vascular disorder, supraventricular extrasystoles, ventricular extrasystoles, cardiomegaly.
- Digestive System:Frequent: constipation, gastroenteritis, fecal incontinence, dyspepsia; Infrequent: gamma glutamyl transpeptidase increase, gastritis, dysphagia, periodontitis, stomach ulcer, periodontal abscess, flatulence, liver function tests abnormal, eructation, esophagitis, rectal hemorrhage.
- Endocrine System:Infrequent: diabetes mellitus.
- Hemic and Lymphatic System:Frequent: anemia; Infrequent: leukocytosis.
- Metabolic and Nutritional Disorders:Frequent: weight loss, peripheral edema, edema, lactic dehydrogenase increased, alkaline phosphatase increased; Infrequent hypercholesteremia, hypokalemia, hypoglycemia, weight gain, bilirubinemia, BUN increased, B12 deficiency anemia, cachexia, creatinine increased, gout, hyponatremia, hypoproteinemia, iron deficiency anemia, SGOT increased, SGPT increased.
- Musculoskeletal System:Frequent: arthritis; Infrequent: arthrosis, bone fracture, arthralgia, leg cramps, osteoporosis, myalgia.
- Nervous System:Frequent: agitation, anxiety, tremor, convulsion, wandering, abnormal gait; Infrequent: apathy, vertigo, delusions, abnormal dreams, cerebrovascular accident, increased salivation, ataxia, euphoria, vasodilatation, cerebral hemorrhage, cerebral infarction, cerebral ischemia, dementia, extrapyramidal syndrome, grand mal convulsion, hemiplegia, hypertonia, hypokinesia.
- Respiratory System:Frequent: pharyngitis, pneumonia, cough increased, bronchitis; Infrequent: dyspnea, rhinitis, asthma.
- Skin and Appendages:Frequent: rash, skin ulcer, pruritus; Infrequent: psoriasis, skin discoloration, herpes zoster, dry skin, sweating, urticaria, vesiculobullous rash
- Special Senses:Infrequent: conjunctivitis, glaucoma, abnormal vision, ear pain, lacrimation disorder.
- Urogenital System:Frequent: urinary tract infection, cystitis, hematuria, glycosuria; Infrequent: vaginitis, dysuria, urinary frequency, albuminuria.
## Postmarketing Experience
- Voluntary reports of adverse events temporally associated with ARICEPT® that have been received since market introduction that are not listed above, and that there is inadequate data to determine the causal relationship with the drug include the following: abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.
# Drug Interactions
- Effect of ARICEPT® on the Metabolism of Other Drugs
- No in vivo clinical trials have investigated the effect of ARICEPT® on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference.
- Whether ARICEPT® has any potential for enzyme induction is not known.
- Formal pharmacokinetic studies evaluated the potential of ARICEPT® for interaction with theophylline, cimetidine, warfarin and digoxin. No significant effects on the pharmacokinetics of these drugs were observed..
- Effect of Other Drugs on the Metabolism of ARICEPT®
- Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect of these inhibitors is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown.
- Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of ARICEPT®.
- Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT® is not significantly affected by concurrent administration of digoxin or cimetidine.
- Use with Anticholinergics
- Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.
- Use with Cholinomimetics and Other Cholinesterase Inhibitors
- A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratology studies conducted in pregnant rats at doses up to 16 mg/kg/day (approximately 13 times the maximum recommended human dose on a mg/m2 basis) and in pregnant rabbits at doses up to 10 mg/kg/day (approximately 16 times the maximum recommended human dose on a mg/m2 basis) did not disclose any evidence for a teratogenic potential of donepezil. However, in a study in which pregnant rats were given up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m2 basis) from day 17 of gestation through day 20 postpartum, there was a slight increase in still births and a slight decrease in pup survival through day 4 postpartum at this dose; the next lower dose tested was 3 mg/kg/day. There are no adequate or well-controlled studies in pregnant women. ARICEPT® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Donepezil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Donepezil during labor and delivery.
### Nursing Mothers
- It is not known whether donepezil is excreted in human breast milk. ARICEPT® has no indication for use in nursing mothers.
### Pediatric Use
- There are no adequate and well-controlled trials to document the safety and efficacy of ARICEPT® in any illness occurring in children.
### Geriatic Use
- Alzheimer's disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the clinical studies with ARICEPT® was 73 years; 80% of these patients were between 65 and 84 years old and 49% of patients were at or above the age of 75. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically significant differences in most adverse events reported by patient groups ≥ 65 years old and < 65 years old.
### Gender
There is no FDA guidance on the use of Donepezil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Donepezil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Donepezil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Donepezil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Donepezil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Donepezil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Donepezil in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Donepezil in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug.
- As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether ARICEPT® and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).
- Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation and lower body surface temperature.
### Management
- Tertiary anticholinergics such as atropine may be used as an antidote for ARICEPT® overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Donepezil in the drug label.
# Pharmacology
## Mechanism of Action
- Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process.
## Structure
- ARICEPT® (donepezil hydrochloride) is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2,3-dihydro-5,6-dimethoxy-2-methyl]-1H-inden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24H29NO3HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile and practically insoluble in ethyl acetate and in n-hexane.
- Each 1mL of ARICEPT® Oral Solution contains 1 mg of donepezil hydrochloride. ARICEPT® Oral Solution also contains sorbitol solution 70%, povidone K-30, citric acid anhydrous, sodium citrate dihydrate, sodium benzoate, methylparaben, propylene glycol, sodium metabisulfite, purified water and strawberry flavor.
## Pharmacodynamics
- Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's Disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process.
## Pharmacokinetics
- ARICEPT® Oral Solution is bioequivalent to ARICEPT® Tablets. Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1-10 mg given once daily. Neither food nor time of administration (morning vs. evening dose) influences the rate or extent of absorption of ARICEPT® Tablets. Administration of ARICEPT® Oral Solution to healthy volunteers with a high-fat meal decreased Cmax by 17% and increased Tmax by 1 hour, while the AUC0-72 was similar under fed and fasted conditions. This delay in absorption and decrease in exposure is not likely to be clinically significant; therefore ARICEPT® Oral Solution can be taken without regard to meals.
- The elimination half life of donepezil is about 70 hours and the mean apparent plasma clearance (Cl/F) is 0.13 L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4-7 fold and steady state is reached within 15 days. The steady state volume of distribution is 12 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha1 - acid glycoprotein (about 21%) over the concentration range of 2-1000 ng/mL.
- Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine as unchanged drug.
- Special Populations
- Hepatic Disease
- In a study of 10 patients with stable alcoholic cirrhosis, the clearance of ARICEPT® was decreased by 20% relative to 10 healthy age and sex matched subjects.
- Renal Disease
- In a study of 4 patients with moderate to severe renal impairment (ClCr< 22 mL/min/1.73 m2) the clearance of ARICEPT® did not differ from 4 age and sex matched healthy subjects.
- Age
- No formal pharmacokinetic study was conducted to examine age related differences in the pharmacokinetics of ARICEPT®. However, mean plasma ARICEPT® concentrations measured during therapeutic drug monitoring of elderly patients with Alzheimer's Disease are comparable to those observed in young healthy volunteers.
- Gender and Race
- No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of ARICEPT®. However, retrospective pharmacokinetic analysis indicates that gender and race (Japanese and Caucasians) did not affect the clearance of ARICEPT®.
- Drug-Drug Interactions
- Drugs Highly Bound to Plasma Proteins
- Drug displacement studies have been performed in vitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. ARICEPT® at concentrations of 0.3-10 μg/mL did not affect the binding of furosemide (5 μg/mL), digoxin (2 ng/mL), and warfarin (3 μg/mL) to human albumin. Similarly, the binding of ARICEPT® to human albumin was not affected by furosemide, digoxin and warfarin.
- Effect of ARICEPT® on the Metabolism of Other Drugs
- No in vivo clinical trials have investigated the effect of ARICEPT® on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference.
- Whether ARICEPT® has any potential for enzyme induction is not known.
- Formal pharmacokinetic studies evaluated the potential of ARICEPT® for interaction with theophylline, cimetidine, warfarin and digoxin. No significant effects on the pharmacokinetics of these drugs were observed.
- Effect of Other Drugs on the Metabolism of ARICEPT®
- Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown.
- Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of ARICEPT®.
- Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT® is not significantly affected by concurrent administration of digoxin or cimetidine.
## Nonclinical Toxicology
- No evidence of a carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil hydrochloride conducted in CD-1 mice at doses up to 180 mg/kg/day (approximately 90 times the maximum recommended human dose on a mg/m2 basis), or in a 104-week carcinogenicity study in Sprague-Dawley rats at doses up to 30mg/kg/day (approximately 30 times the maximum recommended human dose on a mg/m2 basis).
- Donepezil was not mutagenic in the Ames reverse mutation assay in bacteria, or in a mouse lymphoma forward mutation assay in vitro. In the chromosome aberration test in cultures of Chinese hamster lung (CHL) cells, some clastogenic effects were observed. Donepezil was not clastogenic in the in vivo mouse micronucleus test and was not genotoxic in an in vivo unscheduled DNA synthesis assay in rats.
- Donepezil had no effect on fertility in rats at doses up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m2 basis).
# Clinical Studies
- The effectiveness of ARICEPT® as a treatment for Alzheimer's Disease is demonstrated by the results of randomized, double-blind, placebo-controlled clinical investigations in mild, moderate and severe patients with Alzheimer's Disease.
- Mild-Moderate Alzheimer's Disease
- The effectiveness of ARICEPT® as a treatment for Alzheimer's Disease is demonstrated by the results of two randomized, double-blind, placebo-controlled clinical investigations in patients with Alzheimer's Disease (diagnosed by NINCDS and DSM III-R criteria, Mini-Mental State Examination ≥ 10 and ≤ 26 and Clinical Dementia Rating of 1 or 2). The mean age of patients participating in ARICEPT® trials was 73 years with a range of 50 to 94. Approximately 62% of patients were women and 38% were men. The racial distribution was white 95%, black 3% and other races 2%.
- Study Outcome Measures
- In each study, the effectiveness of treatment with ARICEPT® was evaluated using a dual outcome assessment strategy.
- The ability of ARICEPT® to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer's Disease patients. The ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis. The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.
- The patients recruited as participants in each study had mean scores on the Alzheimer's Disease Assessment Scale (ADAS-cog) of approximately 26 units, with a range from 4 to 61. Experience gained in longitudinal studies of ambulatory patients with mild to moderate Alzheimer's Disease suggest that they gain 6 to 12 units a year on the ADAS-cog. However, lesser degrees of change are seen in patients with very mild or very advanced disease because the ADAS-cog is not uniformly sensitive to change over the course of the disease. The annualized rate of decline in the placebo patients participating in ARICEPT® trials was approximately 2 to 4 units per year.
- The ability of ARICEPT® to produce an overall clinical effect was assessed using a Clinician's Interview Based Impression of Change that required the use of caregiver information, the CIBIC plus. The CIBIC plus is not a single instrument and is not a standardized instrument like the ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure.
- As such, results from a CIBIC plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC plus evaluations from other clinical trials. The CIBIC plus used in ARICEPT® trials was a semi-structured instrument that was intended to examine four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC plus is scored as a seven point categorical rating, ranging from a score of 1, indicating "markedly improved," to a score of 4, indicating "no change" to a score of 7, indicating "markedly worse." The CIBIC plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.
- Thirty-Week Study
- In a study of 30 weeks duration, 473 patients were randomized to receive single daily doses of placebo, 5 mg/day or 10 mg/day of ARICEPT®. The 30-week study was divided into a 24-week double-blind active treatment phase followed by a 6-week single-blind placebo washout period. The study was designed to compare 5 mg/day or 10 mg/day fixed doses of ARICEPT® to placebo. However, to reduce the likelihood of cholinergic effects, the 10 mg/day treatment was started following an initial 7-day treatment with 5 mg/day doses.
- Effects on the ADAS-cog
- Figure 1 illustrates the time course for the change from baseline in ADAS-cog scores for all three dose groups over the 30 weeks of the study. After 24 weeks of treatment, the mean differences in the ADAS-cog change scores for ARICEPT® treated patients compared to the patients on placebo were 2.8 and 3.1 units for the 5 mg/day and 10 mg/day treatments, respectively. These differences were statistically significant. While the treatment effect size may appear to be slightly greater for the 10 mg/day treatment, there was no statistically significant difference between the two active treatments.
- Following 6 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT® treatment groups were indistinguishable from those patients who had received only placebo for 30 weeks. This suggests that the beneficial effects of ARICEPT® abate over 6 weeks following discontinuation of treatment and do not represent a change in the underlying disease. There was no evidence of a rebound effect 6 weeks after abrupt discontinuation of therapy.
- Figure 2 illustrates the cumulative percentages of patients from each of the three treatment groups who had attained the measure of improvement in ADAS-cog score shown on the X axis. Three change scores, (7-point and 4-point reductions from baseline or no change in score) have been identified for illustrative purposes and the percent of patients in each group achieving that result is shown in the inset table.
- The curves demonstrate that both patients assigned to placebo and ARICEPT® have a wide range of responses, but that the active treatment groups are more likely to show the greater improvements. A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo, respectively.
- Effects on the CIBIC plus
- Figure 3 is a histogram of the frequency distribution of CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 24 weeks of treatment. The mean drug-placebo differences for these groups of patients were 0.35 units and 0.39 units for 5 mg/day and 10 mg/day of ARICEPT®, respectively. These differences were statistically significant. There was no statistically significant difference between the two active treatments.
- Fifteen-Week Study
- In a study of 15 weeks duration, patients were randomized to receive single daily doses of placebo or either 5 mg/day or 10 mg/day of ARICEPT® for 12 weeks, followed by a 3-week placebo washout period. As in the 30-week study, to avoid acute cholinergic effects, the 10 mg/day treatment followed an initial 7-day treatment with 5 mg/day doses.
- Effects on the ADAS-Cog
- Figure 4 illustrates the time course of the change from baseline in ADAS-cog scores for all three dose groups over the 15 weeks of the study.
- After 12 weeks of treatment, the differences in mean ADAS-cog change scores for the ARICEPT® treated patients compared to the patients on placebo were 2.7 and 3.0 units each, for the 5 and 10 mg/day ARICEPT®treatment groups respectively. These differences were statistically significant. The effect size for the 10 mg/day group may appear to be slightly larger than that for 5 mg/day. However, the differences between active treatments were not statistically significant.
- Following 3 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT® treatment groups increased, indicating that discontinuation of ARICEPT® resulted in a loss of its treatment effect. The duration of this placebo washout period was not sufficient to characterize the rate of loss of the treatment effect, but, the 30-week study (see above) demonstrated that treatment effects associated with the use of ARICEPT® abate within 6 weeks of treatment discontinuation.
- Figure 5 illustrates the cumulative percentages of patients from each of the three treatment groups who attained the measure of improvement in ADAS-cog score shown on the X axis. The same three change scores, (7-point and 4-point reductions from baseline or no change in score) as selected for the 30-week study have been used for this illustration. The percentages of patients achieving those results are shown in the inset table.
- As observed in the 30-week study, the curves demonstrate that patients assigned to either placebo or to ARICEPT® have a wide range of responses, but that the ARICEPT® treated patients are more likely to show the greater improvements in cognitive performance.
- Effects on the CIBIC plus
- Figure 6 is a histogram of the frequency distribution of CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 12 weeks of treatment. The differences in mean scores for ARICEPT® treated patients compared to the patients on placebo at Week 12 were 0.36 and 0.38 units for the 5 mg/day and 10 mg/day treatment groups, respectively. These differences were statistically significant.
- In both studies, patient age, sex and race were not found to predict the clinical outcome of ARICEPT® treatment.
- Swedish 24-Week Study
- The effectiveness of ARICEPT® as a treatment for severe Alzheimer's Disease is demonstrated by the results of a randomized, double-blind, placebo-controlled clinical study conducted in Sweden (24-Week Study) in patients with probable or possible Alzheimer's Disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 1-10. Two hundred and forty eight (248) patients with severe Alzheimer's disease were randomized to ARICEPT® or placebo. For patients randomized to ARICEPT®, treatment was initiated at 5 mg once daily for 28-days and then increased to 10 mg once daily. At the end of the 24-week treatment period, 90.5% of the ARICEPT® -treated patients were receiving the 10 mg dose. The mean age of patients was 84.9 years with a range of 59 to 99. Approximately 77 % of patients were women and 23 % were men. Almost all patients were Caucasian. Probable AD was diagnosed in the majority of the patients (83.6% of ARICEPT®-treated patients and 84.2% of placebo-treated patients).
- Study Outcome Measures
- The effectiveness of treatment with ARICEPT® was determined using a dual outcome assessment strategy that evaluated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment. This study showed that patients on ARICEPT® experienced significant improvement on both measures compared to placebo.
- The ability of ARICEPT® to improve cognitive performance was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB evaluates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
- Daily function was assessed using the Modified Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for Severe Alzheimer's Disease (ADCS-ADL-severe). The ADCS-ADL-severe is derived from the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, which is a comprehensive battery of ADL questions used to measure the functional capabilities of patients. Each ADL item is rated from the highest level of independent performance to complete loss. The ADCS-ADL-severe is a subset of 19 items, including ratings of the patient's ability to eat, dress, bathe, use the telephone, get around (or travel), and perform other activities of daily living; it has been validated for the assessment of patients with moderate to severe dementia. The ADCS-ADL-severe has a scoring range of 0 to 54 with the lower scores indicating greater functional impairment. The investigator performs the inventory by interviewing a caregiver, in this study a nurse staff member, familiar with the functioning of the patient.
- Effects on the SIB
- Figure 7 shows the time course for the change from baseline in SIB score for the two treatment groups over the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the SIB change scores for ARICEPT® -treated patients compared to patients on placebo was 5.9 units. ARICEPT® treatment was statistically significantly superior to placebo.
- Figure 8 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to ARICEPT® and to placebo have a wide range of responses, the curves show that the ARICEPT® group is more likely to show a greater improvement in cognitive performance.
- Effects on the ADCS-ADL-severe
- Figure 9 illustrates the time course for the change from baseline in ADCS-ADL-severe scores for patients in the two treatment groups over the 24 weeks of the study. After 24 weeks of treatment, the mean difference in the ADCS-ADL-severe change scores for ARICEPT® treated patients compared to patients on placebo was 1.8 units. ARICEPT® treatment was statistically significantly superior to placebo.
- Figure 10 shows the cumulative percentages of patients from each treatment group with specified changes from baseline ADCS-ADL-severe scores. While both patients assigned to ARICEPT®and placebo have a wide range of responses, the curves demonstrate that the ARICEPT®group is more likely to show a smaller decline or an improvement.
- Japanese 24-Week Study
- In a study of 24 weeks duration, conducted in Japan, 325 patients with severe Alzheimer's Disease were randomized to doses of 5 mg/day or 10 mg/day of donepezil, administered once daily, or placebo. Patients randomized to treatment with donepezil were to achieve their assigned doses by titration, beginning at 3 mg/day, and extending over a maximum of 6 weeks. 248 patients completed the study with similar proportions of patients completing the study in each treatment group. The primary efficacy measures for this study were the SIB and CIBIC plus.
- At 24 weeks of treatment, statistically significant treatment differences were observed between the 10 mg/day dose of donepezil and placebo on both the SIB and CIBIC plus. The 5 mg/day dose of donepezil showed a statistically significant superiority to placebo on the SIB, but not on the CIBIC plus.
# How Supplied
- ARICEPT® Oral Solution is a clear, colorless to light yellow solution containing 1 mg of donepezil hydrochloride in each mL (1 mg/mL). Each teaspoon (5mL) contains 5 mg of donepezil hydrochloride.
- NDC# 62856-851-30 300 mL HDPE Bottles
- Storage: Store at controlled room temperature, 15°C to 30°C (59°F to 86°F).
## Storage
There is limited information regarding Donepezil Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Donepezil in the drug label.
# Precautions with Alcohol
- Alcohol-Donepezil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Aricept®
# Look-Alike Drug Names
- Aricept® — Aciphex®
- Aricept® — Azilect®
# Drug Shortage Status
# Price | Donepezil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Donepezil is a reversible inhibitor of the enzyme acetylcholinesterase that is FDA approved for the {{{indicationType}}} of dementia of the Alzheimer's type. Common adverse reactions include hypertension, syncope, weight decreased, diarrhea, loss of appetite, nausea, vomiting, contusion, asthenia, depression and urinary incontinence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The dosages of ARICEPT® shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once per day.
- The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of ARICEPT® might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.
- Evidence from the controlled trials indicates that the 10 mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events than the 5 mg dose. In open label trials using a 6 week titration, the frequency of these same adverse events was similar between the 5 mg and 10 mg dose groups. Therefore, because steady state is not achieved for 15 days and because the incidence of untoward effects may be influenced by the rate of dose escalation, treatment with a dose of 10 mg should not be contemplated until patients have been on a daily dose of 5 mg for 4 to 6 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Donepezil in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Donepezil 5 to 10 mg daily for 24 weeks.
- Dosing Information
- Donepezil 10 mg/day.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Donepezil in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Donepezil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Donepezil in pediatric patients.
# Contraindications
- ARICEPT® is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.
# Warnings
### Precautions
- Anesthesia
- ARICEPT®, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
- Cardiovascular Conditions
- Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of ARICEPT®.
- Gastrointestinal Conditions
- Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDS). Clinical studies of ARICEPT® have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
- ARICEPT®, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea and vomiting. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose. In most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of ARICEPT®.
- Genitourinary
- Although not observed in clinical trials of ARICEPT®, cholinomimetics may cause bladder outflow obstruction.
- Neurological Conditions
- Seizures: Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's Disease.
- Pulmonary Conditions
- Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.
- Sulfites
- ARICEPT® Oral Solution contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than nonasthmatic people.
# Adverse Reactions
## Clinical Trials Experience
- Adverse Events Leading to Discontinuation
- The rates of discontinuation from controlled clinical trials of ARICEPT® due to adverse events for the ARICEPT® 5 mg/day treatment groups were comparable to those of placebo-treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5 mg/day to 10 mg/day, was higher at 13%.
- The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of patients and at twice the incidence seen in placebo patients, are shown in Table 1.
- Most Frequent Adverse Clinical Events Seen in Association with the Use of ARICEPT®
- The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by ARICEPT®'s cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT® treatment without the need for dose modification.
- There is evidence to suggest that the frequency of these common adverse events may be affected by the rate of titration. An open-label study was conducted with 269 patients who received placebo in the 15 and 30-week studies. These patients were titrated to a dose of 10 mg/day over a 6-week period. The rates of common adverse events were lower than those seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day.
- See Table 2 for a comparison of the most common adverse events following one and six week titration regimens.
- Adverse Events Reported in Controlled Trials
- The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table 3 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT® and for which the rate of occurrence was greater for ARICEPT® assigned than placebo assigned patients. In general, adverse events occurred more frequently in female patients and with advancing age.
- Other Adverse Events Observed During Clinical Trials
- ARICEPT® has been administered to over 1700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months and 116 patients treated for over 1 year. The range of patient exposure is from 1 to 1214 days.
- Treatment emergent signs and symptoms that occurred during 3 controlled clinical trials and two open-label trials in the United States were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 900 patients from these trials who experienced that event while receiving ARICEPT®. All adverse events occurring at least twice are included, except for those already listed in Tables 2 or 3, COSTART terms too general to be informative, or events less likely to be drug caused. Events are classified by body system and listed using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to ARICEPT® treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. No important additional adverse events were seen in studies conducted outside the United States.
- Body as a Whole:Frequent: influenza, chest pain, toothache; Infrequent: fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, listlessness.
- Cardiovascular System:Frequent: hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; Infrequent: angina pectoris,postural hypotension, myocardial infarction, AV block (first degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thrombosis.
- Digestive System:Frequent: fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; Infrequent: eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue edema, epigastric distress, gastroenteritis, increased transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena, polydipsia, duodenal ulcer, stomach ulcer.
- Endocrine System:Infrequent: diabetes mellitus, goiter.
- Hemic and Lymphatic System:Infrequent: anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia.
- Metabolic and Nutritional Disorders:Frequent: dehydration; Infrequent: gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase.
- Musculoskeletal System:Frequent: bone fracture; Infrequent: muscle weakness, muscle fasciculation.
- Nervous System:Frequent: delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia; Infrequent: cerebrovascular accident, intracranial hemorrhage, transient ischemic attack, emotional lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing.
- Respiratory System:Frequent: dyspnea, sore throat, bronchitis; Infrequent: epistaxis, post nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring.
- Skin and Appendages:Frequent: pruritus, diaphoresis, urticaria; Infrequent: dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer.
- Special Senses:Frequent: cataract, eye irritation, vision blurred; Infrequent: dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots before eyes.
- Urogenital System:Frequent: urinary incontinence, nocturia; Infrequent: dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis.
- Adverse Events Leading to Discontinuation
- The rates of discontinuation from controlled clinical trials of ARICEPT® due to adverse events for the ARICEPT® patients were approximately 12% compared to 7% for placebo patients.
- The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of ARICEPT® patients and at twice the incidence seen in placebo patients, were anorexia (2% vs 1% placebo), nausea (2% vs <1% placebo), diarrhea (2% vs 0% placebo) and urinary tract infection (2% vs 1% placebo).
- Most Frequent Adverse Clinical Events Seen in Association with the Use of ARICEPT®
- The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving ARICEPT® and twice the placebo rate, are largely predicted by ARICEPT®'s cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT® treatment without the need for dose modification.
- Adverse Events Reported in Controlled Trials
- Table 4 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT® and for which the rate of occurrence was greater for ARICEPT® assigned than placebo assigned patients.
- Other Adverse Events Observed During Clinical Trials
- ARICEPT® has been administered to over 600 patients with severe Alzheimer's Disease during clinical trials of at least 6 months duration, including 3 double blind placebo controlled trials, one of which had an open label extension. All adverse events occurring at least twice are included, except for those already listed in Table 4, COSTART terms too general to be informative, or events less likely to be drug caused. Events are classified by body system using the COSTART dictionary and listed using the following definitions: frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to ARICEPT® treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.
- Body as a Whole:Frequent: abdominal pain, asthenia, fungal infection, flu syndrome; Infrequent: allergic reaction, cellulitis, malaise, sepsis, face edema, hernia.
- Cardiovascular System:Frequent: hypotension, bradycardia, ECG abnormal, heart failure; Infrequent: myocardial infarction, angina pectoris, atrial fibrillation, congestive heart failure, peripheral vascular disorder, supraventricular extrasystoles, ventricular extrasystoles, cardiomegaly.
- Digestive System:Frequent: constipation, gastroenteritis, fecal incontinence, dyspepsia; Infrequent: gamma glutamyl transpeptidase increase, gastritis, dysphagia, periodontitis, stomach ulcer, periodontal abscess, flatulence, liver function tests abnormal, eructation, esophagitis, rectal hemorrhage.
- Endocrine System:Infrequent: diabetes mellitus.
- Hemic and Lymphatic System:Frequent: anemia; Infrequent: leukocytosis.
- Metabolic and Nutritional Disorders:Frequent: weight loss, peripheral edema, edema, lactic dehydrogenase increased, alkaline phosphatase increased; Infrequent hypercholesteremia, hypokalemia, hypoglycemia, weight gain, bilirubinemia, BUN increased, B12 deficiency anemia, cachexia, creatinine increased, gout, hyponatremia, hypoproteinemia, iron deficiency anemia, SGOT increased, SGPT increased.
- Musculoskeletal System:Frequent: arthritis; Infrequent: arthrosis, bone fracture, arthralgia, leg cramps, osteoporosis, myalgia.
- Nervous System:Frequent: agitation, anxiety, tremor, convulsion, wandering, abnormal gait; Infrequent: apathy, vertigo, delusions, abnormal dreams, cerebrovascular accident, increased salivation, ataxia, euphoria, vasodilatation, cerebral hemorrhage, cerebral infarction, cerebral ischemia, dementia, extrapyramidal syndrome, grand mal convulsion, hemiplegia, hypertonia, hypokinesia.
- Respiratory System:Frequent: pharyngitis, pneumonia, cough increased, bronchitis; Infrequent: dyspnea, rhinitis, asthma.
- Skin and Appendages:Frequent: rash, skin ulcer, pruritus; Infrequent: psoriasis, skin discoloration, herpes zoster, dry skin, sweating, urticaria, vesiculobullous rash
- Special Senses:Infrequent: conjunctivitis, glaucoma, abnormal vision, ear pain, lacrimation disorder.
- Urogenital System:Frequent: urinary tract infection, cystitis, hematuria, glycosuria; Infrequent: vaginitis, dysuria, urinary frequency, albuminuria.
## Postmarketing Experience
- Voluntary reports of adverse events temporally associated with ARICEPT® that have been received since market introduction that are not listed above, and that there is inadequate data to determine the causal relationship with the drug include the following: abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.
# Drug Interactions
- Effect of ARICEPT® on the Metabolism of Other Drugs
- No in vivo clinical trials have investigated the effect of ARICEPT® on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference.
- Whether ARICEPT® has any potential for enzyme induction is not known.
- Formal pharmacokinetic studies evaluated the potential of ARICEPT® for interaction with theophylline, cimetidine, warfarin and digoxin. No significant effects on the pharmacokinetics of these drugs were observed..
- Effect of Other Drugs on the Metabolism of ARICEPT®
- Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect of these inhibitors is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown.
- Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of ARICEPT®.
- Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT® is not significantly affected by concurrent administration of digoxin or cimetidine.
- Use with Anticholinergics
- Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.
- Use with Cholinomimetics and Other Cholinesterase Inhibitors
- A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratology studies conducted in pregnant rats at doses up to 16 mg/kg/day (approximately 13 times the maximum recommended human dose on a mg/m2 basis) and in pregnant rabbits at doses up to 10 mg/kg/day (approximately 16 times the maximum recommended human dose on a mg/m2 basis) did not disclose any evidence for a teratogenic potential of donepezil. However, in a study in which pregnant rats were given up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m2 basis) from day 17 of gestation through day 20 postpartum, there was a slight increase in still births and a slight decrease in pup survival through day 4 postpartum at this dose; the next lower dose tested was 3 mg/kg/day. There are no adequate or well-controlled studies in pregnant women. ARICEPT® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Donepezil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Donepezil during labor and delivery.
### Nursing Mothers
- It is not known whether donepezil is excreted in human breast milk. ARICEPT® has no indication for use in nursing mothers.
### Pediatric Use
- There are no adequate and well-controlled trials to document the safety and efficacy of ARICEPT® in any illness occurring in children.
### Geriatic Use
- Alzheimer's disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the clinical studies with ARICEPT® was 73 years; 80% of these patients were between 65 and 84 years old and 49% of patients were at or above the age of 75. The efficacy and safety data presented in the clinical trials section were obtained from these patients. There were no clinically significant differences in most adverse events reported by patient groups ≥ 65 years old and < 65 years old.
### Gender
There is no FDA guidance on the use of Donepezil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Donepezil with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Donepezil in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Donepezil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Donepezil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Donepezil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Donepezil in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Donepezil in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug.
- As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether ARICEPT® and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).
- Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation and lower body surface temperature.
### Management
- Tertiary anticholinergics such as atropine may be used as an antidote for ARICEPT® overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Donepezil in the drug label.
# Pharmacology
## Mechanism of Action
- Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process.
## Structure
- ARICEPT® (donepezil hydrochloride) is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2,3-dihydro-5,6-dimethoxy-2-[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24H29NO3HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile and practically insoluble in ethyl acetate and in n-hexane.
- Each 1mL of ARICEPT® Oral Solution contains 1 mg of donepezil hydrochloride. ARICEPT® Oral Solution also contains sorbitol solution 70%, povidone K-30, citric acid anhydrous, sodium citrate dihydrate, sodium benzoate, methylparaben, propylene glycol, sodium metabisulfite, purified water and strawberry flavor.
## Pharmacodynamics
- Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's Disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process.
## Pharmacokinetics
- ARICEPT® Oral Solution is bioequivalent to ARICEPT® Tablets. Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1-10 mg given once daily. Neither food nor time of administration (morning vs. evening dose) influences the rate or extent of absorption of ARICEPT® Tablets. Administration of ARICEPT® Oral Solution to healthy volunteers with a high-fat meal decreased Cmax by 17% and increased Tmax by 1 hour, while the AUC0-72 was similar under fed and fasted conditions. This delay in absorption and decrease in exposure is not likely to be clinically significant; therefore ARICEPT® Oral Solution can be taken without regard to meals.
- The elimination half life of donepezil is about 70 hours and the mean apparent plasma clearance (Cl/F) is 0.13 L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4-7 fold and steady state is reached within 15 days. The steady state volume of distribution is 12 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha1 - acid glycoprotein (about 21%) over the concentration range of 2-1000 ng/mL.
- Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine as unchanged drug.
- Special Populations
- Hepatic Disease
- In a study of 10 patients with stable alcoholic cirrhosis, the clearance of ARICEPT® was decreased by 20% relative to 10 healthy age and sex matched subjects.
- Renal Disease
- In a study of 4 patients with moderate to severe renal impairment (ClCr< 22 mL/min/1.73 m2) the clearance of ARICEPT® did not differ from 4 age and sex matched healthy subjects.
- Age
- No formal pharmacokinetic study was conducted to examine age related differences in the pharmacokinetics of ARICEPT®. However, mean plasma ARICEPT® concentrations measured during therapeutic drug monitoring of elderly patients with Alzheimer's Disease are comparable to those observed in young healthy volunteers.
- Gender and Race
- No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of ARICEPT®. However, retrospective pharmacokinetic analysis indicates that gender and race (Japanese and Caucasians) did not affect the clearance of ARICEPT®.
- Drug-Drug Interactions
- Drugs Highly Bound to Plasma Proteins
- Drug displacement studies have been performed in vitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. ARICEPT® at concentrations of 0.3-10 μg/mL did not affect the binding of furosemide (5 μg/mL), digoxin (2 ng/mL), and warfarin (3 μg/mL) to human albumin. Similarly, the binding of ARICEPT® to human albumin was not affected by furosemide, digoxin and warfarin.
- Effect of ARICEPT® on the Metabolism of Other Drugs
- No in vivo clinical trials have investigated the effect of ARICEPT® on the clearance of drugs metabolized by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference.
- Whether ARICEPT® has any potential for enzyme induction is not known.
- Formal pharmacokinetic studies evaluated the potential of ARICEPT® for interaction with theophylline, cimetidine, warfarin and digoxin. No significant effects on the pharmacokinetics of these drugs were observed.
- Effect of Other Drugs on the Metabolism of ARICEPT®
- Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown.
- Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of ARICEPT®.
- Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT® is not significantly affected by concurrent administration of digoxin or cimetidine.
## Nonclinical Toxicology
- No evidence of a carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil hydrochloride conducted in CD-1 mice at doses up to 180 mg/kg/day (approximately 90 times the maximum recommended human dose on a mg/m2 basis), or in a 104-week carcinogenicity study in Sprague-Dawley rats at doses up to 30mg/kg/day (approximately 30 times the maximum recommended human dose on a mg/m2 basis).
- Donepezil was not mutagenic in the Ames reverse mutation assay in bacteria, or in a mouse lymphoma forward mutation assay in vitro. In the chromosome aberration test in cultures of Chinese hamster lung (CHL) cells, some clastogenic effects were observed. Donepezil was not clastogenic in the in vivo mouse micronucleus test and was not genotoxic in an in vivo unscheduled DNA synthesis assay in rats.
- Donepezil had no effect on fertility in rats at doses up to 10 mg/kg/day (approximately 8 times the maximum recommended human dose on a mg/m2 basis).
# Clinical Studies
- The effectiveness of ARICEPT® as a treatment for Alzheimer's Disease is demonstrated by the results of randomized, double-blind, placebo-controlled clinical investigations in mild, moderate and severe patients with Alzheimer's Disease.
- Mild-Moderate Alzheimer's Disease
- The effectiveness of ARICEPT® as a treatment for Alzheimer's Disease is demonstrated by the results of two randomized, double-blind, placebo-controlled clinical investigations in patients with Alzheimer's Disease (diagnosed by NINCDS and DSM III-R criteria, Mini-Mental State Examination ≥ 10 and ≤ 26 and Clinical Dementia Rating of 1 or 2). The mean age of patients participating in ARICEPT® trials was 73 years with a range of 50 to 94. Approximately 62% of patients were women and 38% were men. The racial distribution was white 95%, black 3% and other races 2%.
- Study Outcome Measures
- In each study, the effectiveness of treatment with ARICEPT® was evaluated using a dual outcome assessment strategy.
- The ability of ARICEPT® to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer's Disease patients. The ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis. The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.
- The patients recruited as participants in each study had mean scores on the Alzheimer's Disease Assessment Scale (ADAS-cog) of approximately 26 units, with a range from 4 to 61. Experience gained in longitudinal studies of ambulatory patients with mild to moderate Alzheimer's Disease suggest that they gain 6 to 12 units a year on the ADAS-cog. However, lesser degrees of change are seen in patients with very mild or very advanced disease because the ADAS-cog is not uniformly sensitive to change over the course of the disease. The annualized rate of decline in the placebo patients participating in ARICEPT® trials was approximately 2 to 4 units per year.
- The ability of ARICEPT® to produce an overall clinical effect was assessed using a Clinician's Interview Based Impression of Change that required the use of caregiver information, the CIBIC plus. The CIBIC plus is not a single instrument and is not a standardized instrument like the ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure.
- As such, results from a CIBIC plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC plus evaluations from other clinical trials. The CIBIC plus used in ARICEPT® trials was a semi-structured instrument that was intended to examine four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC plus is scored as a seven point categorical rating, ranging from a score of 1, indicating "markedly improved," to a score of 4, indicating "no change" to a score of 7, indicating "markedly worse." The CIBIC plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.
- Thirty-Week Study
- In a study of 30 weeks duration, 473 patients were randomized to receive single daily doses of placebo, 5 mg/day or 10 mg/day of ARICEPT®. The 30-week study was divided into a 24-week double-blind active treatment phase followed by a 6-week single-blind placebo washout period. The study was designed to compare 5 mg/day or 10 mg/day fixed doses of ARICEPT® to placebo. However, to reduce the likelihood of cholinergic effects, the 10 mg/day treatment was started following an initial 7-day treatment with 5 mg/day doses.
- Effects on the ADAS-cog
- Figure 1 illustrates the time course for the change from baseline in ADAS-cog scores for all three dose groups over the 30 weeks of the study. After 24 weeks of treatment, the mean differences in the ADAS-cog change scores for ARICEPT® treated patients compared to the patients on placebo were 2.8 and 3.1 units for the 5 mg/day and 10 mg/day treatments, respectively. These differences were statistically significant. While the treatment effect size may appear to be slightly greater for the 10 mg/day treatment, there was no statistically significant difference between the two active treatments.
- Following 6 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT® treatment groups were indistinguishable from those patients who had received only placebo for 30 weeks. This suggests that the beneficial effects of ARICEPT® abate over 6 weeks following discontinuation of treatment and do not represent a change in the underlying disease. There was no evidence of a rebound effect 6 weeks after abrupt discontinuation of therapy.
- Figure 2 illustrates the cumulative percentages of patients from each of the three treatment groups who had attained the measure of improvement in ADAS-cog score shown on the X axis. Three change scores, (7-point and 4-point reductions from baseline or no change in score) have been identified for illustrative purposes and the percent of patients in each group achieving that result is shown in the inset table.
- The curves demonstrate that both patients assigned to placebo and ARICEPT® have a wide range of responses, but that the active treatment groups are more likely to show the greater improvements. A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo, respectively.
- Effects on the CIBIC plus
- Figure 3 is a histogram of the frequency distribution of CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 24 weeks of treatment. The mean drug-placebo differences for these groups of patients were 0.35 units and 0.39 units for 5 mg/day and 10 mg/day of ARICEPT®, respectively. These differences were statistically significant. There was no statistically significant difference between the two active treatments.
- Fifteen-Week Study
- In a study of 15 weeks duration, patients were randomized to receive single daily doses of placebo or either 5 mg/day or 10 mg/day of ARICEPT® for 12 weeks, followed by a 3-week placebo washout period. As in the 30-week study, to avoid acute cholinergic effects, the 10 mg/day treatment followed an initial 7-day treatment with 5 mg/day doses.
- Effects on the ADAS-Cog
- Figure 4 illustrates the time course of the change from baseline in ADAS-cog scores for all three dose groups over the 15 weeks of the study.
- After 12 weeks of treatment, the differences in mean ADAS-cog change scores for the ARICEPT® treated patients compared to the patients on placebo were 2.7 and 3.0 units each, for the 5 and 10 mg/day ARICEPT®treatment groups respectively. These differences were statistically significant. The effect size for the 10 mg/day group may appear to be slightly larger than that for 5 mg/day. However, the differences between active treatments were not statistically significant.
- Following 3 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT® treatment groups increased, indicating that discontinuation of ARICEPT® resulted in a loss of its treatment effect. The duration of this placebo washout period was not sufficient to characterize the rate of loss of the treatment effect, but, the 30-week study (see above) demonstrated that treatment effects associated with the use of ARICEPT® abate within 6 weeks of treatment discontinuation.
- Figure 5 illustrates the cumulative percentages of patients from each of the three treatment groups who attained the measure of improvement in ADAS-cog score shown on the X axis. The same three change scores, (7-point and 4-point reductions from baseline or no change in score) as selected for the 30-week study have been used for this illustration. The percentages of patients achieving those results are shown in the inset table.
- As observed in the 30-week study, the curves demonstrate that patients assigned to either placebo or to ARICEPT® have a wide range of responses, but that the ARICEPT® treated patients are more likely to show the greater improvements in cognitive performance.
- Effects on the CIBIC plus
- Figure 6 is a histogram of the frequency distribution of CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 12 weeks of treatment. The differences in mean scores for ARICEPT® treated patients compared to the patients on placebo at Week 12 were 0.36 and 0.38 units for the 5 mg/day and 10 mg/day treatment groups, respectively. These differences were statistically significant.
- In both studies, patient age, sex and race were not found to predict the clinical outcome of ARICEPT® treatment.
- Swedish 24-Week Study
- The effectiveness of ARICEPT® as a treatment for severe Alzheimer's Disease is demonstrated by the results of a randomized, double-blind, placebo-controlled clinical study conducted in Sweden (24-Week Study) in patients with probable or possible Alzheimer's Disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 1-10. Two hundred and forty eight (248) patients with severe Alzheimer's disease were randomized to ARICEPT® or placebo. For patients randomized to ARICEPT®, treatment was initiated at 5 mg once daily for 28-days and then increased to 10 mg once daily. At the end of the 24-week treatment period, 90.5% of the ARICEPT® -treated patients were receiving the 10 mg dose. The mean age of patients was 84.9 years with a range of 59 to 99. Approximately 77 % of patients were women and 23 % were men. Almost all patients were Caucasian. Probable AD was diagnosed in the majority of the patients (83.6% of ARICEPT®-treated patients and 84.2% of placebo-treated patients).
- Study Outcome Measures
- The effectiveness of treatment with ARICEPT® was determined using a dual outcome assessment strategy that evaluated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment. This study showed that patients on ARICEPT® experienced significant improvement on both measures compared to placebo.
- The ability of ARICEPT® to improve cognitive performance was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB evaluates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
- Daily function was assessed using the Modified Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for Severe Alzheimer's Disease (ADCS-ADL-severe). The ADCS-ADL-severe is derived from the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, which is a comprehensive battery of ADL questions used to measure the functional capabilities of patients. Each ADL item is rated from the highest level of independent performance to complete loss. The ADCS-ADL-severe is a subset of 19 items, including ratings of the patient's ability to eat, dress, bathe, use the telephone, get around (or travel), and perform other activities of daily living; it has been validated for the assessment of patients with moderate to severe dementia. The ADCS-ADL-severe has a scoring range of 0 to 54 with the lower scores indicating greater functional impairment. The investigator performs the inventory by interviewing a caregiver, in this study a nurse staff member, familiar with the functioning of the patient.
- Effects on the SIB
- Figure 7 shows the time course for the change from baseline in SIB score for the two treatment groups over the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the SIB change scores for ARICEPT® -treated patients compared to patients on placebo was 5.9 units. ARICEPT® treatment was statistically significantly superior to placebo.
- Figure 8 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to ARICEPT® and to placebo have a wide range of responses, the curves show that the ARICEPT® group is more likely to show a greater improvement in cognitive performance.
- Effects on the ADCS-ADL-severe
- Figure 9 illustrates the time course for the change from baseline in ADCS-ADL-severe scores for patients in the two treatment groups over the 24 weeks of the study. After 24 weeks of treatment, the mean difference in the ADCS-ADL-severe change scores for ARICEPT® treated patients compared to patients on placebo was 1.8 units. ARICEPT® treatment was statistically significantly superior to placebo.
- Figure 10 shows the cumulative percentages of patients from each treatment group with specified changes from baseline ADCS-ADL-severe scores. While both patients assigned to ARICEPT®and placebo have a wide range of responses, the curves demonstrate that the ARICEPT®group is more likely to show a smaller decline or an improvement.
- Japanese 24-Week Study
- In a study of 24 weeks duration, conducted in Japan, 325 patients with severe Alzheimer's Disease were randomized to doses of 5 mg/day or 10 mg/day of donepezil, administered once daily, or placebo. Patients randomized to treatment with donepezil were to achieve their assigned doses by titration, beginning at 3 mg/day, and extending over a maximum of 6 weeks. 248 patients completed the study with similar proportions of patients completing the study in each treatment group. The primary efficacy measures for this study were the SIB and CIBIC plus.
- At 24 weeks of treatment, statistically significant treatment differences were observed between the 10 mg/day dose of donepezil and placebo on both the SIB and CIBIC plus. The 5 mg/day dose of donepezil showed a statistically significant superiority to placebo on the SIB, but not on the CIBIC plus.
# How Supplied
- ARICEPT® Oral Solution is a clear, colorless to light yellow solution containing 1 mg of donepezil hydrochloride in each mL (1 mg/mL). Each teaspoon (5mL) contains 5 mg of donepezil hydrochloride.
- NDC# 62856-851-30 300 mL HDPE Bottles
- Storage: Store at controlled room temperature, 15°C to 30°C (59°F to 86°F).
## Storage
There is limited information regarding Donepezil Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Donepezil in the drug label.
# Precautions with Alcohol
- Alcohol-Donepezil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Aricept®[1]
# Look-Alike Drug Names
- Aricept® — Aciphex®[2]
- Aricept® — Azilect®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Aricept | |
6c072f12fc325b3a0512274bb5f74454d8ebf842 | wikidoc | Aromatase | Aromatase
Aromatase, also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily (EC 1.14.14.1), which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into estrogens. The aromatase enzyme can be found in many tissues including gonads (granulosa cells), brain, adipose tissue, placenta, blood vessels, skin, and bone, as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer. It is an important factor in sexual development.
# Function
Aromatase is localized in the endoplasmic reticulum where it is regulated by tissue-specific promoters that are in turn controlled by hormones, cytokines, and other factors. It catalyzes the last steps of estrogen biosynthesis from androgens (specifically, it transforms androstenedione to estrone and testosterone to estradiol). These steps include three successive hydroxylations of the 19-methyl group of androgens, followed by simultaneous elimination of the methyl group as formate and aromatization of the A-ring.
# Genomics
The gene expresses two transcript variants. In humans, the gene CYP19, located on chromosome 15q21.1, encodes the aromatase enzyme. The gene has nine coding exons and a number of alternative non-coding first exons that regulate tissue specific expression.
CYP19 is present in an early-diverging chordate, the cephalochordate amphioxus (the Florida lancelet, Branchiostoma floridae), but not in the earlier diverging tunicate Ciona intestinalis. Thus, the aromatase gene evolved early in chordate evolution and does not appear to be present in nonchordate invertebrates (e.g. insects, molluscs, echinoderms, sponges, corals). However, estrogens may be synthesized in some of these organisms, via other unknown pathways.
# Activity
Factors known to increase aromatase activity include age, obesity, insulin, gonadotropins, and alcohol. Aromatase activity is decreased by prolactin, anti-Müllerian hormone and the common herbicide glyphosate.
Aromatase activity appears to be enhanced in certain estrogen-dependent local tissue next to breast tissue, endometrial cancer, endometriosis, and uterine fibroids.
# Role in sex-determination
Aromatase is generally highly present during the differentiation of ovaries. It is also susceptible to environmental influences, particularly temperature. In species with temperature-dependent sex determination, aromatase is expressed in higher quantities at temperatures that yield female offspring. Despite the fact that data suggest temperature controls aromatase quantities, other studies have shown that aromatase can overpower the effects of temperature: if exposed to more aromatase at a male-producing temperature, the organism will develop female and conversely, if exposed to less aromatase at female-producing temperatures, the organism will develop male (see sex reversal). In organisms that develop through genetic sex determination, temperature does not affect aromatase expression and function, suggesting that aromatase is the target molecule for temperature during TSD (for challenges to this argument, see temperature-dependent sex determination). It varies from species to species whether it is the aromatase protein that has different activity at different temperatures or whether the amount of transcription undergone by the aromatase gene is what is temperature-sensitive, but in either case, differential development is observed at different temperatures.
# Role in neuroprotection
Aromatase in the brain is usually only expressed in neurons. However, following penetrative brain injury of both mice and zebra finches, it has been shown to be expressed in astrocytes. Furthermore, it has also been shown to decrease apoptosis following brain injury in zebra finches. This is thought to be due to the neuroprotective actions of estrogens, including estradiol. Research has found that two pro-inflammatory cytokines, interleukin-1β (IL-1β) and interleukin-6 (IL-6), are responsible for the induction of aromatase expression in astrocytes following penetrative brain injury in the zebra finch.
# Disorders
## Aromatase excess syndrome
A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it can lead to gynecomastia, and in girls to precocious puberty and gigantomastia. In both sexes, early epiphyseal closure leads to short stature. This condition is due to mutations in the CYP19A1 gene which encodes aromatase. It is inherited in an autosomal dominant fashion. It has been suggested that the pharaoh Akhenaten and other members of his family may have suffered from this disorder, but more recent genetic tests suggest otherwise. It is one of the causes of familial precocious puberty—a condition first described in 1937.
## Aromatase deficiency syndrome
This syndrome is due to a mutation of gene CYP19 and inherited in an autosomal recessive pattern. It occurs due to inability to synthesize estrogens from androgens. Accumulations of androgens during pregnancy may lead to masculinization and virilization of a female at birth (males are not affected). Females will have primary amenorrhea. Individuals of both sexes will be tall, as lack of estrogen does not bring the epiphyseal lines to closure. Mothers affected may present with virilization during pregnancy as androgen hormones cross the placenta.
# Inhibition of aromatase
The inhibition of aromatase can cause hypoestrogenism (low estrogen levels). The following natural products have been found to have inhibiting effects on aromatase.
- Apigenin
- Catechin
- Chalcones
- Eriodictyol
- Isoliquiritigenin
- Mangostin
- Myosmine
- Nicotine
- Resveratrol
- Vitamin E
- Zinc
- Hesperetin
Extracts of certain (white button variety: Agaricus bisporus) mushrooms have been shown to inhibit aromatase in vitro.
## Pharmaceutical aromatase inhibitors
Aromatase inhibitors, which stop the production of estrogen in postmenopausal women, have become useful in the management of patients with breast cancer whose lesion was found to be estrogen receptor positive. Inhibitors that are in current clinical use include anastrozole, exemestane, and letrozole. Aromatase inhibitors are also beginning to be prescribed to men on testosterone replacement therapy as a way to keep estrogen levels from spiking once doses of testosterone are introduced to their systems. | Aromatase
Aromatase, also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily (EC 1.14.14.1), which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into estrogens. The aromatase enzyme can be found in many tissues including gonads (granulosa cells), brain, adipose tissue, placenta, blood vessels, skin, and bone, as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer.[citation needed] It is an important factor in sexual development.
# Function
Aromatase is localized in the endoplasmic reticulum where it is regulated by tissue-specific promoters that are in turn controlled by hormones, cytokines, and other factors. It catalyzes the last steps of estrogen biosynthesis from androgens (specifically, it transforms androstenedione to estrone and testosterone to estradiol). These steps include three successive hydroxylations of the 19-methyl group of androgens, followed by simultaneous elimination of the methyl group as formate and aromatization of the A-ring.
# Genomics
The gene expresses two transcript variants.[2] In humans, the gene CYP19, located on chromosome 15q21.1, encodes the aromatase enzyme.[3] The gene has nine coding exons and a number of alternative non-coding first exons that regulate tissue specific expression.[4]
CYP19 is present in an early-diverging chordate, the cephalochordate amphioxus (the Florida lancelet, Branchiostoma floridae), but not in the earlier diverging tunicate Ciona intestinalis. Thus, the aromatase gene evolved early in chordate evolution and does not appear to be present in nonchordate invertebrates (e.g. insects, molluscs, echinoderms, sponges, corals). However, estrogens may be synthesized in some of these organisms, via other unknown pathways.
# Activity
Factors known to increase aromatase activity include age, obesity, insulin, gonadotropins, and alcohol. Aromatase activity is decreased by prolactin, anti-Müllerian hormone and the common herbicide glyphosate.[5]
Aromatase activity appears to be enhanced in certain estrogen-dependent local tissue next to breast tissue, endometrial cancer, endometriosis, and uterine fibroids.
# Role in sex-determination
Aromatase is generally highly present during the differentiation of ovaries.[6][7] It is also susceptible to environmental influences, particularly temperature. In species with temperature-dependent sex determination, aromatase is expressed in higher quantities at temperatures that yield female offspring.[6] Despite the fact that data suggest temperature controls aromatase quantities, other studies have shown that aromatase can overpower the effects of temperature: if exposed to more aromatase at a male-producing temperature, the organism will develop female and conversely, if exposed to less aromatase at female-producing temperatures, the organism will develop male (see sex reversal).[6] In organisms that develop through genetic sex determination, temperature does not affect aromatase expression and function, suggesting that aromatase is the target molecule for temperature during TSD[6] (for challenges to this argument, see temperature-dependent sex determination). It varies from species to species whether it is the aromatase protein that has different activity at different temperatures or whether the amount of transcription undergone by the aromatase gene is what is temperature-sensitive, but in either case, differential development is observed at different temperatures.[8]
# Role in neuroprotection
Aromatase in the brain is usually only expressed in neurons. However, following penetrative brain injury of both mice and zebra finches, it has been shown to be expressed in astrocytes.[9] Furthermore, it has also been shown to decrease apoptosis following brain injury in zebra finches.[10] This is thought to be due to the neuroprotective actions of estrogens, including estradiol. Research has found that two pro-inflammatory cytokines, interleukin-1β (IL-1β) and interleukin-6 (IL-6), are responsible for the induction of aromatase expression in astrocytes following penetrative brain injury in the zebra finch.[11]
# Disorders
## Aromatase excess syndrome
A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it can lead to gynecomastia, and in girls to precocious puberty and gigantomastia. In both sexes, early epiphyseal closure leads to short stature. This condition is due to mutations in the CYP19A1 gene which encodes aromatase.[12] It is inherited in an autosomal dominant fashion.[13] It has been suggested that the pharaoh Akhenaten and other members of his family may have suffered from this disorder,[14] but more recent genetic tests suggest otherwise.[15] It is one of the causes of familial precocious puberty—a condition first described in 1937.[16]
## Aromatase deficiency syndrome
This syndrome is due to a mutation of gene CYP19 and inherited in an autosomal recessive pattern. It occurs due to inability to synthesize estrogens from androgens. Accumulations of androgens during pregnancy may lead to masculinization and virilization of a female at birth (males are not affected). Females will have primary amenorrhea. Individuals of both sexes will be tall, as lack of estrogen does not bring the epiphyseal lines to closure. Mothers affected may present with virilization during pregnancy as androgen hormones cross the placenta.
# Inhibition of aromatase
The inhibition of aromatase can cause hypoestrogenism (low estrogen levels). The following natural products have been found to have inhibiting effects on aromatase.
- Apigenin[17]
- Catechin[18][19]
- Chalcones[20]
- Eriodictyol[17]
- Isoliquiritigenin[17]
- Mangostin[17]
- Myosmine[21]
- Nicotine[22]
- Resveratrol[23]
- Vitamin E[24]
- Zinc[25]
- Hesperetin[26]
Extracts of certain (white button variety: Agaricus bisporus) mushrooms have been shown to inhibit aromatase in vitro.[27]
## Pharmaceutical aromatase inhibitors
Aromatase inhibitors, which stop the production of estrogen in postmenopausal women, have become useful in the management of patients with breast cancer whose lesion was found to be estrogen receptor positive.[28] Inhibitors that are in current clinical use include anastrozole, exemestane, and letrozole. Aromatase inhibitors are also beginning to be prescribed to men on testosterone replacement therapy as a way to keep estrogen levels from spiking once doses of testosterone are introduced to their systems. | https://www.wikidoc.org/index.php/Aromatase | |
ab78da129213486dbbb25b5dce318416c16afe42 | wikidoc | Arteriole | Arteriole
# Overview
An arteriole is a small diameter blood vessel that extends and branches out from an artery and leads to capillaries.
Arterioles have thin muscular walls (usually only one to two layers of smooth muscle) and are the primary site of vascular resistance.
This means blood pressure in the arteries supplying the body is a result of the interaction between the cardiac output (the volume of blood the heart is pumping per minute) and the vascular resistance, usually termed total peripheral resistance by physicians and researchers.
# Natural fluctuation
The up and down fluctuation of the arterial blood pressure is due to the pulsatile nature of the cardiac output and determined by the interaction of the stroke volume versus the volume and elasticity of the major arteries.
In a healthy vascular system the endothelium, inner lining of arterioles and other blood vessels, is smooth and the vessel is relaxed.
This healthy condition is promoted by the ample production of nitric oxide in the endothelium, which biochemical reaction is regulated by a complex balance of polyphenols, various nitric oxide synthase enzymes and L-arginine. In addition there is direct communication via gap junctions between the endothelial cells and the vascular smooth muscle
# Pathology
Any pathogen which constricts blood flow, such as stenosis, will increase total peripheral resistance and lead to hypertension.
# Medication
The muscular contraction of arterioles is targeted by drugs that lower blood pressure (antihypertensives), for example the dihydropyridines (nifedipine and nicardipine), which block the calcium conductance in the muscular layer of the arterioles, causing relaxation.
This decreases the resistance to flow into peripheral vascular beds, lowering overall systemic pressure.
# Metarterioles
A "metarteriole" is an arteriole which bypasses capillary circulation. | Arteriole
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An arteriole is a small diameter blood vessel that extends and branches out from an artery and leads to capillaries.
Arterioles have thin muscular walls (usually only one to two layers of smooth muscle) and are the primary site of vascular resistance[1].
This means blood pressure in the arteries supplying the body is a result of the interaction between the cardiac output (the volume of blood the heart is pumping per minute) and the vascular resistance, usually termed total peripheral resistance by physicians and researchers.
# Natural fluctuation
The up and down fluctuation of the arterial blood pressure is due to the pulsatile nature of the cardiac output and determined by the interaction of the stroke volume versus the volume and elasticity of the major arteries.
In a healthy vascular system the endothelium, inner lining of arterioles and other blood vessels, is smooth and the vessel is relaxed.
This healthy condition is promoted by the ample production of nitric oxide in the endothelium, which biochemical reaction is regulated by a complex balance of polyphenols, various nitric oxide synthase enzymes and L-arginine. In addition there is direct communication via gap junctions between the endothelial cells and the vascular smooth muscle
# Pathology
Any pathogen which constricts blood flow, such as stenosis, will increase total peripheral resistance and lead to hypertension.
# Medication
The muscular contraction of arterioles is targeted by drugs that lower blood pressure (antihypertensives), for example the dihydropyridines (nifedipine and nicardipine), which block the calcium conductance in the muscular layer of the arterioles, causing relaxation.
This decreases the resistance to flow into peripheral vascular beds, lowering overall systemic pressure.
# Metarterioles
A "metarteriole" is an arteriole which bypasses capillary circulation.[2] | https://www.wikidoc.org/index.php/Arteriole | |
caa158ed099724b2da82b7ecd7cae3cf678c2b94 | wikidoc | Arthritis | Arthritis
# Overview
Arthritis (from Greek arthro-, joint + -itis, inflammation; plural: arthritides) could be defined as painful joint damage. It might be as part of a systemic disorder or a single joint involvement. Arthritis may present as joint pain (arthralgia), swelling, erythema, warmness, and limitation of movement. It could be classified according to the number of involved joints, presence of inflammation, or duration of symptoms. Osteoarthritis (also known as degenerative joint disease) is the most common form of arthritis in the United States which involves up to 10% of population older than 60 years. Inflammatory arthritis is common in systemic autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus (SLE) and is part of diagnostic criteria for this spectrum of diseases. Disease course in systemic disorders is usually chronic and multiple joints (polyarticular) are involved. In the other hand, infectious conditions like septic arthritis are acute in nature and they usually involve single joints (monoarticular). Crystal induced arthropathies may result in inflammatory joint(s) involvement, mainly are due to uric acid crystal deposition (gout) in articular space. Although, disease course and presence of other systemic manifestations are important for diagnosis but the gold standard method for diagnosis is joint aspiration, fluid analysis, and microscopic evaluation. Imaging might be helpful in certain condition to find the disease chronicity and structural changes in articular and periarticular structures. Prompt treatment is necessary specially for septic and inflammatory conditions to prevent structural joint damage and deformities.
# Classification
## Primary Forms of Arthritis:
- Osteoarthritis
- Rheumatoid arthritis
- Septic arthritis
- Gout and pseudogout
- Juvenile idiopathic arthritis
- Still's disease
- Ankylosing spondylitis
# Differential Diagnosis
## Differential Diagnosis of Monoarthritis
To review the differential diagnosis of monoarthritis with joint swelling, click here.
To review the differential diagnosis of monoarthritis with fever, click here.
To review the differential diagnosis of monoarthritis with weight loss, click here.
To review the differential diagnosis of monoarthritis with claudication, click here.
To review the differential diagnosis of monoarthritis with morning stiffness, click here.
To review the differential diagnosis of monoarthritis with local erythema, click here.
To review the differential diagnosis of monoarthritis with joint swelling and fever, click here.
To review the differential diagnosis of monoarthritis with joint swelling, fever, and weight loss, click here.
## Differential Diagnosis of Diseases That Cause Polyarthritis
### Differentiating the diseases that can cause polyarthritis:
To review the differential diagnosis of polyarthritis with joint swelling, click here.
To review the differential diagnosis of polyarthritis with fever, click here.
To review the differential diagnosis of polyarthritis with weight loss, click here.
To review the differential diagnosis of polyarthritis with claudication, click here.
To review the differential diagnosis of polyarthritis with morning stiffness, click here.
To review the differential diagnosis of polyarthritis with local erythema, click here.
To review the differential diagnosis of polyarthritis with joint swelling and fever, click here.
To review the differential diagnosis of polyarthritis with joint swelling, fever, and weight loss, click here. | Arthritis
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2], Cafer Zorkun, M.D., Ph.D. [3]
# Overview
Arthritis (from Greek arthro-, joint + -itis, inflammation; plural: arthritides) could be defined as painful joint damage. It might be as part of a systemic disorder or a single joint involvement. Arthritis may present as joint pain (arthralgia), swelling, erythema, warmness, and limitation of movement. It could be classified according to the number of involved joints, presence of inflammation, or duration of symptoms. Osteoarthritis (also known as degenerative joint disease) is the most common form of arthritis in the United States which involves up to 10% of population older than 60 years. Inflammatory arthritis is common in systemic autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus (SLE) and is part of diagnostic criteria for this spectrum of diseases. Disease course in systemic disorders is usually chronic and multiple joints (polyarticular) are involved. In the other hand, infectious conditions like septic arthritis are acute in nature and they usually involve single joints (monoarticular). Crystal induced arthropathies may result in inflammatory joint(s) involvement, mainly are due to uric acid crystal deposition (gout) in articular space. Although, disease course and presence of other systemic manifestations are important for diagnosis but the gold standard method for diagnosis is joint aspiration, fluid analysis, and microscopic evaluation. Imaging might be helpful in certain condition to find the disease chronicity and structural changes in articular and periarticular structures. Prompt treatment is necessary specially for septic and inflammatory conditions to prevent structural joint damage and deformities.
# Classification
## Primary Forms of Arthritis:
- Osteoarthritis
- Rheumatoid arthritis
- Septic arthritis
- Gout and pseudogout
- Juvenile idiopathic arthritis
- Still's disease
- Ankylosing spondylitis
# Differential Diagnosis
## Differential Diagnosis of Monoarthritis
To review the differential diagnosis of monoarthritis with joint swelling, click here.
To review the differential diagnosis of monoarthritis with fever, click here.
To review the differential diagnosis of monoarthritis with weight loss, click here.
To review the differential diagnosis of monoarthritis with claudication, click here.
To review the differential diagnosis of monoarthritis with morning stiffness, click here.
To review the differential diagnosis of monoarthritis with local erythema, click here.
To review the differential diagnosis of monoarthritis with joint swelling and fever, click here.
To review the differential diagnosis of monoarthritis with joint swelling, fever, and weight loss, click here.
## Differential Diagnosis of Diseases That Cause Polyarthritis
### Differentiating the diseases that can cause polyarthritis:
To review the differential diagnosis of polyarthritis with joint swelling, click here.
To review the differential diagnosis of polyarthritis with fever, click here.
To review the differential diagnosis of polyarthritis with weight loss, click here.
To review the differential diagnosis of polyarthritis with claudication, click here.
To review the differential diagnosis of polyarthritis with morning stiffness, click here.
To review the differential diagnosis of polyarthritis with local erythema, click here.
To review the differential diagnosis of polyarthritis with joint swelling and fever, click here.
To review the differential diagnosis of polyarthritis with joint swelling, fever, and weight loss, click here. | https://www.wikidoc.org/index.php/Arthritic | |
875492bad8fd72ed3d40a02aea0347375329d0bb | wikidoc | Arthropod | Arthropod
# Overview
Arthropods (Phylum Arthropoda, from Greek ἄρθρον arthron, "joint", and ποδός podos, "foot") are the largest phylum of animals and include the insects, arachnids, crustaceans, and others. Arthropods are characterised by the possession of a segmented body with appendages on at least one segment. They have a dorsal heart and a ventral nervous system. All arthropods are covered by a hard exoskeleton made of chitin, a polysaccharide, which provides physical protection and resistance to desiccation. Periodically, an arthropod sheds this covering when it molts.
More than 80% of described living animal species are arthropods, with over a million modern species described and a fossil record reaching back to the late proterozoic era. Arthropods are common throughout marine, freshwater, terrestrial, and even aerial environments, as well as including various symbiotic and parasitic forms. They range in size from microscopic plankton (~¼ mm) up to forms several metres long. The largest living arthropod is the Japanese spider crab, with a leg span up to 3½ m (12 ft), and some prehistoric arthropods were even larger, such as Jaekelopterus and Arthropleura.
# Basic arthropod structure
The success of arthropods is related to their hard exoskeleton, segmentation, and jointed appendages. The appendages are used for feeding, sensory reception, defense, and locomotion. The muscle system is more or less assisted by hydraulics originated from the blood pressure, created by the hearts of the animals. The hydraulic system in spiders is especially well developed.
Aquatic arthropods use gills to exchange gases. These gills have an extensive surface area in contact with the surrounding water. Terrestrial arthropods have internal surfaces that are specialised for gas exchange. Insects and most other terrestrial species have tracheal systems: air sacs leading into the body from pores called spiracles in the epidermis cuticle. Others use book lungs, or gills modified for breathing air as seen in species like the coconut crab. Some areas of the legs of soldier crabs are covered with an oxygen absorbing membrane. The gill chambers in terrestrial crabs sometimes have two different structures: one that is gilled and used for breathing underwater, and another specially adapted to take up oxygen from the air (a pseudolung). Arthropods also have a complete digestive system with both a mouth and anus.
Arthropods have an open circulatory system. Haemolymph containing haemocyanin, a copper-based oxygen-carrying protein (the copper makes the blood blue, unlike humans that use hemoglobin which uses iron that makes it red). The blood is propelled by a series of hearts into the body cavity where it comes in direct contact with the tissues. Arthropods are protostomes. There is a coelom, but it is reduced to a tiny cavity around the reproductive and excretory organs, and the dominant body cavity is a haemocoel, filled with haemolymph which bathes the organs directly. The arthropod body is divided into a series of distinct segments, plus a pre-segmental acron which usually supports compound and simple eyes and a post-segmental telson. These are grouped into distinct, specialised body regions called tagmata. Each segment, at least primitively, supports a pair of appendages.
The cuticle in arthropods forms a rigid exoskeleton, composed mainly of chitin, which is periodically shed as the animal grows. They contain an inner zone (procuticle) which is made of protein and chitin and is responsible for the strength of the exoskeleton. The outer zone (epicuticle) lies on the surface of the procuticle. It is nonchitinous and is a complex of proteins and lipids. It provides the moisture proofing and protection to the procuticle. The exoskeleton takes the form of plates called sclerites on the segments, plus rings on the appendages that divide them into segments separated by joints. This is in fact what gives arthropods their name — jointed feet — and separates them from their relatives, the Onychophora and Tardigrada, also called Lobopoda (and which is sometimes included in a group called Panarthropoda that also includes arthropods). The exoskeletons of arthropods strengthen them against attack by predators and are impermeable to water. In order to grow, an arthropod must shed its old exoskeleton and secrete a new one. This process, ecdysis, is expensive in terms of energy, and during the moulting period, an arthropod is vulnerable.
# Classification of arthropods
Arthropods are typically classified into five subphyla, of which one is extinct:
- Trilobites are a group of formerly numerous marine animals that died in the mass extinction at the end of the Permian-Triassic extinction event.
- Chelicerates include spiders, mites, scorpions and related organisms. They are characterised by the presence of chelicerae.
- Myriapods comprise millipedes and centipedes and their relatives and have many body segments, each bearing one or two pairs of legs. They are sometimes grouped with the hexapods.
- Hexapods comprise insects and three small orders of insect-like animals with six thoracic legs. They are sometimes grouped with the myriapods, in a group called Uniramia, though genetic evidence tends to support a closer relationship between hexapods and crustaceans.
- Crustaceans are primarily aquatic (a notable exception being woodlice) and are characterised by having biramous appendages. They include lobsters, crabs, barnacles, crayfish, shrimp and many others.
Aside from these major groups, there are also a number of fossil forms - mostly from the lower Cambrian - including anomalocarids, euthycarcinoids and Arthrogyrinus which are difficult to place, either from lack of obvious affinity to any of the main groups or from clear affinity to several of them.
The phylogeny of the arthropods has been an area of considerable interest and dispute. The validity of many of the arthropod groups suggested by earlier authors is being questioned by recent studies; these include Mandibulata, Uniramia and Atelocerata. The most recent studies tend to suggest a paraphyletic Crustacea with different hexapod groups nested within it. The remaining clade of Myriapoda and Chelicerata is referred to as Paradoxopoda or Myriochelata.
Since the International Code of Zoological Nomenclature recognises no priority above the rank of family, many of the higher groups can be referred to by a variety of different names.
# Evolution
Arthropods are today almost universally considered to be monophyletic, i.e. they only arose once, a view supported by both morphological and molecular studies. Such a view contradicts the widespread view in the 1970s that the arthropods had evolved on several occasions from soft-bodied, annelid-like ancestors.
The closest relatives of the arthropods are usually considered to be the Tardigrada and Onychophora, together forming the monophyletic group Panarthropoda (the crustaceans, myriapods, chelicerates and insects are often referred to as "Euarthropoda" to distinguish them from their soft-bodied relatives). Comparison between these groups suggests that the euarthropods evolved from a soft-bodied ancestor not too dissimilar to the living onychophorans, a view that has found some support from the fossil record.
Traditionally the Annelida have been considered the closest relatives of these three phyla, on account of their common segmentation. Molecular data however, is strongly against this grouping (known as the Articulata), suggesting instead that the panarthropods belong in a clade including both the arthropods and various pseudocoelomates such as roundworms and priapulids that share with them growth by moulting, or ecdysis, from which its name, the Ecdysozoa. is derived. If this new grouping is correct, then segmentation of arthropods and annelids has either evolved through convergence, or has been inherited from a very deep ancestor, and has been subsequently lost in several other lineages, such as the non-arthropod members of the Ecdysozoa. | Arthropod
# Overview
Arthropods (Phylum Arthropoda, from Greek ἄρθρον arthron, "joint", and ποδός podos, "foot") are the largest phylum of animals and include the insects, arachnids, crustaceans, and others. Arthropods are characterised by the possession of a segmented body with appendages on at least one segment. They have a dorsal heart and a ventral nervous system. All arthropods are covered by a hard exoskeleton made of chitin, a polysaccharide, which provides physical protection and resistance to desiccation. Periodically, an arthropod sheds this covering when it molts.
More than 80% of described living animal species are arthropods,[1] with over a million modern species described and a fossil record reaching back to the late proterozoic era. Arthropods are common throughout marine, freshwater, terrestrial, and even aerial environments, as well as including various symbiotic and parasitic forms. They range in size from microscopic plankton (~¼ mm) up to forms several metres long. The largest living arthropod is the Japanese spider crab, with a leg span up to 3½ m (12 ft), and some prehistoric arthropods were even larger, such as Jaekelopterus and Arthropleura.
# Basic arthropod structure
The success of arthropods is related to their hard exoskeleton, segmentation, and jointed appendages. The appendages are used for feeding, sensory reception, defense, and locomotion. The muscle system is more or less assisted by hydraulics originated from the blood pressure, created by the hearts of the animals.[2] The hydraulic system in spiders is especially well developed.
Aquatic arthropods use gills to exchange gases. These gills have an extensive surface area in contact with the surrounding water. Terrestrial arthropods have internal surfaces that are specialised for gas exchange. Insects and most other terrestrial species have tracheal systems: air sacs leading into the body from pores called spiracles in the epidermis cuticle. Others use book lungs, or gills modified for breathing air as seen in species like the coconut crab. Some areas of the legs of soldier crabs are covered with an oxygen absorbing membrane. The gill chambers in terrestrial crabs sometimes have two different structures: one that is gilled and used for breathing underwater, and another specially adapted to take up oxygen from the air (a pseudolung). Arthropods also have a complete digestive system with both a mouth and anus.
Arthropods have an open circulatory system. Haemolymph containing haemocyanin, a copper-based oxygen-carrying protein (the copper makes the blood blue, unlike humans that use hemoglobin which uses iron that makes it red). The blood is propelled by a series of hearts into the body cavity where it comes in direct contact with the tissues. Arthropods are protostomes. There is a coelom, but it is reduced to a tiny cavity around the reproductive and excretory organs, and the dominant body cavity is a haemocoel, filled with haemolymph which bathes the organs directly. The arthropod body is divided into a series of distinct segments, plus a pre-segmental acron which usually supports compound and simple eyes and a post-segmental telson. These are grouped into distinct, specialised body regions called tagmata. Each segment, at least primitively, supports a pair of appendages.
The cuticle in arthropods forms a rigid exoskeleton, composed mainly of chitin, which is periodically shed as the animal grows. They contain an inner zone (procuticle) which is made of protein and chitin and is responsible for the strength of the exoskeleton. The outer zone (epicuticle) lies on the surface of the procuticle. It is nonchitinous and is a complex of proteins and lipids. It provides the moisture proofing and protection to the procuticle. The exoskeleton takes the form of plates called sclerites on the segments, plus rings on the appendages that divide them into segments separated by joints. This is in fact what gives arthropods their name — jointed feet — and separates them from their relatives, the Onychophora and Tardigrada, also called Lobopoda (and which is sometimes included in a group called Panarthropoda that also includes arthropods). The exoskeletons of arthropods strengthen them against attack by predators and are impermeable to water. In order to grow, an arthropod must shed its old exoskeleton and secrete a new one. This process, ecdysis, is expensive in terms of energy, and during the moulting period, an arthropod is vulnerable.
# Classification of arthropods
Template:Userboxtop
Template:Clade
Template:Userboxbottom
Arthropods are typically classified into five subphyla, of which one is extinct:[4]
- Trilobites are a group of formerly numerous marine animals that died in the mass extinction at the end of the Permian-Triassic extinction event.
- Chelicerates include spiders, mites, scorpions and related organisms. They are characterised by the presence of chelicerae.
- Myriapods comprise millipedes and centipedes and their relatives and have many body segments, each bearing one or two pairs of legs. They are sometimes grouped with the hexapods.
- Hexapods comprise insects and three small orders of insect-like animals with six thoracic legs. They are sometimes grouped with the myriapods, in a group called Uniramia, though genetic evidence tends to support a closer relationship between hexapods and crustaceans.
- Crustaceans are primarily aquatic (a notable exception being woodlice) and are characterised by having biramous appendages. They include lobsters, crabs, barnacles, crayfish, shrimp and many others.
Aside from these major groups, there are also a number of fossil forms - mostly from the lower Cambrian - including anomalocarids, euthycarcinoids [5] and Arthrogyrinus which are difficult to place, either from lack of obvious affinity to any of the main groups or from clear affinity to several of them.
The phylogeny of the arthropods has been an area of considerable interest and dispute. The validity of many of the arthropod groups suggested by earlier authors is being questioned by recent studies; these include Mandibulata, Uniramia and Atelocerata. The most recent studies tend to suggest a paraphyletic Crustacea with different hexapod groups nested within it.[3][6] The remaining clade of Myriapoda and Chelicerata is referred to as Paradoxopoda or Myriochelata.
Since the International Code of Zoological Nomenclature recognises no priority above the rank of family, many of the higher groups can be referred to by a variety of different names.[7]
# Evolution
Template:Userboxtop
Template:Clade
Template:Userboxbottom
Arthropods are today almost universally considered to be monophyletic, i.e. they only arose once, a view supported by both morphological and molecular studies. Such a view contradicts the widespread view in the 1970s that the arthropods had evolved on several occasions from soft-bodied, annelid-like ancestors.
The closest relatives of the arthropods are usually considered to be the Tardigrada and Onychophora, together forming the monophyletic group Panarthropoda (the crustaceans, myriapods, chelicerates and insects are often referred to as "Euarthropoda" to distinguish them from their soft-bodied relatives). Comparison between these groups suggests that the euarthropods evolved from a soft-bodied ancestor not too dissimilar to the living onychophorans, a view that has found some support from the fossil record.
Traditionally the Annelida have been considered the closest relatives of these three phyla, on account of their common segmentation. Molecular data however, is strongly against this grouping (known as the Articulata), suggesting instead that the panarthropods belong in a clade including both the arthropods and various pseudocoelomates such as roundworms and priapulids that share with them growth by moulting, or ecdysis, from which its name, the Ecdysozoa. is derived. If this new grouping is correct, then segmentation of arthropods and annelids has either evolved through convergence, or has been inherited from a very deep ancestor, and has been subsequently lost in several other lineages, such as the non-arthropod members of the Ecdysozoa. | https://www.wikidoc.org/index.php/Arthropod | |
3e1333d555f3549c806cf854da366a6c8da90d89 | wikidoc | Articaine | Articaine
# Disclaimer
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# Overview
Articaine is a amide local anesthetic that is FDA approved for the procedure of local, infiltrative, or conductive anesthesia in both simple and complex dental procedures. Common adverse reactions include headache and pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Articadent, an amide local anesthetic containing a vasoconstrictor, is indicated for local, infiltrative, or conductive anesthesia in both simple and complex dental procedures.
### General Dosing Information
- Table 1 (below) summarizes the recommended volumes and concentrations of Articadent for various types of anesthetic procedures. The dosages suggested in this table are for normal healthy adults, administered by submucosal infiltration or nerve block.
- The recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures. The actual volumes to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia, degree of muscular relaxation, and condition of the patient. In all cases, the smallest dose that will produce the desired result should be given.
- The onset of anesthesia, and the duration of anesthesia are proportional to the volume and concentration (i.e., total dose) of local anesthetic used. Caution should be exercised when employing large volumes because the incidence of side effects may be dose-related.
- For most routine dental procedures, Articadent containing epinephrine 1:200,000 is preferred. However, when more pronounced hemostasis or improved visualization of the surgical field are required, Articadent containing epinephrine 1:100,000 may be used.
- Adults: For normal healthy adults, the maximum dose of articaine HCl administered by submucosal infiltration and/or nerve block should not exceed 7 mg/kg (0.175 mL/kg).
- Pediatric Patients Ages 4 to 16 Years: The quantity of articaine HCl in children ages 4 to 16 years of age to be injected should be determined by the age and weight of the child and the magnitude of the operation. The maximum dose of articaine HCl should not exceed 7 mg/kg (0.175 mL/kg).
- Safety and effectiveness of Articadent in pediatric patients below the age of 4 years have not been established.
- Dose reduction may be required in debilitated patients, acutely ill patients, elderly patients, and pediatric patients commensurate with their age and physical condition. No studies have been performed in patients with renal or liver dysfunction. Caution should be used in patients with severe liver disease
### DOSAGE FORMS AND STRENGTHS
- Injection (clear colorless solution) containing:
- Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL)
- Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Articaine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Articaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Articaine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Articaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Articaine in pediatric patients.
# Contraindications
- Articadent is contraindicated in patients who are hypersensitive to products containing sulfites. Products containing sulfites may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episode in certain susceptible people. Sulfite sensitivity is seen more frequently in asthmatic that in non-asthmatic people
# Warnings
- Accidental intravascular injection of Articadent may be associated with convulsions, followed by central nervous system or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Dental practitioners who employ local anesthetic agents including Articadent should be well versed in diagnosis and management of emergencies that may arise from their use. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. To avoid intravascular injection, aspiration should be performed before Articadent is injected. The needle must be repositioned until no return of blood can be elicited by aspiration. Note, however, that the absence of blood in the syringe does not guarantee that intravascular injection has been avoided.
- Small doses of local anesthetics injected in dental blocks may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should be observed constantly. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded.
- This includes toxicity arising from accidental intravascular injection of Articadent discussed in Section 5.1, as well as that related to higher systemic concentrations of local anesthetics or epinephrine. Systemic absorption of local anesthetics including Articadent can produce effects on the central nervous and cardiovascular systems.
- At blood concentrations achieved with therapeutic doses of Articadent, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations of Articadent can depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, possibly resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Articadent should also be used with caution in patients with heart block as well as those with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.
- Restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression, or drowsiness may be early warning signs of central nervous system toxicity.
- Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after each local anesthetic injection of Articadent. Repeated doses of Articadent may cause significant increases in blood levels because of possible accumulation of the drug or its metabolites. The lowest dosage that results in effective anesthesia should be used to decrease the risk of high plasma levels and serious adverse effects. Tolerance to elevated blood levels varies with the status of the patient. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. Precautions for epinephrine administration, discussed in Section 5.3 should be observed.
- Debilitated patients, elderly patients, acutely ill patients, and pediatric patients should be given reduced doses commensurate with their age and physical condition. No studies have been performed in patients with liver dysfunction, and caution should be used in patients with severe hepatic disease.
- Articadent contains epinephrine, a vasoconstrictor that can cause local or systemic toxicity and should be used cautiously. Local toxicity may include ischemic injury or necrosis, which may be related to vascular spasm. Articadent should be used with caution in patients during or following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response.
- The American Heart Association has made the following recommendation regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: "Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used." (Kaplan, 1986).
- It is essential to aspirate before any injection to avoid administration of the drug into the blood stream.
- Articadent, like other local anesthetics, can cause methemoglobinemia, particularly in conjunction with methemoglobin-inducing agents. Articadent should not be used in patients with congenital or idiopathic methemoglobinemia, or in patients who are receiving treatment with methemoglobin-inducing agents since they are more susceptible to drug-induced methemoglobinemia.
- Signs and symptoms of methemoglobinemia may be delayed some hours after exposure. Initial signs and symptoms of methemoglobinemia include slate grey cyanosis seen in buccal mucus membranes, lips and nail beds. In severe cases, symptoms may include central cyanosis, headache, lethargy, dizziness, fatigue, syncope, dyspnea, CNS depression, seizures, dysrhythmia and shock. Methemoglobinemia should be considered if central cyanosis unresponsive to oxygen therapy occurs, especially if methemoglobin-inducing agents have been used. Calculated oxygen saturation and pulse oximetry are inaccurate in the setting of methemoglobinemia. The diagnosis can be confirmed by an elevated methemoglobin level of at least 10% is present. The development of methemoglobinemia is dose-related.
- Management of methemoglobinemia: If methemoglobinemia does not respond to administration of oxygen, clinically significant symptoms of methemoglobinemia should be treated with administration of a slow intravenous injection (over 5 minutes) of methylene blue at a dosage of 1-2 mg/kg body weight.
- Articadent contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.
# Adverse Reactions
## Clinical Trials Experience
- Reactions to articaine are characteristic of those associated with other amide-type local anesthetics. Adverse reactions to this group of drugs may also result from excessive plasma levels (which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation), injection technique, volume of injection, or hypersensitivity or they may be idiosyncratic.
- 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 reported adverse reactions are derived from clinical trials in the United States and the United Kingdom. Table 2 displays the adverse reactions reported in clinical trials where 882 individuals were exposed to Articadent containing epinephrine 1:100,000. Table 3 displays the adverse reactions reported in clinical trials where 182 individuals were exposed to Articadent containing epinephrine 1:100,000 and 179 individuals were exposed to Articadent containing epinephrine 1:200,000.
- Adverse reactions observed in at least 1% of patients:
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Articadent. 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.
- Persistent paresthesia of the lips, tongue, and oral tissues have been reported with use of articaine hydrochloride, with slow, incomplete, or no recovery. These postmarketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches.
- Hypoesthesia has been reported with use of articaine, especially in pediatric age groups, which is usually reversible. Prolonged numbness can result in soft tissue injuries such as that of the lips and tongue in these age groups.
- Ischemic injury and necrosis have been described following use of articaine with epinephrine and have been postulated to be due to vascular spasm of terminal arterial branches.
- Paralysis of ocular muscles has been reported, especially after posterior, superior alveolar injections of articaine during dental anesthesia. Symptoms include diplopia, mydriasis, ptosis and difficulty in abduction of the affected eye. These symptoms have been described as developing immediately after injection of the anesthetic solution and persisting one minute to several hours, with generally complete recovery.
# Drug Interactions
- The administration of local anesthetic solutions containing epinephrine to patients receiving monoamine oxidase inhibitors, nonselective beta-andregernic antagonists or tricyclic antidepressants may produce severe, prolonged hypertension. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of these agents should be avoided; however, in situations when concurrent therapy is necessary, careful patient monitoring is essential
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women with Articadent. Articaine hydrochloride and epinephrine (1:100,000) has been shown to increase fetal deaths and skeletal variations in rabbits when given in doses approximately 4 times the maximum recommended human dose (MRHD). Articadent should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In embryo-fetal toxicity studies in rabbits, 80 mg/kg, subcutaneously (approximately 4 times the MRHD based on body surface area) caused fetal death and increased fetal skeletal variations, but these effects may be attributable to the severe maternal toxicity, including seizures, observed at this dose. In contrast, no embryo-fetal toxicities were observed when articaine and epinephrine (1:100,000) was administered subcutaneously throughout organogenesis at doses up to 40 mg/kg in rabbits and 80 mg/kg in rats (approximately 2 times the MRHD based on body surface area).
- In pre- and postnatal developmental studies subcutaneous administration of articaine hydrochloride to pregnant rats throughout gestation and lactation, at a dose of 80 mg/kg (approximately 2 times the MRHD based on body surface area) increased the number of stillbirths and adversely affected passive avoidance, a measure of learning, in pups. This dose also produced severe maternal toxicity in some animals. A dose of 40 mg/kg (approximately equal to the MRHD on a mg/m2 basis) did not produce these effects. A similar study using articaine and epinephrine (1:100,000) rather than articaine hydrochloride alone produced maternal toxicity, but no effects on offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Articaine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Articaine during labor and delivery.
### Nursing Mothers
- It is not known whether Articadent is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Articadent is administered to a nursing woman. When using Articadent, nursing mothers may choose to pump and discard breast milk for approximately 4 hours (based on plasma half-life) following an injection of Articadent (to minimize infant ingestion) and then resume breastfeeding.
### Pediatric Use
- Safety and effectiveness of Articadent in pediatric patients below the age of 4 years have not been established. Safety of doses greater than 7 mg/kg (0.175 mL/kg) in pediatric patients has not been established. Safety and effectiveness was established in clinical trials with 61 pediatric patients between the ages of 4 and 16 years administered articaine hydrochloride 4% with epinephrine 1:100,000 injections. Fifty-one of these patients received doses from 0.76 mg/kg to 5.65 mg/kg (0.9 mL to 5.1 mL) for simple dental procedures and 10 patients received doses between 0.37 mg/kg and 7.48 mg/kg (0.7 mL to 3.9 mL) for complex dental procedures. Approximately 13% of these pediatric patients required additional injections of anesthetic for complete anesthesia. Dosages in pediatric patients should be reduced, commensurate with age, body weight, and physical condition
### Geriatic Use
- In clinical trials, 54 patients between the ages of 65 and 75 years, and 11 patients 75 years and over received Articadent containing epinephrine 1:100,000. Among all patients between 65 and 75 years, doses from 0.43 mg/kg to 4.76 mg/kg (0.9 to 11.9 mL) were administered to 35 patients for simple procedures and doses from 1.05 mg/kg to 4.27 mg/kg (1.3 to 6.8 mL) were administered to 19 patients for complex procedures. Among the 11 patients ≥ 75 years old, doses from 0.78 mg/kg to 4.76 mg/kg (1.3 to 11.9 mL) were administered to 7 patients for simple procedures and doses of 1.12 mg/kg to 2.17 mg/kg (1.3 to 5.1 mL) were administered to 4 patients for complex procedures.
- Approximately 6% of patients between the ages of 65 and 75 years and none of the 11 patients 75 years of age or older required additional injections of anesthetic for complete anesthesia compared with 11% of patients between 17 and 65 years old who required additional injections.
- No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Articaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Articaine with respect to specific racial populations.
### Renal Impairment
- No studies have been performed with articaine hydrochloride 4% with epinephrine 1:200,000 injection or articaine hydrochloride 4% with epinephrine 1:100,000 injection in patients with renal or hepatic dysfunction
### Hepatic Impairment
- No studies have been performed with articaine hydrochloride 4% with epinephrine 1:200,000 injection or articaine hydrochloride 4% with epinephrine 1:100,000 injection in patients with renal or hepatic dysfunction
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Articaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Articaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- submucosal infiltration or nerve block.
### Monitoring
There is limited information regarding Monitoring of Articaine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Articaine in the drug label.
# Overdosage
- Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution.
- The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.
- The first step in the management of convulsions, as well as hypo-ventilation, consists of immediate attention to the maintenance of a patient airway and assisted or controlled ventilation as needed. The adequacy of the circulation should be assessed. Should convulsions persist despite adequate respiratory support, treatment with appropriate anticonvulsant therapy is indicated. The practitioner should be familiar with the use of anticonvulsant drugs, prior to the use of local anesthetics. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor.
- If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and/or cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted.
- For additional information about overdose treatment, call a poison control center
# Pharmacology
## Mechanism of Action
- Articaine HCl is an amide local anesthetic. Local anesthetics block the generation and conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of the affected nerve fibers. Epinephrine is a vasoconstrictor added to articaine HCl to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration.
## Structure
- Articadent injection is a sterile, aqueous solution that contains articaine HCl 4% (40 mg/mL) with epinephrine bitartrate in an epinephrine 1:200,000 or epinephrine 1:100,000 strength. Articaine HCl is an amino amide local anesthetic, chemically designated as 4-methyl-3--2-thiophene-carboxylic acid, methyl ester hydrochloride and is a racemic mixture. Articaine HCl has a molecular weight of 320.84 and the following structural formula:
- Articaine HCl has a partition coefficient in n-octanol/Soerensen buffer (pH: 7.35) of 17 and a pKa of 7.8.
- Epinephrine bitartrate, (-)-1-(3,4-dihydroxyphenyl)-2-methylamino-ethanol (+) tartrate (1:1) salt, is a vasoconstrictor that is added to articaine HCl in a concentration of 1:200,000 or 1:100,000 (expressed as free base). It has a molecular weight of 333.3 and the following structural formula:
## Pharmacodynamics
- Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.
- The onset of anesthesia has been shown to be within 1 to 9 minutes of injection of ARTICADENT. Complete anesthesia lasts approximately 1 hour for infiltrations and up to approximately 2 hours for nerve block.
- Administration of Articadent results in a 3- to 5-fold increase in plasma epinephrine concentrations compared to baseline; however, in healthy adults it does not appear to be associated with marked increases in blood pressure or heart rate, except in the case of accidental intravascular injection
## Pharmacokinetics
- Following dental injection by the submucosal route of an articaine solution containing epinephrine1:200,000, articaine reaches peak blood concentration about 25 minutes after a single dose injection and 48 minutes after three doses. Peak plasma levels of articaine achieved after 68 and 204 mg doses are 385 and 900 ng/mL, respectively. Following intraoral administration of a near maximum dose of 476 mg, articaine reaches peak blood concentrations of 2037 and 2145 ng/mL for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively, approximately 22 minutes post-dose.
- Approximately 60 to 80% of articaine HCl is bound to human serum albumin and γ-globulins at 37°C in vitro.
- Articaine HCl is metabolized by plasma carboxyesterase to its primary metabolite, articainic acid, which is inactive. In vitro studies show that the human liver microsome P450 isoenzyme system metabolizes approximately 5% to 10% of available articaine with nearly quantitative conversion to articainic acid.
- At the dose of 476 mg of articaine, the elimination half-life was 43.8 minutes and 44.4 minutes for articaine solution with epinephrine 1:100,000 and 1:200,000, respectively. Articaine is excreted primarily through urine with 53% to 57% of the administered dose eliminated in the first 24 hours following submucosal administration. Articainic acid is the primary metabolite in urine. A minor metabolite, articainic acid glucuronide, is also excreted in urine. Articaine constitutes only 2% of the total dose excreted in urine.
- No studies have been performed to evaluate the pharmacokinetics of Articadent injection in pediatric subjects. There is insufficient information to determine whether the pharmacokinetics of ARTICADENT differs by race.
## Nonclinical Toxicology
- Studies to evaluate the carcinogenic potential of articaine HCI in animals have not been conducted. Five standard mutagenicity tests, including three in vitro tests (the nonmammalian Ames test, the mammalian Chinese hamster ovary chromosomal aberration test and a mammalian gene mutation test with articaine HCl) and two in vivo mouse micronucleous tests (one with articaine and epinephrine 1:100,000 and one with articaine HCl alone) showed no mutagenic effects.
- No effects on male or female fertility were observed in rats for articaine and epinephrine 1:100,000 administered subcutaneously in doses up to 80 mg/kg/day (approximately 2 times the MRHD based on body surface area).
# Clinical Studies
- Three randomized, double-blind, active-controlled studies were designed to evaluate the effectiveness of Articadent containing epinephrine 1:100,000 as a dental anesthetic. Patients ranging in age from 4 years to over 65 years old underwent simple dental procedures such as single uncomplicated extractions, routine operative procedures, single apical resections, and single crown procedures, or complex dental procedures such as multiple extractions, multiple crowns and/or bridge procedures, multiple apical resections, alveolectomies, muco-gingival operations, and other surgical procedures on the bone. Articadent containing epinephrine 1:100,000 was administered as submucosal infiltration and/or nerve block. Efficacy was measured immediately following the procedure by having the patient and investigator rate the patient's procedural pain using a 10 cm visual analog scale (VAS), in which a score of zero represented no pain and a score of 10 represented the worst pain imaginable. Mean patient and investigator VAS pain scores were 0.3 cm-0.4 cm for simple procedures and 0.5 cm-0.6 cm for complex procedures.
- Four randomized, double-blind, active-controlled studies were performed comparing Articadent containing epinephrine 1:100,000 versus Articadent containing epinephrine 1:200,000. The first two studies used electric pulp testers (EPT) to evaluate the success rate (maximum EPT value within 10 minutes), onset, and duration of Articadent containing epinephrine 1:100,000 versus Articadent containing epinephrine 1:200,000 and articaine solution without epinephrine in healthy adults between 18 and 65 years old. Results indicated that the anesthetic characteristics of the 1:100,000 and 1:200,000 formulations were not significantly different.
- A third study compared the difference in visualization of the surgical field after administration of Articadent containing epinephrine 1:100,000 versus Articadent containing epinephrine1:200,000 during bilateral maxillary periodontal surgeries in patients ranging from 21 to 65 years old. Articadent containing epinephrine1:100,000 provided better visualization of the surgical field and less blood loss during the procedures. In a fourth study, designed to assess and compare cardiovascular safety, when the maximum dose of each formulation was administered, no clinically relevant differences in blood pressure or heart rate between formulations were observed.
# How Supplied
- Articadent (articaine HCl with epinephrine) Injection is available in 1.7 mL single use glass cartridges, packaged in boxes of 50 cartridges in the following two strengths:
## Storage
- Store at controlled room temperature 25°C (77°F) with brief excursions permitted between 15° and 30°C (59°F - 86°F) . Protect from light. Do Not Freeze.
- For chemical disinfection of the carpule, either isopropyl alcohol (91%) or ethyl alcohol (70%) is recommended. Many commercially available brands of isopropyl (rubbing) alcohol, as well as solutions of ethyl alcohol not of U.S.P. grade, contain denaturants that are injurious to rubber and therefore are not to be used.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 1.7 ML CARTRIDGE CARTON (EPINEPHRINE 1:100,000)
NDC 66312-601-16
DENTSPLY
PHARMACEUTICAL
Articadent® DENTAL
(articaine HCl and epinephrine) Injection
Articaine hydrochloride 4% and epinephrine 1:100,000
Intraoral Submucosal Injection
Contains sodium metabisulfite
Store at 25°C (77°F)
DO NOT PERMIT TO FREEZE.
Rx only
50 Cartridges, 1.7 mL each
COLOR
CODED
STERILE AQUEOUS
SOLUTION FOR INJECTION
DENTSPLY Reorder #: 51116
### PRINCIPAL DISPLAY PANEL - 1.7 ML CARTRIDGE CARTON (EPINEPHRINE 1:200,000)
NDC 66312-602-16
DENTSPLY
PHARMACEUTICAL
Articadent® DENTAL
(articaine HCl and epinephrine) Injection
Articaine hydrochloride 4% and epinephrine 1:200,000
Intraoral Submucosal Injection
Contains sodium metabisulfite
Store at 25°C (77°F)
DO NOT PERMIT TO FREEZE.
Rx only
50 Cartridges, 1.7 mL each
COLOR
CODED
STERILE AQUEOUS
SOLUTION FOR INJECTION
DENTSPLY Reorder #: 52216
### Ingredients and Appearance
# Patient Counseling Information
- Loss of Sensation and Muscle Function:
# Precautions with Alcohol
- Alcohol-Articaine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARTICADENT ®
# Look-Alike Drug Names
There is limited information regarding Articaine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Articaine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Overview
Articaine is a amide local anesthetic that is FDA approved for the procedure of local, infiltrative, or conductive anesthesia in both simple and complex dental procedures. Common adverse reactions include headache and pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Articadent, an amide local anesthetic containing a vasoconstrictor, is indicated for local, infiltrative, or conductive anesthesia in both simple and complex dental procedures.
### General Dosing Information
- Table 1 (below) summarizes the recommended volumes and concentrations of Articadent for various types of anesthetic procedures. The dosages suggested in this table are for normal healthy adults, administered by submucosal infiltration or nerve block.
- The recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures. The actual volumes to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia, degree of muscular relaxation, and condition of the patient. In all cases, the smallest dose that will produce the desired result should be given.
- The onset of anesthesia, and the duration of anesthesia are proportional to the volume and concentration (i.e., total dose) of local anesthetic used. Caution should be exercised when employing large volumes because the incidence of side effects may be dose-related.
- For most routine dental procedures, Articadent containing epinephrine 1:200,000 is preferred. However, when more pronounced hemostasis or improved visualization of the surgical field are required, Articadent containing epinephrine 1:100,000 may be used.
- Adults: For normal healthy adults, the maximum dose of articaine HCl administered by submucosal infiltration and/or nerve block should not exceed 7 mg/kg (0.175 mL/kg).
- Pediatric Patients Ages 4 to 16 Years: The quantity of articaine HCl in children ages 4 to 16 years of age to be injected should be determined by the age and weight of the child and the magnitude of the operation. The maximum dose of articaine HCl should not exceed 7 mg/kg (0.175 mL/kg).
- Safety and effectiveness of Articadent in pediatric patients below the age of 4 years have not been established.
- Dose reduction may be required in debilitated patients, acutely ill patients, elderly patients, and pediatric patients commensurate with their age and physical condition. No studies have been performed in patients with renal or liver dysfunction. Caution should be used in patients with severe liver disease
### DOSAGE FORMS AND STRENGTHS
- Injection (clear colorless solution) containing:
- Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL)
- Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Articaine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Articaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Articaine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Articaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Articaine in pediatric patients.
# Contraindications
- Articadent is contraindicated in patients who are hypersensitive to products containing sulfites. Products containing sulfites may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episode in certain susceptible people. Sulfite sensitivity is seen more frequently in asthmatic that in non-asthmatic people
# Warnings
- Accidental intravascular injection of Articadent may be associated with convulsions, followed by central nervous system or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Dental practitioners who employ local anesthetic agents including Articadent should be well versed in diagnosis and management of emergencies that may arise from their use. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. To avoid intravascular injection, aspiration should be performed before Articadent is injected. The needle must be repositioned until no return of blood can be elicited by aspiration. Note, however, that the absence of blood in the syringe does not guarantee that intravascular injection has been avoided.
- Small doses of local anesthetics injected in dental blocks may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should be observed constantly. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded.
- This includes toxicity arising from accidental intravascular injection of Articadent discussed in Section 5.1, as well as that related to higher systemic concentrations of local anesthetics or epinephrine. Systemic absorption of local anesthetics including Articadent can produce effects on the central nervous and cardiovascular systems.
- At blood concentrations achieved with therapeutic doses of Articadent, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations of Articadent can depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, possibly resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Articadent should also be used with caution in patients with heart block as well as those with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.
- Restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression, or drowsiness may be early warning signs of central nervous system toxicity.
- Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after each local anesthetic injection of Articadent. Repeated doses of Articadent may cause significant increases in blood levels because of possible accumulation of the drug or its metabolites. The lowest dosage that results in effective anesthesia should be used to decrease the risk of high plasma levels and serious adverse effects. Tolerance to elevated blood levels varies with the status of the patient. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. Precautions for epinephrine administration, discussed in Section 5.3 should be observed.
- Debilitated patients, elderly patients, acutely ill patients, and pediatric patients should be given reduced doses commensurate with their age and physical condition. No studies have been performed in patients with liver dysfunction, and caution should be used in patients with severe hepatic disease.
- Articadent contains epinephrine, a vasoconstrictor that can cause local or systemic toxicity and should be used cautiously. Local toxicity may include ischemic injury or necrosis, which may be related to vascular spasm. Articadent should be used with caution in patients during or following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response.
- The American Heart Association has made the following recommendation regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: "Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When a vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used." (Kaplan, 1986).
- It is essential to aspirate before any injection to avoid administration of the drug into the blood stream.
- Articadent, like other local anesthetics, can cause methemoglobinemia, particularly in conjunction with methemoglobin-inducing agents. Articadent should not be used in patients with congenital or idiopathic methemoglobinemia, or in patients who are receiving treatment with methemoglobin-inducing agents since they are more susceptible to drug-induced methemoglobinemia.
- Signs and symptoms of methemoglobinemia may be delayed some hours after exposure. Initial signs and symptoms of methemoglobinemia include slate grey cyanosis seen in buccal mucus membranes, lips and nail beds. In severe cases, symptoms may include central cyanosis, headache, lethargy, dizziness, fatigue, syncope, dyspnea, CNS depression, seizures, dysrhythmia and shock. Methemoglobinemia should be considered if central cyanosis unresponsive to oxygen therapy occurs, especially if methemoglobin-inducing agents have been used. Calculated oxygen saturation and pulse oximetry are inaccurate in the setting of methemoglobinemia. The diagnosis can be confirmed by an elevated methemoglobin level of at least 10% is present. The development of methemoglobinemia is dose-related.
- Management of methemoglobinemia: If methemoglobinemia does not respond to administration of oxygen, clinically significant symptoms of methemoglobinemia should be treated with administration of a slow intravenous injection (over 5 minutes) of methylene blue at a dosage of 1-2 mg/kg body weight.
- Articadent contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.
# Adverse Reactions
## Clinical Trials Experience
- Reactions to articaine are characteristic of those associated with other amide-type local anesthetics. Adverse reactions to this group of drugs may also result from excessive plasma levels (which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation), injection technique, volume of injection, or hypersensitivity or they may be idiosyncratic.
- 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 reported adverse reactions are derived from clinical trials in the United States and the United Kingdom. Table 2 displays the adverse reactions reported in clinical trials where 882 individuals were exposed to Articadent containing epinephrine 1:100,000. Table 3 displays the adverse reactions reported in clinical trials where 182 individuals were exposed to Articadent containing epinephrine 1:100,000 and 179 individuals were exposed to Articadent containing epinephrine 1:200,000.
- Adverse reactions observed in at least 1% of patients:
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Articadent. 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.
- Persistent paresthesia of the lips, tongue, and oral tissues have been reported with use of articaine hydrochloride, with slow, incomplete, or no recovery. These postmarketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches.
- Hypoesthesia has been reported with use of articaine, especially in pediatric age groups, which is usually reversible. Prolonged numbness can result in soft tissue injuries such as that of the lips and tongue in these age groups.
- Ischemic injury and necrosis have been described following use of articaine with epinephrine and have been postulated to be due to vascular spasm of terminal arterial branches.
- Paralysis of ocular muscles has been reported, especially after posterior, superior alveolar injections of articaine during dental anesthesia. Symptoms include diplopia, mydriasis, ptosis and difficulty in abduction of the affected eye. These symptoms have been described as developing immediately after injection of the anesthetic solution and persisting one minute to several hours, with generally complete recovery.
# Drug Interactions
- The administration of local anesthetic solutions containing epinephrine to patients receiving monoamine oxidase inhibitors, nonselective beta-andregernic antagonists or tricyclic antidepressants may produce severe, prolonged hypertension. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of these agents should be avoided; however, in situations when concurrent therapy is necessary, careful patient monitoring is essential
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women with Articadent. Articaine hydrochloride and epinephrine (1:100,000) has been shown to increase fetal deaths and skeletal variations in rabbits when given in doses approximately 4 times the maximum recommended human dose (MRHD). Articadent should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In embryo-fetal toxicity studies in rabbits, 80 mg/kg, subcutaneously (approximately 4 times the MRHD based on body surface area) caused fetal death and increased fetal skeletal variations, but these effects may be attributable to the severe maternal toxicity, including seizures, observed at this dose. In contrast, no embryo-fetal toxicities were observed when articaine and epinephrine (1:100,000) was administered subcutaneously throughout organogenesis at doses up to 40 mg/kg in rabbits and 80 mg/kg in rats (approximately 2 times the MRHD based on body surface area).
- In pre- and postnatal developmental studies subcutaneous administration of articaine hydrochloride to pregnant rats throughout gestation and lactation, at a dose of 80 mg/kg (approximately 2 times the MRHD based on body surface area) increased the number of stillbirths and adversely affected passive avoidance, a measure of learning, in pups. This dose also produced severe maternal toxicity in some animals. A dose of 40 mg/kg (approximately equal to the MRHD on a mg/m2 basis) did not produce these effects. A similar study using articaine and epinephrine (1:100,000) rather than articaine hydrochloride alone produced maternal toxicity, but no effects on offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Articaine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Articaine during labor and delivery.
### Nursing Mothers
- It is not known whether Articadent is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Articadent is administered to a nursing woman. When using Articadent, nursing mothers may choose to pump and discard breast milk for approximately 4 hours (based on plasma half-life) following an injection of Articadent (to minimize infant ingestion) and then resume breastfeeding.
### Pediatric Use
- Safety and effectiveness of Articadent in pediatric patients below the age of 4 years have not been established. Safety of doses greater than 7 mg/kg (0.175 mL/kg) in pediatric patients has not been established. Safety and effectiveness was established in clinical trials with 61 pediatric patients between the ages of 4 and 16 years administered articaine hydrochloride 4% with epinephrine 1:100,000 injections. Fifty-one of these patients received doses from 0.76 mg/kg to 5.65 mg/kg (0.9 mL to 5.1 mL) for simple dental procedures and 10 patients received doses between 0.37 mg/kg and 7.48 mg/kg (0.7 mL to 3.9 mL) for complex dental procedures. Approximately 13% of these pediatric patients required additional injections of anesthetic for complete anesthesia. Dosages in pediatric patients should be reduced, commensurate with age, body weight, and physical condition
### Geriatic Use
- In clinical trials, 54 patients between the ages of 65 and 75 years, and 11 patients 75 years and over received Articadent containing epinephrine 1:100,000. Among all patients between 65 and 75 years, doses from 0.43 mg/kg to 4.76 mg/kg (0.9 to 11.9 mL) were administered to 35 patients for simple procedures and doses from 1.05 mg/kg to 4.27 mg/kg (1.3 to 6.8 mL) were administered to 19 patients for complex procedures. Among the 11 patients ≥ 75 years old, doses from 0.78 mg/kg to 4.76 mg/kg (1.3 to 11.9 mL) were administered to 7 patients for simple procedures and doses of 1.12 mg/kg to 2.17 mg/kg (1.3 to 5.1 mL) were administered to 4 patients for complex procedures.
- Approximately 6% of patients between the ages of 65 and 75 years and none of the 11 patients 75 years of age or older required additional injections of anesthetic for complete anesthesia compared with 11% of patients between 17 and 65 years old who required additional injections.
- No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Articaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Articaine with respect to specific racial populations.
### Renal Impairment
- No studies have been performed with articaine hydrochloride 4% with epinephrine 1:200,000 injection or articaine hydrochloride 4% with epinephrine 1:100,000 injection in patients with renal or hepatic dysfunction
### Hepatic Impairment
- No studies have been performed with articaine hydrochloride 4% with epinephrine 1:200,000 injection or articaine hydrochloride 4% with epinephrine 1:100,000 injection in patients with renal or hepatic dysfunction
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Articaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Articaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- submucosal infiltration or nerve block.
### Monitoring
There is limited information regarding Monitoring of Articaine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Articaine in the drug label.
# Overdosage
- Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution.
- The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.
- The first step in the management of convulsions, as well as hypo-ventilation, consists of immediate attention to the maintenance of a patient airway and assisted or controlled ventilation as needed. The adequacy of the circulation should be assessed. Should convulsions persist despite adequate respiratory support, treatment with appropriate anticonvulsant therapy is indicated. The practitioner should be familiar with the use of anticonvulsant drugs, prior to the use of local anesthetics. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor.
- If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and/or cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted.
- For additional information about overdose treatment, call a poison control center
# Pharmacology
## Mechanism of Action
- Articaine HCl is an amide local anesthetic. Local anesthetics block the generation and conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of the affected nerve fibers. Epinephrine is a vasoconstrictor added to articaine HCl to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration.
## Structure
- Articadent injection is a sterile, aqueous solution that contains articaine HCl 4% (40 mg/mL) with epinephrine bitartrate in an epinephrine 1:200,000 or epinephrine 1:100,000 strength. Articaine HCl is an amino amide local anesthetic, chemically designated as 4-methyl-3-[2-(propylamino)-propionamido]-2-thiophene-carboxylic acid, methyl ester hydrochloride and is a racemic mixture. Articaine HCl has a molecular weight of 320.84 and the following structural formula:
- Articaine HCl has a partition coefficient in n-octanol/Soerensen buffer (pH: 7.35) of 17 and a pKa of 7.8.
- Epinephrine bitartrate, (-)-1-(3,4-dihydroxyphenyl)-2-methylamino-ethanol (+) tartrate (1:1) salt, is a vasoconstrictor that is added to articaine HCl in a concentration of 1:200,000 or 1:100,000 (expressed as free base). It has a molecular weight of 333.3 and the following structural formula:
## Pharmacodynamics
- Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.
- The onset of anesthesia has been shown to be within 1 to 9 minutes of injection of ARTICADENT. Complete anesthesia lasts approximately 1 hour for infiltrations and up to approximately 2 hours for nerve block.
- Administration of Articadent results in a 3- to 5-fold increase in plasma epinephrine concentrations compared to baseline; however, in healthy adults it does not appear to be associated with marked increases in blood pressure or heart rate, except in the case of accidental intravascular injection
## Pharmacokinetics
- Following dental injection by the submucosal route of an articaine solution containing epinephrine1:200,000, articaine reaches peak blood concentration about 25 minutes after a single dose injection and 48 minutes after three doses. Peak plasma levels of articaine achieved after 68 and 204 mg doses are 385 and 900 ng/mL, respectively. Following intraoral administration of a near maximum dose of 476 mg, articaine reaches peak blood concentrations of 2037 and 2145 ng/mL for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively, approximately 22 minutes post-dose.
- Approximately 60 to 80% of articaine HCl is bound to human serum albumin and γ-globulins at 37°C in vitro.
- Articaine HCl is metabolized by plasma carboxyesterase to its primary metabolite, articainic acid, which is inactive. In vitro studies show that the human liver microsome P450 isoenzyme system metabolizes approximately 5% to 10% of available articaine with nearly quantitative conversion to articainic acid.
- At the dose of 476 mg of articaine, the elimination half-life was 43.8 minutes and 44.4 minutes for articaine solution with epinephrine 1:100,000 and 1:200,000, respectively. Articaine is excreted primarily through urine with 53% to 57% of the administered dose eliminated in the first 24 hours following submucosal administration. Articainic acid is the primary metabolite in urine. A minor metabolite, articainic acid glucuronide, is also excreted in urine. Articaine constitutes only 2% of the total dose excreted in urine.
- No studies have been performed to evaluate the pharmacokinetics of Articadent injection in pediatric subjects. There is insufficient information to determine whether the pharmacokinetics of ARTICADENT differs by race.
## Nonclinical Toxicology
- Studies to evaluate the carcinogenic potential of articaine HCI in animals have not been conducted. Five standard mutagenicity tests, including three in vitro tests (the nonmammalian Ames test, the mammalian Chinese hamster ovary chromosomal aberration test and a mammalian gene mutation test with articaine HCl) and two in vivo mouse micronucleous tests (one with articaine and epinephrine 1:100,000 and one with articaine HCl alone) showed no mutagenic effects.
- No effects on male or female fertility were observed in rats for articaine and epinephrine 1:100,000 administered subcutaneously in doses up to 80 mg/kg/day (approximately 2 times the MRHD based on body surface area).
# Clinical Studies
- Three randomized, double-blind, active-controlled studies were designed to evaluate the effectiveness of Articadent containing epinephrine 1:100,000 as a dental anesthetic. Patients ranging in age from 4 years to over 65 years old underwent simple dental procedures such as single uncomplicated extractions, routine operative procedures, single apical resections, and single crown procedures, or complex dental procedures such as multiple extractions, multiple crowns and/or bridge procedures, multiple apical resections, alveolectomies, muco-gingival operations, and other surgical procedures on the bone. Articadent containing epinephrine 1:100,000 was administered as submucosal infiltration and/or nerve block. Efficacy was measured immediately following the procedure by having the patient and investigator rate the patient's procedural pain using a 10 cm visual analog scale (VAS), in which a score of zero represented no pain and a score of 10 represented the worst pain imaginable. Mean patient and investigator VAS pain scores were 0.3 cm-0.4 cm for simple procedures and 0.5 cm-0.6 cm for complex procedures.
- Four randomized, double-blind, active-controlled studies were performed comparing Articadent containing epinephrine 1:100,000 versus Articadent containing epinephrine 1:200,000. The first two studies used electric pulp testers (EPT) to evaluate the success rate (maximum EPT value within 10 minutes), onset, and duration of Articadent containing epinephrine 1:100,000 versus Articadent containing epinephrine 1:200,000 and articaine solution without epinephrine in healthy adults between 18 and 65 years old. Results indicated that the anesthetic characteristics of the 1:100,000 and 1:200,000 formulations were not significantly different.
- A third study compared the difference in visualization of the surgical field after administration of Articadent containing epinephrine 1:100,000 versus Articadent containing epinephrine1:200,000 during bilateral maxillary periodontal surgeries in patients ranging from 21 to 65 years old. Articadent containing epinephrine1:100,000 provided better visualization of the surgical field and less blood loss during the procedures. In a fourth study, designed to assess and compare cardiovascular safety, when the maximum dose of each formulation was administered, no clinically relevant differences in blood pressure or heart rate between formulations were observed.
# How Supplied
- Articadent (articaine HCl with epinephrine) Injection is available in 1.7 mL single use glass cartridges, packaged in boxes of 50 cartridges in the following two strengths:
## Storage
- Store at controlled room temperature 25°C (77°F) with brief excursions permitted between 15° and 30°C (59°F - 86°F) [see USP Controlled Room Temperature]. Protect from light. Do Not Freeze.
- For chemical disinfection of the carpule, either isopropyl alcohol (91%) or ethyl alcohol (70%) is recommended. Many commercially available brands of isopropyl (rubbing) alcohol, as well as solutions of ethyl alcohol not of U.S.P. grade, contain denaturants that are injurious to rubber and therefore are not to be used.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 1.7 ML CARTRIDGE CARTON (EPINEPHRINE 1:100,000)
NDC 66312-601-16
DENTSPLY
PHARMACEUTICAL
Articadent® DENTAL
(articaine HCl and epinephrine) Injection
Articaine hydrochloride 4% and epinephrine 1:100,000
Intraoral Submucosal Injection
Contains sodium metabisulfite
Store at 25°C (77°F)
DO NOT PERMIT TO FREEZE.
Rx only
50 Cartridges, 1.7 mL each
COLOR
CODED
STERILE AQUEOUS
SOLUTION FOR INJECTION
DENTSPLY Reorder #: 51116
### PRINCIPAL DISPLAY PANEL - 1.7 ML CARTRIDGE CARTON (EPINEPHRINE 1:200,000)
NDC 66312-602-16
DENTSPLY
PHARMACEUTICAL
Articadent® DENTAL
(articaine HCl and epinephrine) Injection
Articaine hydrochloride 4% and epinephrine 1:200,000
Intraoral Submucosal Injection
Contains sodium metabisulfite
Store at 25°C (77°F)
DO NOT PERMIT TO FREEZE.
Rx only
50 Cartridges, 1.7 mL each
COLOR
CODED
STERILE AQUEOUS
SOLUTION FOR INJECTION
DENTSPLY Reorder #: 52216
### Ingredients and Appearance
# Patient Counseling Information
- Loss of Sensation and Muscle Function:
# Precautions with Alcohol
- Alcohol-Articaine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARTICADENT ®[2]
# Look-Alike Drug Names
There is limited information regarding Articaine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Articaine | |
e7ec1e677a1f4d624314a3180983c6c17159f9c7 | wikidoc | Cartilage | Cartilage
# Overview
Cartilage is a type of dense connective tissue. It is composed of specialized cells called chondrocytes that produce a large amount of extracellular matrix composed of collagen fibers, abundant ground substance rich in proteoglycan, and elastin fibers. Cartilage is classified in three types, elastic cartilage, hyaline cartilage and fibrocartilage, which differ in the relative amounts of these three main components.
Cartilage is found in many places in the body including the articular surface of the bones, the rib cage, the ear, the nose, the bronchial tubes and the intervertebral discs. Its mechanical properties are intermediate between bone and dense connective tissue like tendon.
Unlike other connective tissues, cartilage does not contain blood vessels. The chondrocytes are fed by
diffusion, helped by the pumping action generated by compression of the articular cartilage or flexion of the elastic cartilage. Thus, compared to other connective tissues, cartilage grows and repairs more slowly.
# Types of cartilage
## Hyaline cartilage
Hyaline cartilage is a rather hard, translucent material rich in collagen and proteoglycan. It covers the end of bones to form the smooth articular surface of joints. It is also found in the nose, the larynx and between the ribs and the sternum. Bones grow via a hyaline cartilage intermediate, a process called Endochondral ossification.
## Elastic cartilage
Elastic cartilage contains large amounts of elastic fibers (elastin) scattered throughout the matrix. It is stiff yet elastic, and is important to prevent tubular structures from collapsing. Elastic cartilage is found in the pinna of the ear, in tubular structures such as the auditory (Eustachian) tubes and in the epiglottis.
## Fibrocartilage
Fibrocartilage is the most common form of cartilage by weight. It is characterized by a dense network of Type I collagen. It is a white, very tough material that provides high tensile strength and support. It contains more collagen and less proteoglycan than hyaline cartilage. Thus, its properties are closer to those of tendon than hyaline cartilage. It is present in areas most subject to frequent stress like intervertebral discs, the symphysis pubis and the attachments of certain tendons and ligaments.
# Growth and development
## Cartilage in fetal development
In embryogenesis, the skeletal system is derived from the mesoderm germ layer. Chondrification (also known as chondrogenesis) is the process by which cartilage is formed from condensed mesenchyme tissue, which differentiates into chondrocytes and begins secreting the molecules that form the extracellular matrix.
Early in fetal development, the greater part of the skeleton is cartilaginous. This temporary cartilage is gradually replaced by bone (Endochondral ossification), a process that ends at puberty. In contrast, the cartilage in the joints remains unossified during the whole of life and is, therefore, permanent.
## Mineralization
Adult hyaline articular cartilage is progressively mineralized at the junction between cartilage and bone. It is then termed articular calcified cartilage. A mineralization front advances through the base of the hyaline articular cartilage at a rate dependent on cartilage load and shear stress. Intermittent variations in the rate of advance and mineral deposition density of the mineralizing front, lead to multiple "tidemarks" in the articular calcified cartilage.
Adult articular calcified cartilage is penetrated by vascular buds, and new bone produced in the vascular space in a process similar to endochondral ossification at the physis. A cement line demarcates articular calcified cartilage from subchondral bone.
## Repair
Cartilage has limited repair capabilities. Because chondrocytes are bound in lacunae, they cannot migrate to damaged areas. Also, because hyaline cartilage does not have a blood supply, the deposition of new matrix is slow. Damaged hyaline cartilage is usually replaced by fibrocartilage scar tissue. Cartilage can be replaced surgically through chondroplasty.
# Diseases and treatment
There are several diseases which can affect the cartilage. Chondrodystrophies are a group of diseases characterized by disturbance of growth and subsequent ossification of cartilage. Some common diseases affecting/involving the cartilage are listed below.
- Osteoarthritis: The cartilage covering bones (articular cartilage) is thinned, eventually completely worn out, resulting in a "bone against bone" joint, reduced motion and pain. Osteoarthritis is very common, affects the joints exposed to high stress and is therefore considered the result of "wear and tear" rather than a true disease. It is treated by Arthroplasty, the replacement of the joint by a synthetic joint made of titanium and teflon. Chondroitin sulfate, a monomer of the polysaccharide portion of proteoglycan, has been shown to reduce the symptoms of osteoarthritis, possibly by increasing the synthesis of the extracellular matrix.
- Traumatic rupture or detachment: The cartilage in the knee is frequently damaged, and can be partially repaired through knee cartilage replacement therapy
- Achondroplasia: Reduced proliferation of chondrocytes in the epiphyseal plate of long bones during infancy and childhood, resulting in dwarfism.
- Costochondritis: Inflammation of cartilage in the ribs, causing chest pain.
- Spinal disc herniation : Asymmetrical compression of an intervertebral disc ruptures the sac-like disc, causing a herniation of its soft content. The hernia compresses the adjacent nerves and causes back pain.
- Relapsing polychondritis: a destruction, probably autoimmune, of cartilage, especially of the nose and ears, causing disfiguration. Death occurs by suffocation as the larynx loses its rigidity and collapses.
tumors made up of cartilage tissue, either benign or malignant, can occur. They usually appear in bone, rarely in pre-existing cartilage. The benign tumors are called chondroma, the malignant ones chondrosarcoma. Tumors arising from other tissues may also produce a cartilage-like matrix, the best known being pleomorphic adenoma of the salivary glands.
The matrix of cartilage acts as a barrier, preventing the entry of lymphocytes or diffusion of immunoglobulins. This property allows for the transplantation of cartilage from one individual to another without fear of tissue rejection.
Bioengineering techniques are being developed to generate new cartilage, using a cellular "scaffolding" material and cultured cells to grow artificial cartilage.
# Cartilage in animals
## Cartilaginous fish
Cartilaginous fish (chondrichthyes) like sharks, rays and skates have a skeleton composed entirely of cartilage. Shark cartilage is a popular but unproven dietary supplement.
## Invertebrate cartilage
Cartilage tissue can also be found among invertebrates such as horseshoe crabs, marine snails, and cephalopods. | Cartilage
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cartilage is a type of dense connective tissue. It is composed of specialized cells called chondrocytes that produce a large amount of extracellular matrix composed of collagen fibers, abundant ground substance rich in proteoglycan, and elastin fibers. Cartilage is classified in three types, elastic cartilage, hyaline cartilage and fibrocartilage, which differ in the relative amounts of these three main components.
Cartilage is found in many places in the body including the articular surface of the bones, the rib cage, the ear, the nose, the bronchial tubes and the intervertebral discs. Its mechanical properties are intermediate between bone and dense connective tissue like tendon.
Unlike other connective tissues, cartilage does not contain blood vessels. The chondrocytes are fed by
diffusion, helped by the pumping action generated by compression of the articular cartilage or flexion of the elastic cartilage. Thus, compared to other connective tissues, cartilage grows and repairs more slowly.
# Types of cartilage
## Hyaline cartilage
Hyaline cartilage is a rather hard, translucent material rich in collagen and proteoglycan. It covers the end of bones to form the smooth articular surface of joints. It is also found in the nose, the larynx and between the ribs and the sternum. Bones grow via a hyaline cartilage intermediate, a process called Endochondral ossification.
## Elastic cartilage
Elastic cartilage contains large amounts of elastic fibers (elastin) scattered throughout the matrix. It is stiff yet elastic, and is important to prevent tubular structures from collapsing. Elastic cartilage is found in the pinna of the ear, in tubular structures such as the auditory (Eustachian) tubes and in the epiglottis.
## Fibrocartilage
Fibrocartilage is the most common form of cartilage by weight. It is characterized by a dense network of Type I collagen. It is a white, very tough material that provides high tensile strength and support. It contains more collagen and less proteoglycan than hyaline cartilage. Thus, its properties are closer to those of tendon than hyaline cartilage. It is present in areas most subject to frequent stress like intervertebral discs, the symphysis pubis and the attachments of certain tendons and ligaments.
# Growth and development
## Cartilage in fetal development
In embryogenesis, the skeletal system is derived from the mesoderm germ layer. Chondrification (also known as chondrogenesis) is the process by which cartilage is formed from condensed mesenchyme tissue, which differentiates into chondrocytes and begins secreting the molecules that form the extracellular matrix.
Early in fetal development, the greater part of the skeleton is cartilaginous. This temporary cartilage is gradually replaced by bone (Endochondral ossification), a process that ends at puberty. In contrast, the cartilage in the joints remains unossified during the whole of life and is, therefore, permanent.
## Mineralization
Adult hyaline articular cartilage is progressively mineralized at the junction between cartilage and bone. It is then termed articular calcified cartilage. A mineralization front advances through the base of the hyaline articular cartilage at a rate dependent on cartilage load and shear stress. Intermittent variations in the rate of advance and mineral deposition density of the mineralizing front, lead to multiple "tidemarks" in the articular calcified cartilage.
Adult articular calcified cartilage is penetrated by vascular buds, and new bone produced in the vascular space in a process similar to endochondral ossification at the physis. A cement line demarcates articular calcified cartilage from subchondral bone.
## Repair
Cartilage has limited repair capabilities. Because chondrocytes are bound in lacunae, they cannot migrate to damaged areas. Also, because hyaline cartilage does not have a blood supply, the deposition of new matrix is slow. Damaged hyaline cartilage is usually replaced by fibrocartilage scar tissue. Cartilage can be replaced surgically through chondroplasty.
# Diseases and treatment
There are several diseases which can affect the cartilage. Chondrodystrophies are a group of diseases characterized by disturbance of growth and subsequent ossification of cartilage. Some common diseases affecting/involving the cartilage are listed below.
- Osteoarthritis: The cartilage covering bones (articular cartilage) is thinned, eventually completely worn out, resulting in a "bone against bone" joint, reduced motion and pain. Osteoarthritis is very common, affects the joints exposed to high stress and is therefore considered the result of "wear and tear" rather than a true disease. It is treated by Arthroplasty, the replacement of the joint by a synthetic joint made of titanium and teflon. Chondroitin sulfate, a monomer of the polysaccharide portion of proteoglycan, has been shown to reduce the symptoms of osteoarthritis, possibly by increasing the synthesis of the extracellular matrix.
- Traumatic rupture or detachment: The cartilage in the knee is frequently damaged, and can be partially repaired through knee cartilage replacement therapy
- Achondroplasia: Reduced proliferation of chondrocytes in the epiphyseal plate of long bones during infancy and childhood, resulting in dwarfism.
- Costochondritis: Inflammation of cartilage in the ribs, causing chest pain.
- Spinal disc herniation : Asymmetrical compression of an intervertebral disc ruptures the sac-like disc, causing a herniation of its soft content. The hernia compresses the adjacent nerves and causes back pain.
- Relapsing polychondritis: a destruction, probably autoimmune, of cartilage, especially of the nose and ears, causing disfiguration. Death occurs by suffocation as the larynx loses its rigidity and collapses.
tumors made up of cartilage tissue, either benign or malignant, can occur. They usually appear in bone, rarely in pre-existing cartilage. The benign tumors are called chondroma, the malignant ones chondrosarcoma. Tumors arising from other tissues may also produce a cartilage-like matrix, the best known being pleomorphic adenoma of the salivary glands.
The matrix of cartilage acts as a barrier, preventing the entry of lymphocytes or diffusion of immunoglobulins. This property allows for the transplantation of cartilage from one individual to another without fear of tissue rejection.
Bioengineering techniques are being developed to generate new cartilage, using a cellular "scaffolding" material and cultured cells to grow artificial cartilage.
# Cartilage in animals
## Cartilaginous fish
Cartilaginous fish (chondrichthyes) like sharks, rays and skates have a skeleton composed entirely of cartilage. Shark cartilage is a popular but unproven dietary supplement.
## Invertebrate cartilage
Cartilage tissue can also be found among invertebrates such as horseshoe crabs, marine snails, and cephalopods. | https://www.wikidoc.org/index.php/Articular_cartilage | |
853fb5d4b27357571ed9b33714f540907f88f8e6 | wikidoc | Asciminib | Asciminib
# 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
Asciminib is a kinase inhibitor that is FDA approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia with disease that meets certain criteria. Common adverse reactions include include fatigue, nausea, diarrhea, rash, musculoskeletal pain, and upper respiratory tract infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
For Patients with Ph+ CML-CP, previously treated with two or more TKIs should either take:
- 80 mg taken once a day orally
- 40 mg twice a day in 12 hour intervals orally
For Patients with Ph+ CML-CP with the T315I mutation should take:
- 200 mg twice a day in 12 hour intervals orally
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Asciminib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Asciminib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Asciminib 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 Asciminib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Asciminib in pediatric patients.
# Contraindications
There are no contraindications associated with Asciminib.
# Warnings
Myelosuppression
- Studies conducted show evidence of thrombocytopenia, neutropenia, and anemia.
- Thrombocytopenia was found in 28% of patients taking Asciminib. Of those patients, Grade 3 thrombocytopenia occurred in 7% of patients and Grade 4 thrombocytopenia occurred in 12% of patients.
- Neutropenia was found in 19% of patients taking Asciminib. Of those patients, Grade 3 neutropenia occurred in 8% of patients and Grade 4 neutropenia occurred in 8% of patients.
- Anemia was found in 13% of patients taking Asciminib. Of those patients, Grade 3 anemia occurred in 5% of patients.
- To monitor symptoms, blood counts should be conducted every 2 weeks of initial start to monthly checks after 3 months of treatment. Alter dosage or permanently discontinue Asciminib based on severity of symptoms.
Pancreatic Toxicity
- Serum lipase and amylase should be monitored monthly in patients using Asciminib and frequently in patients that have a history of pancreatitis. *Studies showed pancreatitis in 2.5% of patients with Grade 3 pancreatitis occurring in 1.1% of patients.
- Increase in lipase and amylase occurred in 21% of patients. Of those patients, Grade 3 pancreatic enzyme elevation occurred in 10% of patients and Grade 4 pancreatic enzyme elevation occurred in 2.2% of patients.
- Alter or discontinue the use of Asciminib when levels of serum lipase and amylase change.
Hypertension
- Hypertension should be monitored and treated appropriately. Studies conducted show that hypertension occurred in 19% patients. Of those patients, Grade 3 hypertension was found in 9% of patients and Grade 4 hypertension was found in 0.3% of patients.
- Advise patients who have symptoms of Grade 3 and higher hypertensions to either reduce, temporarily withold, or permanently discontinue the use of Asciminib depending on the severity of the symptoms.
Hypersensitivity
- Hypersensitivity including rash, edema, and bronchospasm have been reported in patients using Asciminib. Studies conducted show that hypersensitivity occurred in 32% patients. Of those patients, Grade 3 or Grade 4 hypersensitivity was found in 1.7% of patients.
- Patients with symptoms of Grade 3 and higher hypersensitivity should either reduce, temporarily withold, or permanently discontinue the use of Asciminib depending on the severity of the symptoms.
Cardiovascular Toxicity
- Cardiovascular toxicity including ischemic cardiac, arterial thrombotic and embolic conditions have been reported in patients using Asciminib. Studies conducted show that cardiovascular toxicity occurred in 13% patients while 2.2% of patients had cardiac failure. Of those patients, Grade 3 cardiovascular toxicity occurred in 3.4% of patients and Grade 3 cardiac failure occurred in 1.1% of patients. The study also showed Grade 4 cardiovascular toxicity occurred in 0.6% of patients.
- Monitor patients regularly who have a history of cardiovascular risks when taking Asciminib. Patients with symptoms of Grade 3 and higher cardiovascular toxicity should either reduce, temporarily withold, or permanently discontinue the use of Asciminib depending on the severity of the symptoms.
Embryo-Fetal Toxicity
- Based on animal data, Asciminib potentially can cause harm to females fetus during pregnancy. Animal studies show mortality and malformations in rats and rabbits occurred during organogenesis.
- Advise females about potential risks to a fetus when taking Asciminib. *Advise females of reproductive potential to use effective contraception during treatment with Asciminib and for at least 1 week after the last dose.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trial Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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. Asciminib has been evaluated for safety in 356 patients who were observed in one of two clinical trials with one trial including patients with Ph+ CML-CP, previously treated with two or more TKIs and the other trial including patients with Ph+ CML-CP with the T315I mutation. Both trials are discussed below and had a median duration of 89 weeks.
Patients with Ph+ CML-CP, previously treated with two or more TKIs
- 15% of patients taking Asciminib received adverse reactions such as pyrexia (1.9%), cardiac failure congestive (1.3%), thrombocytopenia (1.3%), and urinary tract infection (1.3%).
- 7% of patients who had adverse reactions had to permanently discontinue Asciminib with reactions including thrombocytopenia (3.2%) and neutropenia (2.6%).
- 38% of patients had interruptions in their dosage due to adverse reactions which included thrombocytopenia (19%) and neutropenia (18%).
- Dosage reductions occurred due to adverse reactions in 38% of patients which showed thrombocytopenia (19%) and neutropenia (18%).
- Upper respiratory tract infections and musculoskeletal pain were the most common adverse reactions (≥ 20%) in patients.
Table 3 shows the overall adverse reactions in Patients with Ph+ CML-CP, previously treated with two or more TKIs taking Asciminib compared to Bosutinib.
Table 4 shows the overall lab abnormalities in Patients with Ph+ CML-CP, previously treated with two or more TKIs taking Asciminib in ASCEMBL.
Patients with Ph+ CML-CP with the T315I mutation
- 23% of the patients taking Asciminib displayed adverse reactions such as abdominal pain (4.2%), vomiting (4.2%), pneumonia (4.2%), musculoskeletal pain (2.1%), headache (2.1%), hemorrhage (2.1%), constipation (2.1%), arrhythmia (2.1%), and pleural effusion (2.1%).
- 10% of patients who had adverse reactions had to permanently discontinue Asciminib with reactions including pancreatic enzymes increase (2.1%).
- 31% of patients had interruptions in their dosage due to adverse reactions which included thrombocytopenia (19%) and pancreatic enzymes increase (17%).
- Dosage reductions occurred due to adverse reactions in 23% of patients which showed pancreatic enzymes increase (10%), abdominal pain (4.2%), anemia (2.1%), blood bilirubin increase (2.1%), dizziness (2.1%), fatigue (2.1%), hepatic enzymes increase (2.1%), musculoskeletal pain (2.1%), nausea (2.1%), neutropenia (2.1%), pruritus (2.1%), and thrombocytopenia (2.1%). *Musculoskeletal pain, fatigue, nausea, rash, and diarrhea were the most common adverse reactions (≥ 20%) in patients.
Table 5 shows the overall adverse reactions in Patients with Ph+ CML-CP with the T315I mutation taking Asciminib in X2101.
Table 6 shows the overall lab abnormalities in Patients with Ph+ CML-CP with the T315I mutation in X2101
## Postmarketing Experience
There is limited information about "Postmarketing Experiance" in the drug label.
# Drug Interactions
Strong CYP3A4 Inhibitors
- Concomitant use of these drugs potentially increases the likelihood of adverse effects in patients because Asciminib Cmax and AUC increase with concomitant use.
Itraconazole Oral Use containing Hydroxypropyl-β-cyclodextrin
- Concomitant use of these drugs may decrease Asciminib efficacy in patients as both Asciminib Cmax and AUC decrease with concomitant use.
Certain CYP3A4
- Concomitant use of these drugs potentially increases the likelihood of adverse effects in patients because Asciminib Cmax and AUC of CYP3A4 substrates increase with concomitant use.
- Monitor patients using 80 mg Asciminib with concomitant use of certain CYP3A4 substrates which can potentially lead to adverse reactions in patients.
- Advise patients to avoid the coadministration of 200 mg Asciminib and certain CYP3A4 substrates which can potentially lead to adverse reactions in patients.
CYP2C9 Substrates
- Concomitant use of these drugs potentially increases the likelihood of adverse effects in patients because because Asciminib Cmax and AUC of CYP2C9 substrates increase with concomitant use.
- Advise patients to avoid coadministration of both 80 mg and 200 mg Asciminib with certain CYP2C9 substrates which can potentially lead to adverse reactions in patients.
Certain P-gp Substrates
- Concomitant use of these drugs potentially increases the likelihood of adverse effects in patients because of the increase in plasma membrane concentration of these substrates.
- Monitor patients for potential adverse reactions at all dosages of Asciminib with concomitant use of certain P-gp Substrates.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Reproduction studies done on rats and rabbits at doses up to 600 mg/kg/day and 300 mg/kg/day, respectively, revealed both maternal toxicity at the highest doses and malformations in different areas of the body. In rats, malformations occurred in cleft palate, anasarca (edema), and cardiac abnormalities at 150 mg/kg. In rabbits, studies showed cardiac malformations and decrease in live fetus in females at 50mg/kg. These studies display the potential harms and risks in the embryo of pregnant woman when taking Asciminib.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Asciminib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Asciminib during labor and delivery.
### Nursing Mothers
No data has been conducted on nursing in human when taking Asciminib. Based on studies done on rats and rabbits, it is recommended not to lactate when taking Asciminib.
### Pediatric Use
Safety and effectiveness in pediatric populations have not been established.
### Geriatic Use
Of the total number of subjects in the ASCEMBL clinical studies, around 19% of the patients were 65 years or older in age, and 2.6% were 75 years or older in age. In X2101 that tested patients with T315I mutation, around 33% of the patients were 65 years or older in age, and 8% were 75 years or older in age. No differences among young patients compared to patients 65 years or older in age were found when looking at safety and efficacy of Asciminib. More data is required to assess safety and efficacy between young patients and patients 75 year or older in age.
### Gender
There is no FDA guidance on the use of Asciminib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Asciminib with respect to specific racial populations.
### Renal Impairment
Patients with mild and severe renal impairment require no change to dosage usage.
### Hepatic Impairment
Patients with mild and severe hepatic impairment require no change to dosage usage.
### Females of Reproductive Potential and Males
Infertility can be impaired in females based on studies done on rats and rabbits. Asciminib has shown signs of harm in the embryo of pregnant women. There has been no effects recorded in males on their reproductive potential.
### Immunocompromised Patients
There is no FDA guidance on the use of Asciminib with respect to immunocompromised populations.
# Administration and Monitoring
### Administration
- Swallow Asciminib tablets whole.
- Instruct patients to not chew, crush, or break tablets.
- Instruct patients to not eat 2 hours before taking tablet and 1 hour after taking tablet.
- Continue treatment until disease progression or unacceptable toxicity.
- Follow recommended dosage as prescribed by a doctor.
- For pateints that take Asciminib once daily, if a dosage is missed by more than 12 hours, then skip dosage and take next dosage at scheduled time.
- For pateints that take Asciminib twice daily, if a dosage is missed by more than 6 hours, then skip dosage and take next dosage at scheduled time.
### Monitoring
# IV Compatibility
There is limited information regarding the compatibility of Asciminib and IV administrations.
# Overdosage
There is limited information regarding Asciminib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Asciminib is an ABL/BCR-ABL1 tyrosine kinase inhibitor that has an inhibitory effect on the ABL1 Protein. Kinase activity of the ABL1 protein is inhibited on the BCR-ABL1 fusion protein.
- In vitro, Asciminib also showed inhibitory effects against several mutant forms of BCR-ABL1 which also included the T315I mutation.
## Structure
- Asciminib is a kinase inhibitor for oral administration. It has an empirical formula of C20H18ClF2N5O3 and a molecular weight of 449.8.
- The chemical name is N-phenyl]-6--5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.
## Pharmacodynamics
Exposure-Response Relationships
- Lower exposure of asciminib dosages of 10mg to 200mg twice daily at week 24 was associated with a smaller decrease in BCR-ABL1 level and a lower MMR rate.
- Higher exposure of asciminib dosages of 10mg to 280mg twice daily was associated with adverse reactions occurring more frequently.
Cardiac Electrophysiology
- At maximum clincal dosage, no large mean increase in QTc interval is indicated when taking Asciminib.
## Pharmacokinetics
Steady State Exposure
- At 10 mg to 200 mg of Asciminib, AUC and Cmax increased slightly higher in comparison to the dose proportion.
Table 7 shows data conducted on Steady State Asciminib Exposure
Absorption
- Asciminib has a median Tmax of 2.5 hours.
- In high fat meals (1000 calories, 50% fat), AUC decreased by 62% and Cmax decreased by 68%.
- In low fat meals (400 calories, 25% fat), AUC decreased by 30% and Cmax decreased by 35%.
Distribution
- At a steady state, the volume of distribution is 151 L for Asciminib.
- In human plasma protein in vitro, Asciminib is 97% bound.
Elimination
- Total clearance at 40 mg twice daily and 80 mg once daily of Asciminib is 6.7 L/hour.
- Total clearance at 200 mg twice daily of Asciminib is 4.1 L/hour.
- Terminal elimination half-life at 40 mg twice daily and 80 mg once daily of Asciminib is 5.5 hours.
- Terminal elimination half-life at 200 mg twice daily of Asciminib is 9.0 hours.
Metabolism
- UGT2B7-mediated glucuronidation, UGT2B17-mediated glucuronidation, CYP3A4-mediated oxidation metabolizes Asciminib.
Excretion
- In feces after a single 80 mg dosage of Asciminib, 80% of Asciminib was found in which 57% was found unchanged.
- In urine, after a single 80 mg dosage of Asciminib, 11% of Asciminib was found in which 2.5% was found unchanged.
- Biliary Secretion eliminates Asciminib via BCRP.
Specific Populations
- Sex, mild to moderate hepatic impairment, age, race, mild to moderate renal impairment, and body weight showed no significant differences of pharmacokinetics clinically of Asciminib.
Patients with Renal Impairment
- Patients not requiring dialysis who also have eGFR between 13 to < 30 mL/min/1.73 m2 showed increases in both AUCinf (57%) and Cmax (6%) after single 40 mg dose of Asciminib when compared to patients with normal renal function.
- Changes in exposure are not considered clinically meaningful.
Patients with Hepatic Impairment
- Patients with severe hepatic impairment (total bilirubin > 3 times ULN and any AST) showed increases in both AUCinf (33%) and Cmax (4%) after single 40 mg dose of Asciminib when compared to patients with normal hepatic function. *Changes in exposure are not considered clinically meaningful.
Drug Interaction Studies
Drugs that Affect Plasma Concentrations of Asciminib
- Strong CYP3A Inhibitors: Coadministration of clarithromycin (Strong CYP3A Inhibitor) and a single dose of 40 mg of Asciminib showed increases in both AUCinf (36%) and Cmax (19%). Coadministration of itraconazole (Strong CYP3A Inhibitor) and Asciminib showed no significant differences in AUCinf and Cmax clinically.
- Strong CYP3A Inducers: Asciminib in concomitant use of strong CYP3A inducers has not been fully characterized.
- Itraconazole Oral Solution: Coadministration of a single dose of 40 mg of Asciminib and itraconazole oral solution containing hydroxypropyl-β-cyclodextrin showed decreases in both AUCinf (40%) and Cmax (50%). Coadministration of Asciminib and other products containing hydroxypropyl-β-cyclodextrin are not fully characterized.
- Imatinib: Coadministration of imatinib and a single dose 40 mg of Asciminib showed increases in both AUCinf (108%) and Cmax (59%). Changes in exposure are not considered clinically meaningful. Concomitant use of 200 mg of Asciminib twice daily and imatinib are not fully characterized.
- Other Drugs: Coadministration of either quinidine (P-gp inhibitor) or rabeprazole (acid-reducing agent) and Asciminib showed no significant differences clinically.
Drugs That are Affected by Asciminib
- CYP3A4 Substrates: Coadministration of midazolam, CYP3A4 substrate, and a twice daily dosage of 40 mg of Asciminib showed increases in both AUCinf (28%) and Cmax (11%). Coadministration of midazolam and a single daily dosage of 80 mg of Asciminib showed increases in both AUCinf (24%) and Cmax (17%). Coadministration of midazolam and a twice daily dosage of 200 mg of Asciminib showed increases in both AUCinf (88%) and Cmax (58%).
- CYP2C9 Substrates: Coadministration of warfarin, CYP2C9 substrate, and a twice daily dosage of 40 mg of Asciminib showed increases in both AUCinf (41%) and Cmax (8%). Coadministration of warfarin and a single daily dosage of 80 mg of Asciminib showed increases in both AUCinf (52%) and Cmax (4%). Coadministration of midazolam and a twice daily dosage of 200 mg of Asciminib showed increases in both AUCinf (314%) and Cmax (7%).
- CYP2C8 Substrates: Coadministration of repaglinide (substrate of CYP2C8, CYP3A4, and OATP1B) and a twice daily dosage of 40 mg of Asciminib showed increases in both AUCinf (8%) and Cmax (14%). Coadministration of repaglinide and a single daily dosage of 80 mg of Asciminib showed increases in both AUCinf (12%) and Cmax (8%). Coadministration of repaglinide and a twice daily dosage of 200 mg of Asciminib showed increases in both AUCinf (42%) and Cmax (25%). Coadministration of rosiglitazone (substrate of CYP2C8 and CYP2C9) and a twice daily dosage of 40 mg of Asciminib showed increases in both AUCinf (20%) and Cmax (3%). Coadministration of rosiglitazone and a single daily dosage of 80 mg of Asciminib showed increases in both AUCinf (24%) and Cmax (2%). Coadministration of rosiglitazone and a twice daily dosage of 200 mg of Asciminib showed increases in both AUCinf (66%) and Cmax (8%).
- P-gp Substrates: Increases in plasma membrane concentrations and serious toxicities may occur with coadministration of P-gp substrates and Asciminib.
In Vitro Studies
- CYP450 and UGT Enzymes: Plasma concentrations reached at 80 mg twice daily and 200 mg twice daily of Asciminib can reversibly inhibit UGT1A1. At 200 mg of Ascminib twice daily can reversibly inhibit CYP2C19.
- Transporter Systems: OATP1B1, BCRP, OATP1B3, P-gp, and OCT1 are inhibited by Asciminib. The substrate of P-gp and BCRP is Asciminib.
## Nonclinical Toxicology
- No research has been conducted on the carcinogenicity when dealing with Asciminib.
- When looking at fertility, studies conducted on male rats have shown evidence of a decrease in sperm count and motility when dosed with 200 mg/kg/day of Asciminib. Studies on female mice showed evidence of decreased living embryos when dosed with 200 mg/kg/day of Asciminib.
- Mutagenicity studies have shown that Asciminib is not genotoxic.
# Clinical Studies
Two clinical trials were conducted on Patients with Ph+ CML-CP, previously treated with two or more TKIs and Patients with Ph+ CML-CP with the T315I mutation.
Patients with Ph+ CML-CP, previously treated with two or more TKIs
- The efficacy of Asciminib was tested on 233 patients that either received 40 mg of Asciminib twice daily or bosutinib 500 mg once daily. The patient population was largely Caucasian (75%), and included 52% women, and 19% were 65 years or older. Patients in the study took Asciminib for an average duration of 67 weeks and Bosutinib for an average duration 30 weeks. The results of the study are summarized in table 8. The study showed that MMR rate was at 29% for patients taking Asciminib and 13% for patients taking Bosutinib.
Table 8 shows the clinical data conducted in Patients with Ph+ CML-CP, previously treated with two or more TKIs taking Asciminib compared to Bosutinib.
Patients with Ph+ CML-CP with the T315I mutation
- The efficacy of Asciminib was tested on 45 patients that received 200 mg of Asciminib twice daily. The patient population was largely Caucasian (47%), and included 80% male, and 31% were 65 years or older. Patients in the study took Asciminib for an average duration of 108 weeks. The study showed MMR rate at 24 weeks (42%) and 96 weeks (49%) of the patients taking Asciminib.
# How Supplied
- 20 mg Asciminib coated tablets (60 tablets per bottle).
- 40 mg Asciminib coated tablets (60 tablets per bottle).
## Storage
- Store at 20° to 25°C (68° to 77°F) .
- To protect from moisture, store in original container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Myelosuppression
- Asciminib may cause low blood cell counts.
- Patients should be advised to report any signs of bleeding and fever caused by this drug.
Pancreatic Toxicity
- Patients should be advised that pancreatitis may develop accompanied by symptoms such as nausea, vomiting, severe abdominal pain, or abdominal discomfort. Immediately seek medical attention if these symptoms occur.
Hypertension
- Patients should be advised that hypertension may develop along with symptoms such as increased blood pressure, confusion, headache, dizziness, chest pain, or shortness of breath which should be reported to healthcare provider when they persist.
Hypersensitivity
- If symptoms of hypersensitivity including rash, edema, or bronchospasm persist, immediately seek medical attention and stop use of Asciminib.
Cardiovascular Toxicity
- Inform patients that display symptoms of cardiovascular toxicity to seek medical help immediately.
Embryo Fetal Toxicity
- Female patients should be advised about the potential risks that may occur to fetus when taking Aciminib.
- Advise females of reproductive potential to use effective contraception during treatment with Asciminib and for at least 1 week after the last dose.
Lactation
- Inform female patients not to breastfeed when taking Asciminib and 1 week after last dose.
Drug Interactions
- The use of Asciminib and other medications can possibly alter side effects of Asciminib.
Instruction for taking Asciminib
- Take Asciminib orally either once daily or twice daily depending on the dosage prescribed.
- Inform patients to not alter dosage and schedule of each dosage unless told by healthcare provider.
- Swallow tablets whole and do not break or chew tablet.
- Patients advised not to eat two hours before taking tablet and one hour after taking tablet.
- For pateints that take Asciminib once daily, if a dosage is missed by more than 12 hours, then skip dosage and take next dosage at scheduled time.
- For pateints that take Asciminib twice daily, if a dosage is missed by more than 6 hours, then skip dosage and take next dosage at scheduled time.
# Precautions with Alcohol
Alcohol-Asciminib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Scemblix
# Look-Alike Drug Names
There is limited information regarding Asciminib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Asciminib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra
# 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
Asciminib is a kinase inhibitor that is FDA approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia with disease that meets certain criteria. Common adverse reactions include include fatigue, nausea, diarrhea, rash, musculoskeletal pain, and upper respiratory tract infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
For Patients with Ph+ CML-CP, previously treated with two or more TKIs should either take:
- 80 mg taken once a day orally
- 40 mg twice a day in 12 hour intervals orally
For Patients with Ph+ CML-CP with the T315I mutation should take:
- 200 mg twice a day in 12 hour intervals orally
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Asciminib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Asciminib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Asciminib 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 Asciminib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Asciminib in pediatric patients.
# Contraindications
There are no contraindications associated with Asciminib.
# Warnings
Myelosuppression
- Studies conducted show evidence of thrombocytopenia, neutropenia, and anemia.
- Thrombocytopenia was found in 28% of patients taking Asciminib. Of those patients, Grade 3 thrombocytopenia occurred in 7% of patients and Grade 4 thrombocytopenia occurred in 12% of patients.
- Neutropenia was found in 19% of patients taking Asciminib. Of those patients, Grade 3 neutropenia occurred in 8% of patients and Grade 4 neutropenia occurred in 8% of patients.
- Anemia was found in 13% of patients taking Asciminib. Of those patients, Grade 3 anemia occurred in 5% of patients.
- To monitor symptoms, blood counts should be conducted every 2 weeks of initial start to monthly checks after 3 months of treatment. Alter dosage or permanently discontinue Asciminib based on severity of symptoms.
Pancreatic Toxicity
- Serum lipase and amylase should be monitored monthly in patients using Asciminib and frequently in patients that have a history of pancreatitis. *Studies showed pancreatitis in 2.5% of patients with Grade 3 pancreatitis occurring in 1.1% of patients.
- Increase in lipase and amylase occurred in 21% of patients. Of those patients, Grade 3 pancreatic enzyme elevation occurred in 10% of patients and Grade 4 pancreatic enzyme elevation occurred in 2.2% of patients.
- Alter or discontinue the use of Asciminib when levels of serum lipase and amylase change.
Hypertension
- Hypertension should be monitored and treated appropriately. Studies conducted show that hypertension occurred in 19% patients. Of those patients, Grade 3 hypertension was found in 9% of patients and Grade 4 hypertension was found in 0.3% of patients.
- Advise patients who have symptoms of Grade 3 and higher hypertensions to either reduce, temporarily withold, or permanently discontinue the use of Asciminib depending on the severity of the symptoms.
Hypersensitivity
- Hypersensitivity including rash, edema, and bronchospasm have been reported in patients using Asciminib. Studies conducted show that hypersensitivity occurred in 32% patients. Of those patients, Grade 3 or Grade 4 hypersensitivity was found in 1.7% of patients.
- Patients with symptoms of Grade 3 and higher hypersensitivity should either reduce, temporarily withold, or permanently discontinue the use of Asciminib depending on the severity of the symptoms.
Cardiovascular Toxicity
- Cardiovascular toxicity including ischemic cardiac, arterial thrombotic and embolic conditions have been reported in patients using Asciminib. Studies conducted show that cardiovascular toxicity occurred in 13% patients while 2.2% of patients had cardiac failure. Of those patients, Grade 3 cardiovascular toxicity occurred in 3.4% of patients and Grade 3 cardiac failure occurred in 1.1% of patients. The study also showed Grade 4 cardiovascular toxicity occurred in 0.6% of patients.
- Monitor patients regularly who have a history of cardiovascular risks when taking Asciminib. Patients with symptoms of Grade 3 and higher cardiovascular toxicity should either reduce, temporarily withold, or permanently discontinue the use of Asciminib depending on the severity of the symptoms.
Embryo-Fetal Toxicity
- Based on animal data, Asciminib potentially can cause harm to females fetus during pregnancy. Animal studies show mortality and malformations in rats and rabbits occurred during organogenesis.
- Advise females about potential risks to a fetus when taking Asciminib. *Advise females of reproductive potential to use effective contraception during treatment with Asciminib and for at least 1 week after the last dose.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trial Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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. Asciminib has been evaluated for safety in 356 patients who were observed in one of two clinical trials with one trial including patients with Ph+ CML-CP, previously treated with two or more TKIs and the other trial including patients with Ph+ CML-CP with the T315I mutation. Both trials are discussed below and had a median duration of 89 weeks.
Patients with Ph+ CML-CP, previously treated with two or more TKIs
- 15% of patients taking Asciminib received adverse reactions such as pyrexia (1.9%), cardiac failure congestive (1.3%), thrombocytopenia (1.3%), and urinary tract infection (1.3%).
- 7% of patients who had adverse reactions had to permanently discontinue Asciminib with reactions including thrombocytopenia (3.2%) and neutropenia (2.6%).
- 38% of patients had interruptions in their dosage due to adverse reactions which included thrombocytopenia (19%) and neutropenia (18%).
- Dosage reductions occurred due to adverse reactions in 38% of patients which showed thrombocytopenia (19%) and neutropenia (18%).
- Upper respiratory tract infections and musculoskeletal pain were the most common adverse reactions (≥ 20%) in patients.
Table 3 shows the overall adverse reactions in Patients with Ph+ CML-CP, previously treated with two or more TKIs taking Asciminib compared to Bosutinib.
Table 4 shows the overall lab abnormalities in Patients with Ph+ CML-CP, previously treated with two or more TKIs taking Asciminib in ASCEMBL.
Patients with Ph+ CML-CP with the T315I mutation
- 23% of the patients taking Asciminib displayed adverse reactions such as abdominal pain (4.2%), vomiting (4.2%), pneumonia (4.2%), musculoskeletal pain (2.1%), headache (2.1%), hemorrhage (2.1%), constipation (2.1%), arrhythmia (2.1%), and pleural effusion (2.1%).
- 10% of patients who had adverse reactions had to permanently discontinue Asciminib with reactions including pancreatic enzymes increase (2.1%).
- 31% of patients had interruptions in their dosage due to adverse reactions which included thrombocytopenia (19%) and pancreatic enzymes increase (17%).
- Dosage reductions occurred due to adverse reactions in 23% of patients which showed pancreatic enzymes increase (10%), abdominal pain (4.2%), anemia (2.1%), blood bilirubin increase (2.1%), dizziness (2.1%), fatigue (2.1%), hepatic enzymes increase (2.1%), musculoskeletal pain (2.1%), nausea (2.1%), neutropenia (2.1%), pruritus (2.1%), and thrombocytopenia (2.1%). *Musculoskeletal pain, fatigue, nausea, rash, and diarrhea were the most common adverse reactions (≥ 20%) in patients.
Table 5 shows the overall adverse reactions in Patients with Ph+ CML-CP with the T315I mutation taking Asciminib in X2101.
Table 6 shows the overall lab abnormalities in Patients with Ph+ CML-CP with the T315I mutation in X2101
## Postmarketing Experience
There is limited information about "Postmarketing Experiance" in the drug label.
# Drug Interactions
Strong CYP3A4 Inhibitors
- Concomitant use of these drugs potentially increases the likelihood of adverse effects in patients because Asciminib Cmax and AUC increase with concomitant use.
Itraconazole Oral Use containing Hydroxypropyl-β-cyclodextrin
- Concomitant use of these drugs may decrease Asciminib efficacy in patients as both Asciminib Cmax and AUC decrease with concomitant use.
Certain CYP3A4
- Concomitant use of these drugs potentially increases the likelihood of adverse effects in patients because Asciminib Cmax and AUC of CYP3A4 substrates increase with concomitant use.
- Monitor patients using 80 mg Asciminib with concomitant use of certain CYP3A4 substrates which can potentially lead to adverse reactions in patients.
- Advise patients to avoid the coadministration of 200 mg Asciminib and certain CYP3A4 substrates which can potentially lead to adverse reactions in patients.
CYP2C9 Substrates
- Concomitant use of these drugs potentially increases the likelihood of adverse effects in patients because because Asciminib Cmax and AUC of CYP2C9 substrates increase with concomitant use.
- Advise patients to avoid coadministration of both 80 mg and 200 mg Asciminib with certain CYP2C9 substrates which can potentially lead to adverse reactions in patients.
Certain P-gp Substrates
- Concomitant use of these drugs potentially increases the likelihood of adverse effects in patients because of the increase in plasma membrane concentration of these substrates.
- Monitor patients for potential adverse reactions at all dosages of Asciminib with concomitant use of certain P-gp Substrates.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Reproduction studies done on rats and rabbits at doses up to 600 mg/kg/day and 300 mg/kg/day, respectively, revealed both maternal toxicity at the highest doses and malformations in different areas of the body. In rats, malformations occurred in cleft palate, anasarca (edema), and cardiac abnormalities at 150 mg/kg. In rabbits, studies showed cardiac malformations and decrease in live fetus in females at 50mg/kg. These studies display the potential harms and risks in the embryo of pregnant woman when taking Asciminib.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Asciminib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Asciminib during labor and delivery.
### Nursing Mothers
No data has been conducted on nursing in human when taking Asciminib. Based on studies done on rats and rabbits, it is recommended not to lactate when taking Asciminib.
### Pediatric Use
Safety and effectiveness in pediatric populations have not been established.
### Geriatic Use
Of the total number of subjects in the ASCEMBL clinical studies, around 19% of the patients were 65 years or older in age, and 2.6% were 75 years or older in age. In X2101 that tested patients with T315I mutation, around 33% of the patients were 65 years or older in age, and 8% were 75 years or older in age. No differences among young patients compared to patients 65 years or older in age were found when looking at safety and efficacy of Asciminib. More data is required to assess safety and efficacy between young patients and patients 75 year or older in age.
### Gender
There is no FDA guidance on the use of Asciminib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Asciminib with respect to specific racial populations.
### Renal Impairment
Patients with mild and severe renal impairment require no change to dosage usage.
### Hepatic Impairment
Patients with mild and severe hepatic impairment require no change to dosage usage.
### Females of Reproductive Potential and Males
Infertility can be impaired in females based on studies done on rats and rabbits. Asciminib has shown signs of harm in the embryo of pregnant women. There has been no effects recorded in males on their reproductive potential.
### Immunocompromised Patients
There is no FDA guidance on the use of Asciminib with respect to immunocompromised populations.
# Administration and Monitoring
### Administration
- Swallow Asciminib tablets whole.
- Instruct patients to not chew, crush, or break tablets.
- Instruct patients to not eat 2 hours before taking tablet and 1 hour after taking tablet.
- Continue treatment until disease progression or unacceptable toxicity.
- Follow recommended dosage as prescribed by a doctor.
- For pateints that take Asciminib once daily, if a dosage is missed by more than 12 hours, then skip dosage and take next dosage at scheduled time.
- For pateints that take Asciminib twice daily, if a dosage is missed by more than 6 hours, then skip dosage and take next dosage at scheduled time.
### Monitoring
# IV Compatibility
There is limited information regarding the compatibility of Asciminib and IV administrations.
# Overdosage
There is limited information regarding Asciminib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Asciminib is an ABL/BCR-ABL1 tyrosine kinase inhibitor that has an inhibitory effect on the ABL1 Protein. Kinase activity of the ABL1 protein is inhibited on the BCR-ABL1 fusion protein.
- In vitro, Asciminib also showed inhibitory effects against several mutant forms of BCR-ABL1 which also included the T315I mutation.
## Structure
- Asciminib is a kinase inhibitor for oral administration. It has an empirical formula of C20H18ClF2N5O3 and a molecular weight of 449.8.
- The chemical name is N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.
## Pharmacodynamics
Exposure-Response Relationships
- Lower exposure of asciminib dosages of 10mg to 200mg twice daily at week 24 was associated with a smaller decrease in BCR-ABL1 level and a lower MMR rate.
- Higher exposure of asciminib dosages of 10mg to 280mg twice daily was associated with adverse reactions occurring more frequently.
Cardiac Electrophysiology
- At maximum clincal dosage, no large mean increase in QTc interval is indicated when taking Asciminib.
## Pharmacokinetics
Steady State Exposure
- At 10 mg to 200 mg of Asciminib, AUC and Cmax increased slightly higher in comparison to the dose proportion.
Table 7 shows data conducted on Steady State Asciminib Exposure
Absorption
- Asciminib has a median Tmax of 2.5 hours.
- In high fat meals (1000 calories, 50% fat), AUC decreased by 62% and Cmax decreased by 68%.
- In low fat meals (400 calories, 25% fat), AUC decreased by 30% and Cmax decreased by 35%.
Distribution
- At a steady state, the volume of distribution is 151 L for Asciminib.
- In human plasma protein in vitro, Asciminib is 97% bound.
Elimination
- Total clearance at 40 mg twice daily and 80 mg once daily of Asciminib is 6.7 L/hour.
- Total clearance at 200 mg twice daily of Asciminib is 4.1 L/hour.
- Terminal elimination half-life at 40 mg twice daily and 80 mg once daily of Asciminib is 5.5 hours.
- Terminal elimination half-life at 200 mg twice daily of Asciminib is 9.0 hours.
Metabolism
- UGT2B7-mediated glucuronidation, UGT2B17-mediated glucuronidation, CYP3A4-mediated oxidation metabolizes Asciminib.
Excretion
- In feces after a single 80 mg dosage of Asciminib, 80% of Asciminib was found in which 57% was found unchanged.
- In urine, after a single 80 mg dosage of Asciminib, 11% of Asciminib was found in which 2.5% was found unchanged.
- Biliary Secretion eliminates Asciminib via BCRP.
Specific Populations
- Sex, mild to moderate hepatic impairment, age, race, mild to moderate renal impairment, and body weight showed no significant differences of pharmacokinetics clinically of Asciminib.
Patients with Renal Impairment
- Patients not requiring dialysis who also have eGFR between 13 to < 30 mL/min/1.73 m2 showed increases in both AUCinf (57%) and Cmax (6%) after single 40 mg dose of Asciminib when compared to patients with normal renal function.
- Changes in exposure are not considered clinically meaningful.
Patients with Hepatic Impairment
- Patients with severe hepatic impairment (total bilirubin > 3 times ULN and any AST) showed increases in both AUCinf (33%) and Cmax (4%) after single 40 mg dose of Asciminib when compared to patients with normal hepatic function. *Changes in exposure are not considered clinically meaningful.
Drug Interaction Studies
Drugs that Affect Plasma Concentrations of Asciminib
- Strong CYP3A Inhibitors: Coadministration of clarithromycin (Strong CYP3A Inhibitor) and a single dose of 40 mg of Asciminib showed increases in both AUCinf (36%) and Cmax (19%). Coadministration of itraconazole (Strong CYP3A Inhibitor) and Asciminib showed no significant differences in AUCinf and Cmax clinically.
- Strong CYP3A Inducers: Asciminib in concomitant use of strong CYP3A inducers has not been fully characterized.
- Itraconazole Oral Solution: Coadministration of a single dose of 40 mg of Asciminib and itraconazole oral solution containing hydroxypropyl-β-cyclodextrin showed decreases in both AUCinf (40%) and Cmax (50%). Coadministration of Asciminib and other products containing hydroxypropyl-β-cyclodextrin are not fully characterized.
- Imatinib: Coadministration of imatinib and a single dose 40 mg of Asciminib showed increases in both AUCinf (108%) and Cmax (59%). Changes in exposure are not considered clinically meaningful. Concomitant use of 200 mg of Asciminib twice daily and imatinib are not fully characterized.
- Other Drugs: Coadministration of either quinidine (P-gp inhibitor) or rabeprazole (acid-reducing agent) and Asciminib showed no significant differences clinically.
Drugs That are Affected by Asciminib
- CYP3A4 Substrates: Coadministration of midazolam, CYP3A4 substrate, and a twice daily dosage of 40 mg of Asciminib showed increases in both AUCinf (28%) and Cmax (11%). Coadministration of midazolam and a single daily dosage of 80 mg of Asciminib showed increases in both AUCinf (24%) and Cmax (17%). Coadministration of midazolam and a twice daily dosage of 200 mg of Asciminib showed increases in both AUCinf (88%) and Cmax (58%).
- CYP2C9 Substrates: Coadministration of warfarin, CYP2C9 substrate, and a twice daily dosage of 40 mg of Asciminib showed increases in both AUCinf (41%) and Cmax (8%). Coadministration of warfarin and a single daily dosage of 80 mg of Asciminib showed increases in both AUCinf (52%) and Cmax (4%). Coadministration of midazolam and a twice daily dosage of 200 mg of Asciminib showed increases in both AUCinf (314%) and Cmax (7%).
- CYP2C8 Substrates: Coadministration of repaglinide (substrate of CYP2C8, CYP3A4, and OATP1B) and a twice daily dosage of 40 mg of Asciminib showed increases in both AUCinf (8%) and Cmax (14%). Coadministration of repaglinide and a single daily dosage of 80 mg of Asciminib showed increases in both AUCinf (12%) and Cmax (8%). Coadministration of repaglinide and a twice daily dosage of 200 mg of Asciminib showed increases in both AUCinf (42%) and Cmax (25%). Coadministration of rosiglitazone (substrate of CYP2C8 and CYP2C9) and a twice daily dosage of 40 mg of Asciminib showed increases in both AUCinf (20%) and Cmax (3%). Coadministration of rosiglitazone and a single daily dosage of 80 mg of Asciminib showed increases in both AUCinf (24%) and Cmax (2%). Coadministration of rosiglitazone and a twice daily dosage of 200 mg of Asciminib showed increases in both AUCinf (66%) and Cmax (8%).
- P-gp Substrates: Increases in plasma membrane concentrations and serious toxicities may occur with coadministration of P-gp substrates and Asciminib.
In Vitro Studies
- CYP450 and UGT Enzymes: Plasma concentrations reached at 80 mg twice daily and 200 mg twice daily of Asciminib can reversibly inhibit UGT1A1. At 200 mg of Ascminib twice daily can reversibly inhibit CYP2C19.
- Transporter Systems: OATP1B1, BCRP, OATP1B3, P-gp, and OCT1 are inhibited by Asciminib. The substrate of P-gp and BCRP is Asciminib.
## Nonclinical Toxicology
- No research has been conducted on the carcinogenicity when dealing with Asciminib.
- When looking at fertility, studies conducted on male rats have shown evidence of a decrease in sperm count and motility when dosed with 200 mg/kg/day of Asciminib. Studies on female mice showed evidence of decreased living embryos when dosed with 200 mg/kg/day of Asciminib.
- Mutagenicity studies have shown that Asciminib is not genotoxic.
# Clinical Studies
Two clinical trials were conducted on Patients with Ph+ CML-CP, previously treated with two or more TKIs and Patients with Ph+ CML-CP with the T315I mutation.
Patients with Ph+ CML-CP, previously treated with two or more TKIs
- The efficacy of Asciminib was tested on 233 patients that either received 40 mg of Asciminib twice daily or bosutinib 500 mg once daily. The patient population was largely Caucasian (75%), and included 52% women, and 19% were 65 years or older. Patients in the study took Asciminib for an average duration of 67 weeks and Bosutinib for an average duration 30 weeks. The results of the study are summarized in table 8. The study showed that MMR rate was at 29% for patients taking Asciminib and 13% for patients taking Bosutinib.
Table 8 shows the clinical data conducted in Patients with Ph+ CML-CP, previously treated with two or more TKIs taking Asciminib compared to Bosutinib.
Patients with Ph+ CML-CP with the T315I mutation
- The efficacy of Asciminib was tested on 45 patients that received 200 mg of Asciminib twice daily. The patient population was largely Caucasian (47%), and included 80% male, and 31% were 65 years or older. Patients in the study took Asciminib for an average duration of 108 weeks. The study showed MMR rate at 24 weeks (42%) and 96 weeks (49%) of the patients taking Asciminib.
# How Supplied
- 20 mg Asciminib coated tablets (60 tablets per bottle).
- 40 mg Asciminib coated tablets (60 tablets per bottle).
## Storage
- Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
- To protect from moisture, store in original container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Myelosuppression
- Asciminib may cause low blood cell counts.
- Patients should be advised to report any signs of bleeding and fever caused by this drug.
Pancreatic Toxicity
- Patients should be advised that pancreatitis may develop accompanied by symptoms such as nausea, vomiting, severe abdominal pain, or abdominal discomfort. Immediately seek medical attention if these symptoms occur.
Hypertension
- Patients should be advised that hypertension may develop along with symptoms such as increased blood pressure, confusion, headache, dizziness, chest pain, or shortness of breath which should be reported to healthcare provider when they persist.
Hypersensitivity
- If symptoms of hypersensitivity including rash, edema, or bronchospasm persist, immediately seek medical attention and stop use of Asciminib.
Cardiovascular Toxicity
- Inform patients that display symptoms of cardiovascular toxicity to seek medical help immediately.
Embryo Fetal Toxicity
- Female patients should be advised about the potential risks that may occur to fetus when taking Aciminib.
- Advise females of reproductive potential to use effective contraception during treatment with Asciminib and for at least 1 week after the last dose.
Lactation
- Inform female patients not to breastfeed when taking Asciminib and 1 week after last dose.
Drug Interactions
- The use of Asciminib and other medications can possibly alter side effects of Asciminib.
Instruction for taking Asciminib
- Take Asciminib orally either once daily or twice daily depending on the dosage prescribed.
- Inform patients to not alter dosage and schedule of each dosage unless told by healthcare provider.
- Swallow tablets whole and do not break or chew tablet.
- Patients advised not to eat two hours before taking tablet and one hour after taking tablet.
- For pateints that take Asciminib once daily, if a dosage is missed by more than 12 hours, then skip dosage and take next dosage at scheduled time.
- For pateints that take Asciminib twice daily, if a dosage is missed by more than 6 hours, then skip dosage and take next dosage at scheduled time.
# Precautions with Alcohol
Alcohol-Asciminib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Scemblix
# Look-Alike Drug Names
There is limited information regarding Asciminib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Asciminib | |
e648fd495e7c202a801ea69e6ff35f32a47aecc4 | wikidoc | Asclepias | Asclepias
# Overview
Asclepias L. (1753), the milkweeds, is an American genus of herbaceous perennial, dicotyledonous plants that contains over 140 known species. It previously belonged to the family Asclepiadaceae, but this is now classified as the subfamily Asclepiadoideae of the dogbane family Apocynaceae.
Milkweed is named for its milky sap, which consists of a latex containing alkaloids and several other complex compounds including cardenolides. Some species are known to be toxic.
Carl Linnaeus named the genus after Asclepius, the Greek god of healing.
# Milkweed flowers
Asclepias species produce some of the most complex flowers in the plant kingdom, comparable to orchids in complexity. Five petals reflex backwards revealing a gynostegium (fused stamen filamens and styles) surrounded by a five-membered corona. The corona is composed of a five paired hood and horn structures with the hood acting as a sheath for the inner horn. Glands holding pollinia are found between the hoods. The size, shape and color of the horns and hoods are often important identifying characteristics for species in the genus Asclepias.
Pollination in this genus is accomplished in an unusual manner. Pollen is grouped into complex structures called pollinia (or "pollen sacs"), rather than being individual grains or tetrads, as is typical for most plants. The feet or mouthparts of flower-visiting insects such as bees, wasps and Butterfly|butterflies, slip into one of the five slits in each flower formed by adjacent anthers. The bases of the pollinia then mechanically attach to the insect, so that a pair of pollen sacs can be pulled free when the pollinator flies off, assuming the insect is large enough to produce the necessary pulling force (if not, the insect may become trapped and die). Pollination is effected by the reverse procedure in which one of the pollinia becomes trapped within the anther slit.
Asclepias species produce their seeds in follicles. The seeds, which are arranged in overlapping rows, bear a cluster white, silky, filament-like hairs known as the coma (often referred to by other names such as pappus, "floss", "plume", or "silk"). The follicles ripen and split open, and the seeds, each carried by its coma, are blown by the wind.
# Ecology
American milkweeds are an important nectar source for native bees, wasps, and other nectar-seeking insects, though non-native honey bees commonly get trapped in the stigmatic slits and die, and a larval food source for Monarch (butterfly)|monarch butterflies and their relatives, as well as a variety of other herbivorous insects (including numerous beetles, moths, and true bugs) specialized to feed on the plants despite their Plant defense against herbivory|chemical defenses.
Milkweeds use three primary defenses to limit damage caused by caterpillars: hairs on the leaves, cardenolide toxins, and latex fluids. Data from a DNA study indicate that more recently evolved milkweed species use these preventative strategies less but grow faster than older species, potentially regrowing faster than caterpillars can consume them.
# Uses
The milkweed filaments from the coma (the "floss") are hollow and coated with wax, and have good insulation qualities. During World War II, over of milkweed floss were collected in the United States as a substitute for kapok. As of 2007, milkweed is grown commercially as a hypoallergenic filling for pillows. A study of the insulative properties of various materials found that milkweed floss was outperformed by other materials in insulation, loft, and lumpiness, but scored well on various metrics when mixed with down feathers. Milkweed fibers are used to clean up oil spills.
In the past, the high dextrose content of the nectar led to milkweed's use as a source of sweetener for Native Americans and voyageurs.
The bast fibers of some species can be used for cordage.
Milkweed latex contains about 1 to 2% latex, and was attempted as a source of natural rubber by both Germany and the United States during World War II. No record has been found of large-scale success.
Milkweed is beneficial to nearby plants, repelling some pests, especially wireworms.
Milkweed also contains cardiac glycoside poisons that inhibit animal cells from maintaining a proper K+, Ca+ concentration gradient. As a result, many natives of South America and Africa used arrows poisoned with these glycosides to fight and hunt more effectively. Milkweed is toxic and may cause death when animals consume 10% of their body weight in any part of the plant. Milkweed also causes mild dermatitis in some who come in contact with it.
The leaves of Asclepias species, and of some species formerly classified as Asclepias such as Gomphocarpus physocarpus, are the only food source for monarch butterfly larvae and other milkweed butterflies. These plants are therefore often used in butterfly gardening.
# Species
Some Asclepias species:
## Formerly placed here
Some species formerly classified under the Asclepias genus include:
- Calotropis gigantea (L.) W.T.Aiton (as A. gigantea L.)
- Calotropis procera (Aiton) W.T.Aiton (as A. procera Aiton)
- Cynanchum louiseae Kartesz & Gandhi (as A. nigra L.)
- Cynanchum thesioides (Freyn) K.Schum. (as A. sibirica L.)
- Funastrum clausum (Jacq.) Schltr. (as A. clausa Jacq.)
- Gomphocarpus cancellatus (Burm.f.) Bruyns (as A. cancellatus Burm.f. or A. rotundifolia Mill.)
- Gomphocarpus fruticosus (L.) W.T.Aiton (as A. fruticosa L.)
- Marsdenia macrophylla (Humb. & Bonpl. ex Willd.) E.Fourn. (as A. macrophylla Humb. & Bonpl. ex Schult.)
- Marsdenia tenacissima (Roxb.) Moon (as A. tenacissima Roxb.)
- Matelea maritima (Jacq.) Woodson (as A. maritima Jacq.)
- Sarcostemma acidum (Roxb.) Voigt (as A. acida Roxb.)
- Sarcostemma viminale (L.) R.Br. (as A. viminalis (L.) Steud.)
- Telosma cordata (Burm.f.) Merr. (as A. cordata Burm.f.)
- Telosma pallida (Roxb.) Craib (as A. pallida Roxb.)
- Tylophora indica (Burm.f.) Merr. (as A. asthmatica L.f.)
- Vincetoxicum hirundinaria Medik. (as A. vincetoxicum L.)
- Vincetoxicum pycnostelma Kitag. (as A. paniculata Bunge)
- Xysmalobium undulatum (L.) R.Br. (as A. undulata L.) | Asclepias
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Asclepias L. (1753), the milkweeds, is an American genus of herbaceous perennial, dicotyledonous plants that contains over 140 known species. It previously belonged to the family Asclepiadaceae, but this is now classified as the subfamily Asclepiadoideae of the dogbane family Apocynaceae.
Milkweed is named for its milky sap, which consists of a latex containing alkaloids and several other complex compounds including cardenolides.[1] Some species are known to be toxic.
Carl Linnaeus named the genus after Asclepius, the Greek god of healing.[2]
# Milkweed flowers
Asclepias species produce some of the most complex flowers in the plant kingdom, comparable to orchids in complexity. Five petals reflex backwards revealing a gynostegium (fused stamen filamens and styles) surrounded by a five-membered corona. The corona is composed of a five paired hood and horn structures with the hood acting as a sheath for the inner horn. Glands holding pollinia are found between the hoods. The size, shape and color of the horns and hoods are often important identifying characteristics for species in the genus Asclepias.[3]
Pollination in this genus is accomplished in an unusual manner. Pollen is grouped into complex structures called pollinia (or "pollen sacs"), rather than being individual grains or tetrads, as is typical for most plants. The feet or mouthparts of flower-visiting insects such as bees, wasps and Butterfly|butterflies, slip into one of the five slits in each flower formed by adjacent anthers. The bases of the pollinia then mechanically attach to the insect, so that a pair of pollen sacs can be pulled free when the pollinator flies off, assuming the insect is large enough to produce the necessary pulling force (if not, the insect may become trapped and die).[4] Pollination is effected by the reverse procedure in which one of the pollinia becomes trapped within the anther slit.
Asclepias species produce their seeds in follicles. The seeds, which are arranged in overlapping rows, bear a cluster white, silky, filament-like hairs known as the coma[5] (often referred to by other names such as pappus, "floss", "plume", or "silk"). The follicles ripen and split open, and the seeds, each carried by its coma, are blown by the wind.
# Ecology
American milkweeds are an important nectar source for native bees, wasps, and other nectar-seeking insects, though non-native honey bees commonly get trapped in the stigmatic slits and die,[4][6] and a larval food source for Monarch (butterfly)|monarch butterflies and their relatives, as well as a variety of other herbivorous insects (including numerous beetles, moths, and true bugs) specialized to feed on the plants despite their Plant defense against herbivory|chemical defenses.
Milkweeds use three primary defenses to limit damage caused by caterpillars: hairs on the leaves, cardenolide toxins, and latex fluids. Data from a DNA study indicate that more recently evolved milkweed species use these preventative strategies less but grow faster than older species, potentially regrowing faster than caterpillars can consume them.[7]
# Uses
The milkweed filaments from the coma (the "floss") are hollow and coated with wax, and have good insulation qualities. During World War II, over of milkweed floss were collected in the United States as a substitute for kapok. As of 2007, milkweed is grown commercially as a hypoallergenic filling for pillows.[8] A study of the insulative properties of various materials found that milkweed floss was outperformed by other materials in insulation, loft, and lumpiness, but scored well on various metrics when mixed with down feathers.[9] Milkweed fibers are used to clean up oil spills.[10]
In the past, the high dextrose content of the nectar led to milkweed's use as a source of sweetener for Native Americans and voyageurs.
The bast fibers of some species can be used for cordage.
Milkweed latex contains about 1 to 2% latex, and was attempted as a source of natural rubber by both Germany and the United States during World War II. No record has been found of large-scale success.
Milkweed is beneficial to nearby plants, repelling some pests, especially wireworms.
Milkweed also contains cardiac glycoside poisons that inhibit animal cells from maintaining a proper K+, Ca+ concentration gradient.[citation needed] As a result, many natives of South America and Africa used arrows poisoned with these glycosides to fight and hunt more effectively. Milkweed is toxic and may cause death when animals consume 10% of their body weight in any part of the plant.[citation needed] Milkweed also causes mild dermatitis in some who come in contact with it.
The leaves of Asclepias species, and of some species formerly classified as Asclepias such as Gomphocarpus physocarpus, are the only food source for monarch butterfly larvae and other milkweed butterflies. These plants are therefore often used in butterfly gardening.[citation needed]
# Species
Some Asclepias species:
## Formerly placed here
Some species formerly classified under the Asclepias genus include:
- Calotropis gigantea (L.) W.T.Aiton (as A. gigantea L.)
- Calotropis procera (Aiton) W.T.Aiton (as A. procera Aiton)
- Cynanchum louiseae Kartesz & Gandhi (as A. nigra L.)
- Cynanchum thesioides (Freyn) K.Schum. (as A. sibirica L.)
- Funastrum clausum (Jacq.) Schltr. (as A. clausa Jacq.)
- Gomphocarpus cancellatus (Burm.f.) Bruyns (as A. cancellatus Burm.f. or A. rotundifolia Mill.)
- Gomphocarpus fruticosus (L.) W.T.Aiton (as A. fruticosa L.)
- Marsdenia macrophylla (Humb. & Bonpl. ex Willd.) E.Fourn. (as A. macrophylla Humb. & Bonpl. ex Schult.)
- Marsdenia tenacissima (Roxb.) Moon (as A. tenacissima Roxb.)
- Matelea maritima (Jacq.) Woodson (as A. maritima Jacq.)
- Sarcostemma acidum (Roxb.) Voigt (as A. acida Roxb.)
- Sarcostemma viminale (L.) R.Br. (as A. viminalis (L.) Steud.)
- Telosma cordata (Burm.f.) Merr. (as A. cordata Burm.f.)
- Telosma pallida (Roxb.) Craib (as A. pallida Roxb.)
- Tylophora indica (Burm.f.) Merr. (as A. asthmatica L.f.)
- Vincetoxicum hirundinaria Medik. (as A. vincetoxicum L.)
- Vincetoxicum pycnostelma Kitag. (as A. paniculata Bunge)
- Xysmalobium undulatum (L.) R.Br. (as A. undulata L.)[12] | https://www.wikidoc.org/index.php/Asclepias | |
9644af451c5cb082e3501cfcfe28bfd6e78e5d71 | wikidoc | Vitamin C | Vitamin C
# Overview
Vitamin C or L-ascorbate is an essential nutrient for higher primates, and a small number of other species. The presence of ascorbate is required for a range of essential metabolic reactions in all animals and plants. It is made internally by almost all organisms, humans being one notable exception. It is widely known as the vitamin whose deficiency causes scurvy in humans. It is also widely used as a food additive.
The pharmacophore of vitamin C is the ascorbate ion. In living organisms, ascorbate is an antioxidant, as it protects the body against oxidative stress, and is a cofactor in several vital enzymatic reactions.
The uses and the daily requirement of vitamin C are matters of on-going debate.
# Biological significance
Vitamin C is purely the L-enantiomer of ascorbate; the opposite D-enantiomer has no physiological significance. Both forms are mirror images of the same molecular structure. When L-ascorbate, which is a strong reducing agent, carries out its reducing function, it is converted to its oxidized form, L-dehydroascorbate. L-dehydroascorbate can then be reduced back to the active L-ascorbate form in the body by enzymes and glutathione.
L-ascorbate is a weak sugar acid structurally related to glucose which naturally occurs either attached to a hydrogen ion, forming ascorbic acid, or to a metal ion, forming a mineral ascorbate.
## Function
In humans, vitamin C is a highly effective antioxidant, acting to lessen oxidative stress, a substrate for ascorbate peroxidase, as well as an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C acts as an electron donor for eight different enzymes:
- Three participate in collagen hydroxylation. These reactions add hydroxyl groups to the amino acids proline or lysine in the collagen molecule (via prolyl hydroxylase and lysyl hydroxylase), thereby allowing the collagen molecule to assume its triple helix structure and making vitamin C essential to the development and maintenance of scar tissue, blood vessels, and cartilage.
- Two are necessary for synthesis of carnitine. Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation.
- The remaining three have the following functions:
dopamine beta hydroxylase participates in the biosynthesis of norepinephrine from dopamine.
another enzyme adds amide groups to peptide hormones, greatly increasing their stability.
-ne modulates tyrosine metabolism.
- dopamine beta hydroxylase participates in the biosynthesis of norepinephrine from dopamine.
- another enzyme adds amide groups to peptide hormones, greatly increasing their stability.
- one modulates tyrosine metabolism.
Biological tissues that accumulate over 100 times the level in blood plasma of vitamin C are the adrenal glands, pituitary, thymus, corpus luteum, and retina.
Those with 10 to 50 times the concentration present in blood plasma include the brain, spleen, lung, testicle, lymph nodes, liver, thyroid, small intestinal mucosa, leukocytes, pancreas, kidney and salivary glands.
## Biosynthesis
The vast majority of animals and plants are able to synthesize their own vitamin C, through a sequence of four enzyme-driven steps, which convert glucose to vitamin C. The glucose needed to produce ascorbate in the liver (in mammals and perching birds) is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process. In reptiles and birds the biosynthesis is carried out in the kidneys.
Among the animals that have lost the ability to synthesise vitamin C are simians, guinea pigs, the red-vented bulbul,and fruit-eating bats. Most notably, humans have no capability to manufacture vitamin C. The cause of this phenomenon is that the last enzyme in the synthesis process, L-gulonolactone oxidase, cannot be made by the listed animals because the gene for this enzyme, Pseudogene ΨGULO, is defective. The mutation has not been lethal because vitamin C is abundant in their food sources, with many of these species' natural diets consisting largely of fruit.
Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans. This discrepancy constitutes the basis of the controversy on current recommended dietary allowances (see Vitamin C as a macronutrient - Evolutionary rationales).
It has been noted that the loss of the ability to synthesize ascorbate strikingly parallels the evolutionary loss of the ability to break down uric acid. Uric acid and ascorbate are both strong reducing agents. This has led to the suggestion that in higher primates, uric acid has taken over some of the functions of ascorbate. Ascorbic acid can be oxidised (broken down) in the human body by the enzyme ascorbic acid oxidase.
An adult goat, a typical example of a vitamin C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and the biosynthesis will increase "many fold under stress". Trauma or injury has also been demonstrated to also use up large quantities of vitamin C in humans.
Some microorganisms such as the yeast Saccharomyces cerevisiae have been shown to be able to synthesize vitamin C from simple sugars.
## Deficiency
Scurvy is an avitaminosis resulting from lack of vitamin C, as without this vitamin, the synthesised collagen is too unstable to meet its function. Scurvy leads to the formation of liver spots on the skin, spongy gums, and bleeding from all mucous membranes. The spots are most abundant on the thighs and legs, and a person with the ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvy there are open, suppurating wounds and loss of teeth and, eventually, death. The human body can store only a certain amount of vitamin C., and so the body soon depletes itself if fresh supplies are not consumed.
Smoking cigarettes has a negative correlation to the amount of vitamin c in the blood stream. The relative amounts of vitamin c drop with the increased amount of cigarettes smoked.
# History of human understanding
The need to include fresh plant food or raw animal flesh in the diet to prevent disease was known from ancient times. Native peoples living in marginal areas incorporated this into their medicinal lore. For example, spruce needles were used in temperate zones in infusions, or the leaves from species of drought-resistant trees in desert areas. In 1536, the French explorer Jacques Cartier, exploring the St. Lawrence River, used the local natives' knowledge to save his men who were dying of scurvy. He boiled the needles of the arbor vitae tree to make a tea that was later shown to contain 50 mg of vitamin C per 100 grams.
Throughout history, the benefit of plant food to survive long sea voyages has been occasionally recommended by authorities. John Woodall, the first appointed surgeon to the British East India Company, recommended the preventive and curative use of lemon juice in his book "The Surgeon's Mate", in 1617. The Dutch writer, Johann Bachstrom, in 1734, gave the firm opinion that "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens; which is alone the primary cause of the disease."
While the earliest documented case of scurvy was described by Hippocrates around the year 400 BC, the first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the British Royal Navy, James Lind. Scurvy was common among those with poor access to fresh fruit and vegetables, such as remote, isolated sailors and soldiers. While at sea in May 1747, Lind provided some crew members with two oranges and one lemon per day, in addition to normal rations, while others continued on cider, vinegar, sulfuric acid or seawater, along with their normal rations. In the history of science this is considered to be the first occurrence of a controlled experiment comparing results on two populations of a factor applied to one group only with all other factors the same. The results conclusively showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.
Lind's work was slow to be noticed, partly because he gave conflicting evidence within the book, and partly because the British admiralty saw care for the well-being of crews as a sign of weakness. In addition, fresh fruit was very expensive to keep on board, whereas boiling it down to juice allowed easy storage but destroyed the vitamin (especially if boiled in copper kettles). Ship captains assumed wrongly that Lind's suggestions didn't work because those juices failed to cure scurvy.
It was 1795 before the British navy adopted lemons or lime as standard issue at sea. Limes were more popular as they could be found in British West Indian Colonies, unlike lemons which weren't found in British Dominions, and were therefore more expensive. This practice led to the American use of the nickname "limey" to refer to the British. Captain James Cook had previously demonstrated and proven the principle of the advantages of fresh and preserved foods, such as sauerkraut, by taking his crews to the Hawaiian Islands and beyond without losing any of his men to scurvy. For this otherwise unheard of feat, the British Admiralty awarded him a medal.
The name "antiscorbutic" was used in the eighteenth and nineteenth centuries as general term for those foods known to prevent scurvy, even though there was no understanding of the reason for this. These foods included but were not limited to: lemons, limes, and oranges; sauerkraut, cabbage, malt, and portable soup.
In 1907, Axel Holst and Theodor Frølich, two Norwegian physicians studying beriberi contracted aboard ship's crews in the Norwegian Fishing Fleet, wanted a small test mammal to substitute for the pigeons they used. They fed guinea pigs their test diet, which had earlier produced beriberi in their pigeons, and were surprised when scurvy resulted instead. Until that time scurvy had not been observed in any organism apart from humans, and had been considered an exclusively human disease.
## Discovery of ascorbic acid
In 1912, the Polish-American biochemist Casimir Funk, while researching deficiency diseases, developed the concept of vitamins to refer to the nutrients which are essential to health. Then, from 1928 to 1933, the Hungarian research team of Joseph L Svirbely and Albert Szent-Györgyi and, independently, the American Charles Glen King, first isolated vitamin C and showed it to be ascorbic acid. For this, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine.
In 1928 the Arctic anthropologist Vilhjalmur Stefansson attempted to prove his theory of how the Eskimos are able to avoid scurvy with almost no plant food in their diet, despite the disease striking European Arctic explorers living on similar high-meat diets. Stefansson theorised that the natives get their vitamin C from fresh meat that is minimally cooked. Starting in February 1928, for one year he and a colleague lived on an exclusively minimally-cooked meat diet while under medical supervision; they remained healthy.
Between 1933 and 1934, the British chemists Sir Walter Norman Haworth and Sir Edmund Hirst and, independently, the Polish chemist Tadeus Reichstein, succeeded in synthesizing the vitamin, the first to be artificially produced. This made possible the cheap mass-production of vitamin C. Only Haworth was awarded the 1937 Nobel Prize in Chemistry for this work, but the process for vitamin C retained Reichstein's name.
In 1934 Hoffmann–La Roche became the first pharmaceutical company to mass-produce synthetic vitamin C, under the brand name of Redoxon.
In 1957 the American J.J. Burns showed that the reason some mammals were susceptible to scurvy was the inability of their liver to produce the active enzyme L-gulonolactone oxidase, which is the last of the chain of four enzymes which synthesize vitamin C. American biochemist Irwin Stone was the first to exploit vitamin C for its food preservative properties. He later developed the theory that humans possess a mutated form of the L-gulonolactone oxidase coding gene.
# Daily requirements
The North American Dietary Reference Intake recommends 90 milligrams per day and no more than 2 grams per day (2000 milligrams per day). Other related species sharing the same inability to produce vitamin C and requiring exogenous vitamin C consume 20 to 80 times this reference intake. There is continuing debate within the scientific community over the best dose schedule (the amount and frequency of intake) of vitamin C for maintaining optimal health in humans. It is generally agreed that a balanced diet without supplementation contains enough vitamin C to prevent scurvy in an average healthy adult, while those who are pregnant, smoke tobacco, or are under stress require slightly more.
High doses (thousands of milligrams) may result in diarrhea. Proponents of alternative medicine (specifically orthomolecular medicine) claim the onset of diarrhea to be an indication of where the body’s true vitamin C requirement lies. Both Cathcart and Cameron have hypothesized that very sick patients with cancer or influenza do not display any evidence of diarrhea at all until ascorbate intake reaches levels as high as 200 grams (nearly half a pound).
## Government recommended intakes
Recommendations for vitamin C intake have been set by various national agencies:
- 40 milligrams per day: the United Kingdom's Food Standards Agency
- 45 milligrams per day: the World Health Organization
- 60 mg/day: Health Canada 2007
- 60–95 milligrams per day: United States' National Academy of Sciences
The United States defined Tolerable Upper Intake Level for a 25-year-old male is 2,000 milligrams per day.
## Alternative recommendations on intakes
Some independent researchers have calculated the amount needed for an adult human to achieve similar blood serum levels as vitamin C synthesising mammals as follows:
- 400 milligrams per day: the Linus Pauling Institute.
- 500 milligrams per 12 hours: Professor Roc Ordman, from research into biological free radicals.
- 3,000 milligrams per day (or up to 300,000 mg during illness): the Vitamin C Foundation.
- 6,000–12,000 milligrams per day: Thomas E. Levy, Colorado Integrative Medical Centre.
- 6,000–18,000 milligrams per day: Linus Pauling's personal use.
# Vitamin C as a macronutrient
There is a strong advocacy movement for large doses of vitamin C, promoting a great deal of added benefits. Drawing on a wide, but still inconclusive, body of evidence as to the benefits beyond those dosages recommended in the Dietary Reference Intakes, many pro-vitamin C organizations promote usage levels well beyond the current Dietary Reference Intake. The movement is led by scientists and doctors such as Robert Cathcart, Ewan Cameron, Steve Hickey, Irwin Stone and the twice Nobel Prize laureate Linus Pauling and the more controversial Matthias Rath. There is some scientific literature critical of governmental agency dose recommendations. The biological halflife for vitamin C is fairly short, about 30 minutes in blood plasma, a fact which high dose advocates say that mainstream researchers have failed to take into account. Researchers at the National Institutes of Health decided upon the current RDA based upon tests conducted 12 hours (24 half lives) after consumption.
## Evolutionary rationales
Humans carry a mutated and ineffective form of the gene required by all mammals for manufacturing the fourth of the four enzymes that manufacture vitamin C. The inability to produce vitamin C, hypoascorbemia, is, according to the Online Mendeleian Inheritance in Man database, a "public" inborn error of metabolism.
The gene, Pseudogene ΨGULO, lost its function millions of years ago, when the anthropoids branched out. In humans, the three functional enzymes continue to produce the precursors to vitamin C, but the process is incomplete; these enzymes ultimately undergo proteolytic degradation. Stone and Pauling calculated, based on the diet of our primate cousins (similar to what our common descendants are likely to have consumed when the gene mutated), that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human requiring 2,500 kcal a day.
The established RDA has been criticized by Pauling to be one that will prevent acute scurvy, and is not necessarily the dosage for optimal health.
# Therapeutic uses
Since its discovery vitamin C has been considered by some enthusiastic proponents a "universal panacea", although this led to suspicions by others of it being over-hyped. Other proponents of high dose vitamin C consider that if it is given "in the right form, with the proper technique, in frequent enough doses, in high enough doses, along with certain additional agents and for a long enough period of time," it can prevent and, in many cases, cure, a wide range of common and/or lethal diseases, notably the common cold and heart disease, although the NIH considers there to be "fair scientific evidence against this use." Some proponents issued controversial statements involving it being a cure for AIDS, bird flu, and SARS.
Probably the most controversial issue, the putative role of ascorbate in the management of AIDS, is still unresolved, more than 16 years after the landmark study published in the Proceedings of National Academy of Sciences (USA) showing that non toxic doses of ascorbate suppress HIV replication in vitro. Other studies expanded on those results, but still, no large scale trials have yet been conducted.
In an animal model of lead intoxication, vitamin C demonstrated "protective effects" on lead-induced nerve and muscle abnormalities In smokers, blood lead levels declined by an average of 81% when supplemented with 1000 mg of vitamin C, while 200 mg were ineffective, suggesting that vitamin C supplements may be an "economical and convenient" approach to reduce lead levels in the blood. The Journal of the American Medical Association published a study which concluded, based on an analysis of blood lead levels in the subjects of the Third National Health and Nutrition Examination Survey, that the independent, inverse relationship between lead levels and vitamin C in the blood, if causal, would "have public health implications for control of lead toxicity".
Vitamin C has limited popularity as a treatment for autism spectrum symptoms. A 1993 study of 18 children with ASD found some symptoms reduced after treatment with vitamin C, but these results have not been replicated. Small clinical trials have found that vitamin C might improve the sperm count, sperm motility, and sperm morphology in infertile men, or improve immune function related to the prevention and treatment of age-associated diseases. However, to date, no large clinical trials have verified these findings.
A preliminary study published in the Annals of Surgery found that the early administration of antioxidant supplementation using α-tocopherol and ascorbic acid reduces the incidence of organ failure and shortens ICU length of stay in this cohort of critically ill surgical patients. More research on this topic is pending.
Dehydroascorbic acid, the main form of oxidized Vitamin C in the body, was shown to reduce neurological deficits and mortality following stroke, due to its ability to cross the blood-brain barrier, while "the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier". In this study published by the Proceedings of the National Academy of Sciences in 2001, the authors concluded that such "a pharmacological strategy to increase cerebral levels of ascorbate in stroke has tremendous potential to represent the timely translation of basic research into a relevant therapy for thromboembolic stroke in humans". No such "relevant therapies" are available yet and no clinical trials have been planned.
In January 2007 the US Food and Drug Administration approved a Phase I toxicity trial to determine the safe dosage of intravenous vitamin C as a possible cancer treatment for "patients who have exhausted all other conventional treatment options." Additional studies over several years would be needed to demonstrate whether it is effective.
In February 2007, an uncontrolled study of 39 terminal cancer patients showed that, on subjective questionnaires, patients reported an improvement in health, cancer symptoms, and daily function after administration of high-dose intravenous vitamin C. The authors concluded that "Although there is still controversy regarding anticancer effects of vitamin C, the use of vitamin C is considered a safe and effective therapy to improve the quality of life of terminal cancer patients".
# Testing for ascorbate levels in the body
Simple tests use DCPIP to measure the levels of vitamin C in the urine and in serum or blood plasma. However these reflect recent dietary intake rather than the level of vitamin C in body stores. Reverse phase high performance liquid chromatography is used for determining the storage levels of vitamin C within lymphocytes and tissue.
It has been observed that while serum or blood plasma levels follow the circadian rhythm or short term dietary changes, those within tissues themselves are more stable and give a better view of the availability of ascorbate within the organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses, and require samples to be analyzed in specialized laboratories.
# Adverse effects
While being harmless in most typical quantities, as with all substances to which the human body is exposed, vitamin C can still cause harm under certain conditions.
## Common side-effects
Relatively large doses of vitamin C may cause indigestion, particularly when taken on an empty stomach.
When taken in large doses, vitamin C causes diarrhea. In one trial, doses up to 6 grams of ascorbic acid were given to 29 infants, 93 children of preschool and school age, and 20 adults for more than 1400 days. With the higher doses, toxic manifestations were observed in five adults and four infants. The signs and symptoms in adults were nausea, vomiting, diarrhea, flushing of the face, headache, fatigue and disturbed sleep. The main toxic reactions in the infants were skin rashes.
## Possible side-effects
As vitamin C enhances iron absorption, iron poisoning can become an issue to people with rare iron overload disorders, such as haemochromatosis. A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD), can cause sufferers to develop hemolytic anemia after ingesting specific oxidizing substances, such as very large dosages of vitamin C.
For decades, large doses of vitamin C have been speculated to trigger oxalate formation and increase absorption of dietary oxalate, possibly causing kidney stones. However, this speculation may not be justified since there is no clear relationship between excess ascorbic acid intake and kidney stone formation.
During the first month of pregnancy, high doses of vitamin C may suppress the production of progesterone from the corpus luteum. Progesterone, necessary for the maintenance of a pregnancy, is produced by the corpus luteum for the first few weeks, until the placenta is developed enough to produce its own source. By blocking this function of the corpus luteum, high doses of vitamin C (1000+ mg) is theorized to induce an early miscarriage. In a group of spontaneously aborting women at the end of the first trimester, the mean values of vitamin C were significantly higher in the aborting group. However, the authors point out that this relationship may not necessarily be a causal one.
## Chance of overdose
As discussed previously, vitamin C exhibits remarkably low toxicity. The LD50 (the dose that will kill 50% of a population) in rats is generally accepted to be 11.9 grams per kilogram when taken orally. The LD50 in humans remains unknown, owing to medical ethics that preclude experiments which would put patients at risk of harm. However, as with all substances tested in this way, the LD50 is taken as a guide to its toxicity in humans and no data to contradict this has been found.
# Natural and artificial dietary sources
The richest natural sources are fruits and vegetables, and of those, the camu camu fruit and the Kakadu plum contain the highest concentration of the vitamin. It is also present in some cuts of meat, especially liver. Vitamin C is the most widely taken nutritional supplement and is available in a variety of forms, including tablets, drink mixes, crystals in capsules or naked crystals.
Vitamin C is absorbed by the intestines using a sodium-ion dependent channel. It is transported through the intestine via both glucose-sensitive and glucose-insensitive mechanisms. The presence of large quantities of sugar either in the intestines or in the blood can slow absorption.
## Plant sources
While plants are generally a good source of vitamin C, the amount in foods of plant origin depends on: the precise variety of the plant, the soil condition, the climate in which it grew, the length of time since it was picked, the storage conditions, and the method of preparation.
The following table is approximate and shows the relative abundance in different raw plant sources. As some plants were analyzed fresh while others were dried (thus, artifactually increasing concentration of individual constituents like vitamin C), the data are subject to potential variation and difficulties for comparison. The amount is given in milligrams per 100 grams of fruit or vegetable and is a rounded average from multiple authoritative sources:
^ average of 3 sources; dried
## Animal sources
The overwhelming majority of species of animals and plants synthesise their own vitamin C, making some, but not all, animal products, sources of dietary vitamin C.
Vitamin C is most present in the liver and least present in the muscle. Since muscle provides the majority of meat consumed in the western human diet, animal products are not a reliable source of the vitamin. Vitamin C is present in mother's milk and, in lower amounts, in raw cow's milk, with pasteurized milk containing only trace amounts. All excess Vitamin C is disposed of through the urinary system.
The following table shows the relative abundance of vitamin C in various foods of animal origin, given in milligram of vitamin C per 100 grams of food:
## Food preparation
Vitamin C chemically decomposes under certain conditions, many of which may occur during the cooking of food. Normally, boiling water at 100°C is not hot enough to cause any significant destruction of the nutrient, which only decomposes at 190°C,
despite popular opinion. However, pressure cooking, roasting, frying and grilling food is more likely to reach the decomposition temperature of vitamin C. Longer cooking times also add to this effect, as will copper food vessels, which catalyse the decomposition.
Another cause of vitamin C being lost from food is leaching, where the water-soluble vitamin dissolves into the cooking water, which is later poured away and not consumed. However, vitamin C doesn't leach in all vegetables at the same rate; research shows broccoli seems to retain more than any other. Research has also shown that fresh-cut fruit don't lose significant nutrients when stored in the refrigerator for a few days.
## Vitamin C supplements
Vitamin C is the most widely taken dietary supplement. It is available in many forms including caplets, tablets, capsules, drink mix packets, in multi-vitamin formulations, in multiple antioxidant formulations, and crystalline powder. Timed release versions are available, as are formulations containing bioflavonoids such as quercetin, hesperidin and rutin. Tablet and capsule sizes range from 25 mg to 1500 mg. Vitamin C (as ascorbic acid) crystals are typically available in bottles containing 300 g to 1 kg of powder (a teaspoon of vitamin C crystals equals 5,000 mg).
## Artificial modes of synthesis
Vitamin C is produced from glucose by two main routes. The Reichstein process, developed in the 1930s, uses a single pre-fermentation followed by a purely chemical route. The modern two-step fermentation process, originally developed in China in the 1960s, uses additional fermentation to replace part of the later chemical stages. Both processes yield approximately 60% vitamin C from the glucose feed.
Research is underway at the Scottish Crop Research Institute in the interest of creating a strain of yeast that can synthesise vitamin C in a single fermentation step from galactose, a technology expected to reduce manufacturing costs considerably.
World production of synthesised vitamin C is currently estimated at approximately 110,000 tonnes annually.
Main producers today are BASF/Takeda, DSM, Merck and the China Pharmaceutical Group Ltd. of the People's Republic of China. China is slowly becoming the major world supplier as its prices undercut those of the US and European manufacturers. | Vitamin C
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Vitamin C or L-ascorbate is an essential nutrient for higher primates, and a small number of other species. The presence of ascorbate is required for a range of essential metabolic reactions in all animals and plants. It is made internally by almost all organisms, humans being one notable exception. It is widely known as the vitamin whose deficiency causes scurvy in humans.[1][2][3] It is also widely used as a food additive.
The pharmacophore of vitamin C is the ascorbate ion. In living organisms, ascorbate is an antioxidant, as it protects the body against oxidative stress,[4] and is a cofactor in several vital enzymatic reactions.[5]
The uses and the daily requirement of vitamin C are matters of on-going debate.
# Biological significance
Vitamin C is purely the L-enantiomer of ascorbate; the opposite D-enantiomer has no physiological significance. Both forms are mirror images of the same molecular structure. When L-ascorbate, which is a strong reducing agent, carries out its reducing function, it is converted to its oxidized form, L-dehydroascorbate.[5] L-dehydroascorbate can then be reduced back to the active L-ascorbate form in the body by enzymes and glutathione.[6]
L-ascorbate is a weak sugar acid structurally related to glucose which naturally occurs either attached to a hydrogen ion, forming ascorbic acid, or to a metal ion, forming a mineral ascorbate.
## Function
In humans, vitamin C is a highly effective antioxidant, acting to lessen oxidative stress, a substrate for ascorbate peroxidase,[3] as well as an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C acts as an electron donor for eight different enzymes:[7]
- Three participate in collagen hydroxylation.[8][9][10] These reactions add hydroxyl groups to the amino acids proline or lysine in the collagen molecule (via prolyl hydroxylase and lysyl hydroxylase), thereby allowing the collagen molecule to assume its triple helix structure and making vitamin C essential to the development and maintenance of scar tissue, blood vessels, and cartilage.[11]
- Two are necessary for synthesis of carnitine.[12][13] Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation.
- The remaining three have the following functions:
dopamine beta hydroxylase participates in the biosynthesis of norepinephrine from dopamine.[14][15]
another enzyme adds amide groups to peptide hormones, greatly increasing their stability.[16][17]
one modulates tyrosine metabolism.[18][19]
- dopamine beta hydroxylase participates in the biosynthesis of norepinephrine from dopamine.[14][15]
- another enzyme adds amide groups to peptide hormones, greatly increasing their stability.[16][17]
- one modulates tyrosine metabolism.[18][19]
Biological tissues that accumulate over 100 times the level in blood plasma of vitamin C are the adrenal glands, pituitary, thymus, corpus luteum, and retina.[20]
Those with 10 to 50 times the concentration present in blood plasma include the brain, spleen, lung, testicle, lymph nodes, liver, thyroid, small intestinal mucosa, leukocytes, pancreas, kidney and salivary glands.
## Biosynthesis
The vast majority of animals and plants are able to synthesize their own vitamin C, through a sequence of four enzyme-driven steps, which convert glucose to vitamin C.[5] The glucose needed to produce ascorbate in the liver (in mammals and perching birds) is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process.[21] In reptiles and birds the biosynthesis is carried out in the kidneys.
Among the animals that have lost the ability to synthesise vitamin C are simians, guinea pigs, the red-vented bulbul,and fruit-eating bats.[5] Most notably, humans have no capability to manufacture vitamin C. The cause of this phenomenon is that the last enzyme in the synthesis process, L-gulonolactone oxidase, cannot be made by the listed animals because the gene for this enzyme, Pseudogene ΨGULO, is defective.[22] The mutation has not been lethal because vitamin C is abundant in their food sources, with many of these species' natural diets consisting largely of fruit.
Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans.[23] This discrepancy constitutes the basis of the controversy on current recommended dietary allowances (see Vitamin C as a macronutrient - Evolutionary rationales).
It has been noted that the loss of the ability to synthesize ascorbate strikingly parallels the evolutionary loss of the ability to break down uric acid. Uric acid and ascorbate are both strong reducing agents. This has led to the suggestion that in higher primates, uric acid has taken over some of the functions of ascorbate.[24] Ascorbic acid can be oxidised (broken down) in the human body by the enzyme ascorbic acid oxidase.
An adult goat, a typical example of a vitamin C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and the biosynthesis will increase "many fold under stress".[25] Trauma or injury has also been demonstrated to also use up large quantities of vitamin C in humans.[26]
Some microorganisms such as the yeast Saccharomyces cerevisiae have been shown to be able to synthesize vitamin C from simple sugars.[27][28]
## Deficiency
Scurvy is an avitaminosis resulting from lack of vitamin C, as without this vitamin, the synthesised collagen is too unstable to meet its function. Scurvy leads to the formation of liver spots on the skin, spongy gums, and bleeding from all mucous membranes. The spots are most abundant on the thighs and legs, and a person with the ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvy there are open, suppurating wounds and loss of teeth and, eventually, death. The human body can store only a certain amount of vitamin C.,[29] and so the body soon depletes itself if fresh supplies are not consumed.
Smoking cigarettes has a negative correlation to the amount of vitamin c in the blood stream. The relative amounts of vitamin c drop with the increased amount of cigarettes smoked. [30]
# History of human understanding
The need to include fresh plant food or raw animal flesh in the diet to prevent disease was known from ancient times. Native peoples living in marginal areas incorporated this into their medicinal lore. For example, spruce needles were used in temperate zones in infusions, or the leaves from species of drought-resistant trees in desert areas. In 1536, the French explorer Jacques Cartier, exploring the St. Lawrence River, used the local natives' knowledge to save his men who were dying of scurvy. He boiled the needles of the arbor vitae tree to make a tea that was later shown to contain 50 mg of vitamin C per 100 grams.[31][32]
Throughout history, the benefit of plant food to survive long sea voyages has been occasionally recommended by authorities. John Woodall, the first appointed surgeon to the British East India Company, recommended the preventive and curative use of lemon juice in his book "The Surgeon's Mate", in 1617. The Dutch writer, Johann Bachstrom, in 1734, gave the firm opinion that "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens; which is alone the primary cause of the disease."
While the earliest documented case of scurvy was described by Hippocrates around the year 400 BC, the first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the British Royal Navy, James Lind. Scurvy was common among those with poor access to fresh fruit and vegetables, such as remote, isolated sailors and soldiers. While at sea in May 1747, Lind provided some crew members with two oranges and one lemon per day, in addition to normal rations, while others continued on cider, vinegar, sulfuric acid or seawater, along with their normal rations. In the history of science this is considered to be the first occurrence of a controlled experiment comparing results on two populations of a factor applied to one group only with all other factors the same. The results conclusively showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.
Lind's work was slow to be noticed, partly because he gave conflicting evidence within the book, and partly because the British admiralty saw care for the well-being of crews as a sign of weakness. In addition, fresh fruit was very expensive to keep on board, whereas boiling it down to juice allowed easy storage but destroyed the vitamin (especially if boiled in copper kettles[33]). Ship captains assumed wrongly that Lind's suggestions didn't work because those juices failed to cure scurvy.
It was 1795 before the British navy adopted lemons or lime as standard issue at sea. Limes were more popular as they could be found in British West Indian Colonies, unlike lemons which weren't found in British Dominions, and were therefore more expensive. This practice led to the American use of the nickname "limey" to refer to the British. Captain James Cook had previously demonstrated and proven the principle of the advantages of fresh and preserved foods, such as sauerkraut, by taking his crews to the Hawaiian Islands and beyond without losing any of his men to scurvy. For this otherwise unheard of feat, the British Admiralty awarded him a medal.
The name "antiscorbutic" was used in the eighteenth and nineteenth centuries as general term for those foods known to prevent scurvy, even though there was no understanding of the reason for this. These foods included but were not limited to: lemons, limes, and oranges; sauerkraut, cabbage, malt, and portable soup.
In 1907, Axel Holst and Theodor Frølich, two Norwegian physicians studying beriberi contracted aboard ship's crews in the Norwegian Fishing Fleet, wanted a small test mammal to substitute for the pigeons they used. They fed guinea pigs their test diet, which had earlier produced beriberi in their pigeons, and were surprised when scurvy resulted instead. Until that time scurvy had not been observed in any organism apart from humans, and had been considered an exclusively human disease.
## Discovery of ascorbic acid
In 1912, the Polish-American biochemist Casimir Funk, while researching deficiency diseases, developed the concept of vitamins to refer to the nutrients which are essential to health. Then, from 1928 to 1933, the Hungarian research team of Joseph L Svirbely and Albert Szent-Györgyi and, independently, the American Charles Glen King, first isolated vitamin C and showed it to be ascorbic acid. For this, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine.[34]
In 1928 the Arctic anthropologist Vilhjalmur Stefansson attempted to prove his theory of how the Eskimos are able to avoid scurvy with almost no plant food in their diet, despite the disease striking European Arctic explorers living on similar high-meat diets. Stefansson theorised that the natives get their vitamin C from fresh meat that is minimally cooked. Starting in February 1928, for one year he and a colleague lived on an exclusively minimally-cooked meat diet while under medical supervision; they remained healthy.
Between 1933 and 1934, the British chemists Sir Walter Norman Haworth and Sir Edmund Hirst and, independently, the Polish chemist Tadeus Reichstein, succeeded in synthesizing the vitamin, the first to be artificially produced. This made possible the cheap mass-production of vitamin C. Only Haworth was awarded the 1937 Nobel Prize in Chemistry for this work, but the process for vitamin C retained Reichstein's name.
In 1934 Hoffmann–La Roche became the first pharmaceutical company to mass-produce synthetic vitamin C, under the brand name of Redoxon.
In 1957 the American J.J. Burns showed that the reason some mammals were susceptible to scurvy was the inability of their liver to produce the active enzyme L-gulonolactone oxidase, which is the last of the chain of four enzymes which synthesize vitamin C.[35][36] American biochemist Irwin Stone was the first to exploit vitamin C for its food preservative properties. He later developed the theory that humans possess a mutated form of the L-gulonolactone oxidase coding gene.
# Daily requirements
The North American Dietary Reference Intake recommends 90 milligrams per day and no more than 2 grams per day (2000 milligrams per day).[37] Other related species sharing the same inability to produce vitamin C and requiring exogenous vitamin C consume 20 to 80 times this reference intake.[38][39] There is continuing debate within the scientific community over the best dose schedule (the amount and frequency of intake) of vitamin C for maintaining optimal health in humans.[40] It is generally agreed that a balanced diet without supplementation contains enough vitamin C to prevent scurvy in an average healthy adult, while those who are pregnant, smoke tobacco, or are under stress require slightly more.[37]
High doses (thousands of milligrams) may result in diarrhea. Proponents of alternative medicine (specifically orthomolecular medicine)[41] claim the onset of diarrhea to be an indication of where the body’s true vitamin C requirement lies. Both Cathcart[41] and Cameron have hypothesized that very sick patients with cancer or influenza do not display any evidence of diarrhea at all until ascorbate intake reaches levels as high as 200 grams (nearly half a pound).
## Government recommended intakes
Recommendations for vitamin C intake have been set by various national agencies:
- 40 milligrams per day: the United Kingdom's Food Standards Agency[1]
- 45 milligrams per day: the World Health Organization[42]
- 60 mg/day: Health Canada 2007 [2]
- 60–95 milligrams per day: United States' National Academy of Sciences[37]
The United States defined Tolerable Upper Intake Level for a 25-year-old male is 2,000 milligrams per day.
## Alternative recommendations on intakes
Some independent researchers have calculated the amount needed for an adult human to achieve similar blood serum levels as vitamin C synthesising mammals as follows:
- 400 milligrams per day: the Linus Pauling Institute.[43]
- 500 milligrams per 12 hours: Professor Roc Ordman, from research into biological free radicals.[44]
- 3,000 milligrams per day (or up to 300,000 mg during illness): the Vitamin C Foundation.[45]
- 6,000–12,000 milligrams per day: Thomas E. Levy, Colorado Integrative Medical Centre.[46]
- 6,000–18,000 milligrams per day: Linus Pauling's personal use.[47]
# Vitamin C as a macronutrient
There is a strong advocacy movement for large doses of vitamin C, promoting a great deal of added benefits. Drawing on a wide, [48] but still inconclusive, body of evidence as to the benefits beyond those dosages recommended in the Dietary Reference Intakes, many pro-vitamin C organizations promote usage levels well beyond the current Dietary Reference Intake. The movement is led by scientists and doctors such as Robert Cathcart, Ewan Cameron, Steve Hickey, Irwin Stone and the twice Nobel Prize laureate Linus Pauling and the more controversial Matthias Rath. There is some scientific literature critical of governmental agency dose recommendations.[40][49] The biological halflife for vitamin C is fairly short, about 30 minutes in blood plasma, a fact which high dose advocates say that mainstream researchers have failed to take into account. Researchers at the National Institutes of Health decided upon the current RDA based upon tests conducted 12 hours (24 half lives) after consumption.
## Evolutionary rationales
Humans carry a mutated and ineffective form of the gene required by all mammals for manufacturing the fourth of the four enzymes that manufacture vitamin C.[50] The inability to produce vitamin C, hypoascorbemia, is, according to the Online Mendeleian Inheritance in Man database, a "public" inborn error of metabolism.
The gene, Pseudogene ΨGULO, lost its function millions of years ago, when the anthropoids branched out.[51] In humans, the three functional enzymes continue to produce the precursors to vitamin C, but the process is incomplete; these enzymes ultimately undergo proteolytic degradation. Stone[52] and Pauling[39] calculated, based on the diet of our primate cousins[38] (similar to what our common descendants are likely to have consumed when the gene mutated), that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human requiring 2,500 kcal a day.
The established RDA has been criticized by Pauling to be one that will prevent acute scurvy, and is not necessarily the dosage for optimal health.[47]
# Therapeutic uses
Since its discovery vitamin C has been considered by some enthusiastic proponents a "universal panacea", although this led to suspicions by others of it being over-hyped.[53] Other proponents of high dose vitamin C consider that if it is given "in the right form, with the proper technique, in frequent enough doses, in high enough doses, along with certain additional agents and for a long enough period of time,"[54] it can prevent and, in many cases, cure, a wide range of common and/or lethal diseases, notably the common cold and heart disease,[55] although the NIH considers there to be "fair scientific evidence against this use."[56] Some proponents issued controversial statements involving it being a cure for AIDS,[57] bird flu, and SARS.[58][59][60]
Probably the most controversial issue, the putative role of ascorbate in the management of AIDS, is still unresolved, more than 16 years after the landmark study published in the Proceedings of National Academy of Sciences (USA) showing that non toxic doses of ascorbate suppress HIV replication in vitro.[61] Other studies expanded on those results, but still, no large scale trials have yet been conducted.[62][63][64]
In an animal model of lead intoxication, vitamin C demonstrated "protective effects" on lead-induced nerve and muscle abnormalities[65] In smokers, blood lead levels declined by an average of 81% when supplemented with 1000 mg of vitamin C, while 200 mg were ineffective, suggesting that vitamin C supplements may be an "economical and convenient" approach to reduce lead levels in the blood.[66] The Journal of the American Medical Association published a study which concluded, based on an analysis of blood lead levels in the subjects of the Third National Health and Nutrition Examination Survey, that the independent, inverse relationship between lead levels and vitamin C in the blood, if causal, would "have public health implications for control of lead toxicity".[67]
Vitamin C has limited popularity as a treatment for autism spectrum symptoms. A 1993 study of 18 children with ASD found some symptoms reduced after treatment with vitamin C,[68] but these results have not been replicated.[69] Small clinical trials have found that vitamin C might improve the sperm count, sperm motility, and sperm morphology in infertile men[70], or improve immune function related to the prevention and treatment of age-associated diseases.[71] However, to date, no large clinical trials have verified these findings.
A preliminary study published in the Annals of Surgery found that the early administration of antioxidant supplementation using α-tocopherol and ascorbic acid reduces the incidence of organ failure and shortens ICU length of stay in this cohort of critically ill surgical patients.[72] More research on this topic is pending.
Dehydroascorbic acid, the main form of oxidized Vitamin C in the body, was shown to reduce neurological deficits and mortality following stroke, due to its ability to cross the blood-brain barrier, while "the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier".[73] In this study published by the Proceedings of the National Academy of Sciences in 2001, the authors concluded that such "a pharmacological strategy to increase cerebral levels of ascorbate in stroke has tremendous potential to represent the timely translation of basic research into a relevant therapy for thromboembolic stroke in humans". No such "relevant therapies" are available yet and no clinical trials have been planned.
In January 2007 the US Food and Drug Administration approved a Phase I toxicity trial to determine the safe dosage of intravenous vitamin C as a possible cancer treatment for "patients who have exhausted all other conventional treatment options."[74] Additional studies over several years would be needed to demonstrate whether it is effective.[75]
In February 2007, an uncontrolled study of 39 terminal cancer patients showed that, on subjective questionnaires, patients reported an improvement in health, cancer symptoms, and daily function after administration of high-dose intravenous vitamin C.[76] The authors concluded that "Although there is still controversy regarding anticancer effects of vitamin C, the use of vitamin C is considered a safe and effective therapy to improve the quality of life of terminal cancer patients".
# Testing for ascorbate levels in the body
Simple tests use DCPIP to measure the levels of vitamin C in the urine and in serum or blood plasma. However these reflect recent dietary intake rather than the level of vitamin C in body stores.[5] Reverse phase high performance liquid chromatography is used for determining the storage levels of vitamin C within lymphocytes and tissue.
It has been observed that while serum or blood plasma levels follow the circadian rhythm or short term dietary changes, those within tissues themselves are more stable and give a better view of the availability of ascorbate within the organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses, and require samples to be analyzed in specialized laboratories.[77][78]
# Adverse effects
While being harmless in most typical quantities, as with all substances to which the human body is exposed, vitamin C can still cause harm under certain conditions.
## Common side-effects
Relatively large doses of vitamin C may cause indigestion, particularly when taken on an empty stomach.
When taken in large doses, vitamin C causes diarrhea. In one trial, doses up to 6 grams of ascorbic acid were given to 29 infants, 93 children of preschool and school age, and 20 adults for more than 1400 days. With the higher doses, toxic manifestations were observed in five adults and four infants. The signs and symptoms in adults were nausea, vomiting, diarrhea, flushing of the face, headache, fatigue and disturbed sleep. The main toxic reactions in the infants were skin rashes.[79]
## Possible side-effects
As vitamin C enhances iron absorption[80], iron poisoning can become an issue to people with rare iron overload disorders, such as haemochromatosis. A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD), can cause sufferers to develop hemolytic anemia after ingesting specific oxidizing substances, such as very large dosages of vitamin C.[81]
For decades, large doses of vitamin C have been speculated to trigger oxalate formation and increase absorption of dietary oxalate, possibly causing kidney stones.[82] However, this speculation may not be justified since there is no clear relationship between excess ascorbic acid intake and kidney stone formation. [83]
During the first month of pregnancy, high doses of vitamin C may suppress the production of progesterone from the corpus luteum.[84] Progesterone, necessary for the maintenance of a pregnancy, is produced by the corpus luteum for the first few weeks, until the placenta is developed enough to produce its own source. By blocking this function of the corpus luteum, high doses of vitamin C (1000+ mg) is theorized to induce an early miscarriage. In a group of spontaneously aborting women at the end of the first trimester, the mean values of vitamin C were significantly higher in the aborting group. However, the authors point out that this relationship may not necessarily be a causal one.[85]
## Chance of overdose
As discussed previously, vitamin C exhibits remarkably low toxicity. The LD50 (the dose that will kill 50% of a population) in rats is generally accepted to be 11.9 grams per kilogram when taken orally.[33] The LD50 in humans remains unknown, owing to medical ethics that preclude experiments which would put patients at risk of harm. However, as with all substances tested in this way, the LD50 is taken as a guide to its toxicity in humans and no data to contradict this has been found.
# Natural and artificial dietary sources
The richest natural sources are fruits and vegetables, and of those, the camu camu fruit and the Kakadu plum contain the highest concentration of the vitamin. It is also present in some cuts of meat, especially liver. Vitamin C is the most widely taken nutritional supplement and is available in a variety of forms, including tablets, drink mixes, crystals in capsules or naked crystals.
Vitamin C is absorbed by the intestines using a sodium-ion dependent channel. It is transported through the intestine via both glucose-sensitive and glucose-insensitive mechanisms. The presence of large quantities of sugar either in the intestines or in the blood can slow absorption.[86]
## Plant sources
While plants are generally a good source of vitamin C, the amount in foods of plant origin depends on: the precise variety of the plant, the soil condition, the climate in which it grew, the length of time since it was picked, the storage conditions, and the method of preparation.[87]
The following table is approximate and shows the relative abundance in different raw plant sources.[88][89][90] As some plants were analyzed fresh while others were dried (thus, artifactually increasing concentration of individual constituents like vitamin C), the data are subject to potential variation and difficulties for comparison. The amount is given in milligrams per 100 grams of fruit or vegetable and is a rounded average from multiple authoritative sources:
^ average of 3 sources; dried
## Animal sources
The overwhelming majority of species of animals and plants synthesise their own vitamin C, making some, but not all, animal products, sources of dietary vitamin C.
Vitamin C is most present in the liver and least present in the muscle. Since muscle provides the majority of meat consumed in the western human diet, animal products are not a reliable source of the vitamin. Vitamin C is present in mother's milk and, in lower amounts, in raw cow's milk, with pasteurized milk containing only trace amounts.[91] All excess Vitamin C is disposed of through the urinary system.
The following table shows the relative abundance of vitamin C in various foods of animal origin, given in milligram of vitamin C per 100 grams of food:
## Food preparation
Vitamin C chemically decomposes under certain conditions, many of which may occur during the cooking of food. Normally, boiling water at 100°C is not hot enough to cause any significant destruction of the nutrient, which only decomposes at 190°C,
[33] despite popular opinion. However, pressure cooking, roasting, frying and grilling food is more likely to reach the decomposition temperature of vitamin C. Longer cooking times also add to this effect, as will copper food vessels, which catalyse the decomposition.[33]
Another cause of vitamin C being lost from food is leaching, where the water-soluble vitamin dissolves into the cooking water, which is later poured away and not consumed. However, vitamin C doesn't leach in all vegetables at the same rate; research shows broccoli seems to retain more than any other.[92] Research has also shown that fresh-cut fruit don't lose significant nutrients when stored in the refrigerator for a few days.[93]
## Vitamin C supplements
Vitamin C is the most widely taken dietary supplement.[94] It is available in many forms including caplets, tablets, capsules, drink mix packets, in multi-vitamin formulations, in multiple antioxidant formulations, and crystalline powder. Timed release versions are available, as are formulations containing bioflavonoids such as quercetin, hesperidin and rutin. Tablet and capsule sizes range from 25 mg to 1500 mg. Vitamin C (as ascorbic acid) crystals are typically available in bottles containing 300 g to 1 kg of powder (a teaspoon of vitamin C crystals equals 5,000 mg).
## Artificial modes of synthesis
Vitamin C is produced from glucose by two main routes. The Reichstein process, developed in the 1930s, uses a single pre-fermentation followed by a purely chemical route. The modern two-step fermentation process, originally developed in China in the 1960s, uses additional fermentation to replace part of the later chemical stages. Both processes yield approximately 60% vitamin C from the glucose feed.[95]
Research is underway at the Scottish Crop Research Institute in the interest of creating a strain of yeast that can synthesise vitamin C in a single fermentation step from galactose, a technology expected to reduce manufacturing costs considerably.[27]
World production of synthesised vitamin C is currently estimated at approximately 110,000 tonnes annually.
Main producers today are BASF/Takeda, DSM, Merck and the China Pharmaceutical Group Ltd. of the People's Republic of China. China is slowly becoming the major world supplier as its prices undercut those of the US and European manufacturers.[96] | https://www.wikidoc.org/index.php/Ascorbate | |
215dbfbbfb4c24575bd1eb77729f46b05d1a2b28 | wikidoc | Asparagus | Asparagus
Asparagus officinalis is a plant species in the family Asparagaceae from which the popular vegetable known as asparagus is obtained. The species probably originated in the eastern Mediterranean region but is now a widely-cultivated vegetable crop.
# Biology
Asparagus officinalis is native to maritime areas around the Mediterranean. Traditionally placed among the Liliaceae, some authorities split out the Asparagaceae as a separate family. Only the young shoots of asparagus are eaten, before they expand into feathery growth about 100-150cm high. The 'leaves' are in fact needle-like cladodes (modified stems) in the axils of scale leaves. Male and female flowers are normally borne on separate plants, but sometimes hermaphrodite flowers are found. Flowers are found in the junctions of the branchlets, singly or in groups of 2-3. The fruit is a small red berry.
Asparagus is low in calories, contains no fat or cholesterol, and is very low in sodium. It is good source of folic acid, potassium, fiber, and rutin. The amino acid asparagine gets its name from asparagus, the asparagus plant being rich in this compound.
# History
Asparagus has been used from very early times as a vegetable and medicine, owing to its delicate flavour and diuretic properties. There is a recipe for cooking asparagus in the oldest surviving book of recipes, Apicius's 3rd century AD De re coquinaria, Book III. It was cultivated by the ancient Egyptians, Greeks and Romans, who ate it fresh when in season and dried the vegetable for use in winter.It lost its popularity in the Middle Ages but returned to favour in the 17th century.
# Uses
## Culinary
The shoots can be prepared and served in a number of ways, but are usually boiled or steamed and served with hollandaise sauce, melted butter or olive oil and Parmesan cheese. Tall asparagus cooking pots allow the shoots to be steamed gently. Cantonese restaurants in the United States often serve asparagus stir-fried with chicken, shrimp, or beef, also wrapped in bacon. Asparagus may also be quickly grilled over charcoal or hardwood embers. The best asparagus tends to be early growth (first of the season) and is normally simply steamed and served with melted butter.
The bottom portion of asparagus often contains sand, and as such proper preparation is generally advised in cooking asparagus. A case of botulism borne on asparagus was recorded in Australia in 1991.
## Medicinal
Asparagus rhizomes and root is used ethnomedically to treat urinary tract infections, as well as kidney and bladder stones.
# Asparagus pee
Proust claimed that asparagus "...as in a Shakespeare fairy-story transforms my chamber-pot into a flask of perfume."
Some of the constituents of asparagus are metabolized and excreted in the urine, giving it a distinctive odor. The odor is due to various sulfur-containing degradation products (e.g. thiols and thioesters) and ammonia. Recent studies suggest that every individual produces the odorous compounds upon eating, but that only about 40% of individuals have the genes required to smell the odor.
The speed of onset of urine smell is rapid, and has been estimated to occur within 15-30 minutes from ingestion.
Legend has it that a gentlemen's club in London, reputedly the Garrick, had a notice saying "During the asparagus season members are requested not to relieve themselves into the umbrella stand."
# Cultivation
Since asparagus originates in maritime habitats, it thrives in soils that are too saline for normal weeds to grow in. Thus a little salt was traditionally used to suppress weeds in beds intended for asparagus; this has the disadvantage that the soil could not be used for anything else. 'Crowns' are planted in Winter, and the first shoots appear in Spring; the first pickings or 'thinnings' are known as sprue asparagus. Sprue have thin stems.
White asparagus, known as spargel is cultivated by denying the plants light and increasing the amount of ultraviolet light the plants are exposed to while they are being grown. Less bitter than the green variety, it is very popular in the Netherlands and Germany where 57,000 tons (61% of consumer demands) are produced annually.
Purple asparagus differs from its green and white counterparts, having high sugar and low fibre levels. Purple asparagus was originally developed in Italy and commercialised under the variety name Violetto d'Albenga. Since then, breeding work has continued in countries such as the United States and New Zealand.
# Commercial production
Peru is currently the world’s leading asparagus exporter, followed by China and Mexico. The top asparagus importers (2004) were the United States (92,405 tons), followed by the European Union (external trade) (18,565 tons), and Japan (17,148 tons). The United States' production for 2005 was on 54,000 acres (220 km²) and yielded 90,200 tons, making it the world's largest producer and consumer. Production was concentrated in California, Michigan, and Washington. The crop is significant enough in California's Sacramento-San Joaquin River Delta region that the city of Stockton holds a festival every year to celebrate it.
The Vale of Evesham is the traditional centre of the UK industry; British asparagus has a more delicate flavour than that grown in hotter climates.
# Vernacular names and etymology
Asparagus officinalis is widely known simply as "asparagus", and may be confused with unrelated plant species also known as "asparagus", such as Ornithogalum pyrenaicum known as "Prussian asparagus" for its edible shoots.
The English word "asparagus" derives from classical Latin, but the plant was once known in English as sperage, from the Medieval Latin sparagus. This term itself derives from the Greek aspharagos or asparagos, and the Greek term originates from the Persian asparag, meaning "sprout" or "shoot."
Asparagus was also corrupted in some places to "sparrow grass"; indeed, John Walker stated in 1791 that "Sparrow-grass is so general that asparagus has an air of stiffness and pedantry." Another known colloquial variation of the term, most common in parts of Texas, is "aspar grass" or "asper grass." Asparagus is commonly known in fruit retail circles as "Sparrows Guts," etymologically distinct from the old term "sparrow grass," thus showing convergent language evolution.
It is known in French and Dutch as asperge, in Portuguese as espargo hortense, and in German Spargel. | Asparagus
Asparagus officinalis is a plant species in the family Asparagaceae from which the popular vegetable known as asparagus is obtained. The species probably originated in the eastern Mediterranean region but is now a widely-cultivated vegetable crop.[1]
# Biology
Asparagus officinalis is native to maritime areas around the Mediterranean. Traditionally placed among the Liliaceae, some authorities split out the Asparagaceae as a separate family. Only the young shoots of asparagus are eaten, before they expand into feathery growth about 100-150cm high. The 'leaves' are in fact needle-like cladodes (modified stems) in the axils of scale leaves. Male and female flowers are normally borne on separate plants, but sometimes hermaphrodite flowers are found. Flowers are found in the junctions of the branchlets, singly or in groups of 2-3. The fruit is a small red berry.
Asparagus is low in calories, contains no fat or cholesterol, and is very low in sodium. It is good source of folic acid, potassium, fiber, and rutin. The amino acid asparagine gets its name from asparagus, the asparagus plant being rich in this compound.
# History
Asparagus has been used from very early times as a vegetable and medicine, owing to its delicate flavour and diuretic properties. There is a recipe for cooking asparagus in the oldest surviving book of recipes, Apicius's 3rd century AD De re coquinaria, Book III. It was cultivated by the ancient Egyptians, Greeks and Romans, who ate it fresh when in season and dried the vegetable for use in winter.It lost its popularity in the Middle Ages but returned to favour in the 17th century.[2]
# Uses
## Culinary
The shoots can be prepared and served in a number of ways, but are usually boiled or steamed and served with hollandaise sauce, melted butter or olive oil and Parmesan cheese. Tall asparagus cooking pots allow the shoots to be steamed gently. Cantonese restaurants in the United States often serve asparagus stir-fried with chicken, shrimp, or beef, also wrapped in bacon. Asparagus may also be quickly grilled over charcoal or hardwood embers. The best asparagus tends to be early growth (first of the season) and is normally simply steamed and served with melted butter.
The bottom portion of asparagus often contains sand, and as such proper preparation is generally advised in cooking asparagus. A case of botulism borne on asparagus was recorded in Australia in 1991.[3]
## Medicinal
Asparagus rhizomes and root is used ethnomedically to treat urinary tract infections, as well as kidney and bladder stones.
# Asparagus pee
Proust claimed that asparagus "...as in a Shakespeare fairy-story transforms my chamber-pot into a flask of perfume."
Some of the constituents of asparagus are metabolized and excreted in the urine, giving it a distinctive odor. The odor is due to various sulfur-containing degradation products (e.g. thiols and thioesters) and ammonia. Recent studies suggest that every individual produces the odorous compounds upon eating, but that only about 40% of individuals have the genes required to smell the odor.[4][5]
The speed of onset of urine smell is rapid, and has been estimated to occur within 15-30 minutes from ingestion.[6]
Legend has it that a gentlemen's club in London, reputedly the Garrick, had a notice saying "During the asparagus season members are requested not to relieve themselves into the umbrella stand."
# Cultivation
Template:Seealso
Since asparagus originates in maritime habitats, it thrives in soils that are too saline for normal weeds to grow in. Thus a little salt was traditionally used to suppress weeds in beds intended for asparagus; this has the disadvantage that the soil could not be used for anything else. 'Crowns' are planted in Winter, and the first shoots appear in Spring; the first pickings or 'thinnings' are known as sprue asparagus. Sprue have thin stems.[7]
White asparagus, known as spargel is cultivated by denying the plants light and increasing the amount of ultraviolet light the plants are exposed to while they are being grown. Less bitter than the green variety, it is very popular in the Netherlands and Germany where 57,000 tons (61% of consumer demands) are produced annually.[8]
Purple asparagus differs from its green and white counterparts, having high sugar and low fibre levels. Purple asparagus was originally developed in Italy and commercialised under the variety name Violetto d'Albenga. Since then, breeding work has continued in countries such as the United States and New Zealand.
# Commercial production
Peru is currently the world’s leading asparagus exporter, followed by China and Mexico.[9] The top asparagus importers (2004) were the United States (92,405 tons), followed by the European Union (external trade) (18,565 tons), and Japan (17,148 tons).[10] The United States' production for 2005 was on 54,000 acres (220 km²) and yielded 90,200 tons, making it the world's largest producer and consumer. Production was concentrated in California, Michigan, and Washington.[11] The crop is significant enough in California's Sacramento-San Joaquin River Delta region that the city of Stockton holds a festival every year to celebrate it.
The Vale of Evesham is the traditional centre of the UK industry; British asparagus has a more delicate flavour than that grown in hotter climates.
# Vernacular names and etymology
Asparagus officinalis is widely known simply as "asparagus", and may be confused with unrelated plant species also known as "asparagus", such as Ornithogalum pyrenaicum known as "Prussian asparagus" for its edible shoots.
The English word "asparagus" derives from classical Latin, but the plant was once known in English as sperage, from the Medieval Latin sparagus. This term itself derives from the Greek aspharagos or asparagos, and the Greek term originates from the Persian asparag, meaning "sprout" or "shoot."
Asparagus was also corrupted in some places to "sparrow grass"; indeed, John Walker stated in 1791 that "Sparrow-grass is so general that asparagus has an air of stiffness and pedantry." Another known colloquial variation of the term, most common in parts of Texas, is "aspar grass" or "asper grass." Asparagus is commonly known in fruit retail circles as "Sparrows Guts," etymologically distinct from the old term "sparrow grass," thus showing convergent language evolution.
It is known in French and Dutch as asperge, in Portuguese as espargo hortense, and in German Spargel. | https://www.wikidoc.org/index.php/Asparagus | |
527a81cb11c20a253ba0c7c21bbbad8b4622f618 | wikidoc | Aspartame | Aspartame
Aspartame(or APM) (IPA: Template:IPA) is the name for an artificial, non-saccharide sweetener, aspartyl-phenylalanine-1-methyl ester; i.e., the methyl ester of the dipeptide of the amino acids aspartic acid and phenylalanine.
This sweetener is marketed under a number of trademark names, including Equal, NutraSweet, Canderel, and is an ingredient of approximately 6,000 consumer foods and beverages sold worldwide. It is commonly used in diet soft drinks, and is often provided as a table condiment. It is also used in some brands of chewable vitamin supplements and common in many sugar-free chewing gums. However, aspartame is not always suitable for baking because it often breaks down when heated and loses much of its sweetness. In the European Union, it is also known under the E number (additive code) E951. Aspartame is also one of the sugar substitutes used by people with diabetes.
Aspartame is a subject of public controversy due to possible health risks. See Aspartame controversy. It has lost market share in recent years to sucralose (Splenda, Altern, or E number E955).
# Chemistry
Aspartame is the methyl ester of the dipeptide of the natural amino acids L-aspartic acid and L-phenylalanine. Under strongly acidic or alkaline conditions, aspartame first generates methanol by hydrolysis. Under more severe conditions, the peptide bonds are also hydrolyzed, resulting in the free amino acids. It is a nonpolar molecule.
# Properties and use
Aspartame is an attractive sweetener because it is 180 times sweeter than sugar in typical concentrations, without the high energy value of sugar. While aspartame, like other peptides, has a caloric value of 4 kilocalories (17 kilojoules) per gram, the quantity of aspartame needed to produce a sweet taste is so small that its caloric contribution is negligible, which makes it a popular sweetener for those trying to avoid calories from sugar. The taste of aspartame is not identical to that of sugar: the sweetness of aspartame has a slower onset and longer duration than that of sugar, and some consumers find it unappealing. Blends of aspartame with acesulfame potassium — usually listed in ingredients as acesulfame K — are alleged to taste more like sugar, and to be sweeter than either substitute used alone.
Like many other peptides, aspartame may hydrolyze (break down) into its constituent amino acids under conditions of elevated temperature or high pH. This makes aspartame undesirable as a baking sweetener, and prone to degradation in products hosting a high-pH, as required for a long shelf life. The stability of aspartame under heating can be improved to some extent by encasing it in fats or in maltodextrin. The stability when dissolved in water depends markedly on pH. At room temperature, it is most stable at pH 4.3, where its half-life is nearly 300 days. At pH 7, however, its half-life is only a few days. Most soft-drinks have a pH between 3 and 5, where aspartame is reasonably stable. In products that may require a longer shelf life, such as syrups for fountain beverages, aspartame is sometimes blended with a more stable sweetener, such as saccharin.
In products such as powdered beverages, the amine in aspartame can undergo a Maillard reaction with the aldehyde groups present in certain aroma compounds. The ensuing loss of both flavor and sweetness can be prevented by protecting the aldehyde as an acetal.
# Discovery and approval
Aspartame was discovered in 1965 by James M. Schlatter, a chemist working for G.D. Searle & Company. Schlatter had synthesized aspartame in the course of producing an anti-ulcer drug candidate. He discovered its sweet taste serendipitously when he licked his finger, which had accidentally become contaminated with aspartame.
Following initial safety testing, there was debate as to whether these tests had indicated that aspartame may cause cancer in rats; as a result, the U.S. Food and Drug Administration (FDA) did not approve its use as a food additive in the United States for many years. In 1980, the FDA convened a Public Board of Inquiry (PBOI) consisting of independent advisors charged with examining the purported relationship between aspartame and brain cancer. The PBOI concluded that aspartame does not cause brain damage, but it recommended against approving aspartame at that time, citing unanswered questions about cancer in laboratory rats. At that point in time, there was no requirement in place in FDA regulations to include brain research in the approval process, only cancer research. In 1981, U.S. President Ronald Reagan appointed Arthur Hull Hayes as FDA commissioner. Citing data from a Japanese study that had not been available to the members of the PBOI, Hayes approved aspartame for use in dry goods. In 1983 FDA further approved aspartame for use in carbonated beverages, and for use in other beverages, baked goods, and confections in 1993. In 1996, the FDA removed all restrictions from aspartame allowing it to be used in all foods.
In 1985, Monsanto bought G.D. Searle — and the aspartame business became a separate Monsanto subsidiary, the NutraSweet Company. On May 25 2000 Monsanto sold it to J.W. Childs Equity Partners II L.P. The U.S. patent on aspartame expired in 1992. Since then the company has faced hot competition in market for aspartame from other manufacturers, including Ajinomoto, Merisant and the Holland Sweetener Company, which stopped making the chemical in late 2006 because "global aspartame markets are facing structural oversupply, which has caused worldwide strong price erosion over the last 5 years" making the business "persistently unprofitable”.
Several European Union states approved aspartame in the 1980s, with EU-wide approval in 1994. The European Commission Scientific Committee on Food reviewed subsequent safety studies and reaffirmed the approval in 2002. The European Food Safety Authority reported in 2006 that the previously established Adequate Daily Intake was appropriate, after reviewing yet another set of studies.
It has also been investigated and approved by the Joint Expert Committee on Food Additives of the United Nations Food and Agricultural Organization and World Health Organization.
# Metabolism
Upon ingestion, aspartame breaks down into several residual chemicals, including aspartic acid, phenylalanine, methanol, and further breakdown products including formaldehyde (when consumed by rats) and formic acid. There is some controversy surrounding the rate of breakdown into these various products and the effects that they have on those that consume aspartame-sweetened foods. (See Aspartame controversy)
The naturally-occurring essential amino acid phenylalanine is a health hazard to those born with phenylketonuria (PKU), a rare inherited disease that prevents phenylalanine from being properly metabolized. Since individuals with PKU must consider aspartame as an additional source of phenylalanine, foods containing aspartame sold in the United States must state "Phenylketonurics: Contains Phenylalanine" on their product labels.
In the UK, foods that contain aspartame must list the chemical among the product's ingredients and carry the warning 'Contains a source of phenylalanine' – this is usually at the foot of the list of ingredients. Manufacturers should print '"with sweetener(s)" on the label close to the main product name' on foods that contain 'sweeteners such as aspartame' or "with sugar and sweetener(s)" on 'foods that contain both sugar and sweetener'. 'This labelling is a legal requirement,'says the country's Food Standards Agency.
# Health Concerns
Aspartame has been the subject of controversy regarding its safety and the circumstances of its approval by the American FDA and European FSA. Some studies have also recommended further investigation into possible connections between aspartame and negative effects such as headaches, brain tumors, brain lesions, and lymphoma. These findings, combined with possible conflicts of interest involving CEO Donald Rumsfeld in the approval process, have engendered vocal activism regarding the possible risks of aspartame. | Aspartame
Aspartame(or APM) (IPA: Template:IPA) is the name for an artificial, non-saccharide sweetener, aspartyl-phenylalanine-1-methyl ester; i.e., the methyl ester of the dipeptide of the amino acids aspartic acid and phenylalanine.
This sweetener is marketed under a number of trademark names, including Equal, NutraSweet, Canderel, and is an ingredient of approximately 6,000 consumer foods and beverages sold worldwide. It is commonly used in diet soft drinks, and is often provided as a table condiment. It is also used in some brands of chewable vitamin supplements and common in many sugar-free chewing gums. However, aspartame is not always suitable for baking because it often breaks down when heated and loses much of its sweetness. In the European Union, it is also known under the E number (additive code) E951. Aspartame is also one of the sugar substitutes used by people with diabetes.
Aspartame is a subject of public controversy due to possible health risks. See Aspartame controversy. It has lost market share in recent years to sucralose (Splenda, Altern, or E number E955).[2]
# Chemistry
Aspartame is the methyl ester of the dipeptide of the natural amino acids L-aspartic acid and L-phenylalanine. Under strongly acidic or alkaline conditions, aspartame first generates methanol by hydrolysis. Under more severe conditions, the peptide bonds are also hydrolyzed, resulting in the free amino acids. It is a nonpolar molecule.[3]
# Properties and use
Aspartame is an attractive sweetener because it is 180 times sweeter than sugar in typical concentrations, without the high energy value of sugar. While aspartame, like other peptides, has a caloric value of 4 kilocalories (17 kilojoules) per gram, the quantity of aspartame needed to produce a sweet taste is so small that its caloric contribution is negligible, which makes it a popular sweetener for those trying to avoid calories from sugar. The taste of aspartame is not identical to that of sugar: the sweetness of aspartame has a slower onset and longer duration than that of sugar, and some consumers find it unappealing. Blends of aspartame with acesulfame potassium — usually listed in ingredients as acesulfame K — are alleged to taste more like sugar, and to be sweeter than either substitute used alone.
Like many other peptides, aspartame may hydrolyze (break down) into its constituent amino acids under conditions of elevated temperature or high pH. This makes aspartame undesirable as a baking sweetener, and prone to degradation in products hosting a high-pH, as required for a long shelf life. The stability of aspartame under heating can be improved to some extent by encasing it in fats or in maltodextrin. The stability when dissolved in water depends markedly on pH. At room temperature, it is most stable at pH 4.3, where its half-life is nearly 300 days. At pH 7, however, its half-life is only a few days. Most soft-drinks have a pH between 3 and 5, where aspartame is reasonably stable. In products that may require a longer shelf life, such as syrups for fountain beverages, aspartame is sometimes blended with a more stable sweetener, such as saccharin.[4]
In products such as powdered beverages, the amine in aspartame can undergo a Maillard reaction with the aldehyde groups present in certain aroma compounds. The ensuing loss of both flavor and sweetness can be prevented by protecting the aldehyde as an acetal.
# Discovery and approval
Aspartame was discovered in 1965 by James M. Schlatter, a chemist working for G.D. Searle & Company. Schlatter had synthesized aspartame in the course of producing an anti-ulcer drug candidate. He discovered its sweet taste serendipitously when he licked his finger, which had accidentally become contaminated with aspartame.[5]
Following initial safety testing, there was debate as to whether these tests had indicated that aspartame may cause cancer in rats; as a result, the U.S. Food and Drug Administration (FDA) did not approve its use as a food additive in the United States for many years. In 1980, the FDA convened a Public Board of Inquiry (PBOI) consisting of independent advisors charged with examining the purported relationship between aspartame and brain cancer. The PBOI concluded that aspartame does not cause brain damage, but it recommended against approving aspartame at that time, citing unanswered questions about cancer in laboratory rats. At that point in time, there was no requirement in place in FDA regulations to include brain research in the approval process, only cancer research. In 1981, U.S. President Ronald Reagan appointed Arthur Hull Hayes as FDA commissioner. Citing data from a Japanese study that had not been available to the members of the PBOI, Hayes approved aspartame for use in dry goods.[6] In 1983 FDA further approved aspartame for use in carbonated beverages, and for use in other beverages, baked goods, and confections in 1993. In 1996, the FDA removed all restrictions from aspartame allowing it to be used in all foods.
In 1985, Monsanto bought G.D. Searle — and the aspartame business became a separate Monsanto subsidiary, the NutraSweet Company. On May 25 2000 Monsanto sold it to J.W. Childs Equity Partners II L.P.[7] The U.S. patent on aspartame expired in 1992. Since then the company has faced hot competition in market for aspartame from other manufacturers, including Ajinomoto, Merisant and the Holland Sweetener Company, which stopped making the chemical in late 2006 because "global aspartame markets are facing structural oversupply, which has caused worldwide strong price erosion over the last 5 years" making the business "persistently unprofitable”.[8]
Several European Union states approved aspartame in the 1980s, with EU-wide approval in 1994. The European Commission Scientific Committee on Food reviewed subsequent safety studies and reaffirmed the approval in 2002. The European Food Safety Authority reported in 2006 that the previously established Adequate Daily Intake was appropriate, after reviewing yet another set of studies.[9]
It has also been investigated and approved by the Joint Expert Committee on Food Additives of the United Nations Food and Agricultural Organization and World Health Organization.[10]
# Metabolism
Upon ingestion, aspartame breaks down into several residual chemicals, including aspartic acid, phenylalanine, methanol, and further breakdown products including formaldehyde (when consumed by rats)[11] and formic acid. There is some controversy surrounding the rate of breakdown into these various products and the effects that they have on those that consume aspartame-sweetened foods. (See Aspartame controversy)
The naturally-occurring essential amino acid phenylalanine is a health hazard to those born with phenylketonuria (PKU), a rare inherited disease that prevents phenylalanine from being properly metabolized. Since individuals with PKU must consider aspartame as an additional source of phenylalanine, foods containing aspartame sold in the United States must state "Phenylketonurics: Contains Phenylalanine" on their product labels.
In the UK, foods that contain aspartame must list the chemical among the product's ingredients and carry the warning 'Contains a source of phenylalanine' – this is usually at the foot of the list of ingredients. Manufacturers should print '"with sweetener(s)" on the label close to the main product name' on foods that contain 'sweeteners such as aspartame' or "with sugar and sweetener(s)" on 'foods that contain both sugar and sweetener'. 'This labelling is a legal requirement,'says the country's Food Standards Agency.[12]
# Health Concerns
Aspartame has been the subject of controversy regarding its safety and the circumstances of its approval by the American FDA and European FSA. Some studies have also recommended further investigation into possible connections between aspartame and negative effects such as headaches, brain tumors, brain lesions, and lymphoma.[13][14][15] These findings, combined with possible conflicts of interest involving CEO Donald Rumsfeld in the approval process, have engendered vocal activism regarding the possible risks of aspartame.[16][17] | https://www.wikidoc.org/index.php/Aspartame | |
bc4ee81a6f572116b72bd820c6a61a5f91baa3a5 | wikidoc | Astrocyte | Astrocyte
Astrocytes (also known collectively as astroglia) are characteristic star-shaped glial cells in the brain. They perform many functions, including the formation of the blood-brain barrier, the provision of nutrients to the nervous tissue, and play a principal role in the repair and scarring process in the brain.
# Description
Astrocytes are a sub-type of the glial cells in the brain. They are also known as astrocytic glial cells. Star-shaped, their many processes envelope synapses made by neurons. Astrocytes are classically identified histologically by their expression of glial fibrillary acidic protein (GFAP). Previously in medical science, the neuronal network was considered the only important one, and astrocytes were looked upon as gap fillers. But recently they have been reconsidered and are now thought to play a number of active roles in the brain. Although they aid in the maintenance of the blood-brain barrier, they do not actually form it.
# Functions
- Structural: involved in the physical structuring of the brain.
- Metabolic support: they provide neurons with nutrients such as glucose.
- Blood-brain barrier: the astrocyte end-feet encircling endothelial cells aid in the maintenance of the blood-brain barrier.
- Transmitter reuptake and release: astrocytes express plasma membrane transporters such as glutamate transporters for several neurotransmitters, including glutamate, ATP and GABA. More recently, astrocytes were shown to release glutamate or ATP in a vesicular, Ca2+-dependent manner.
- Regulation of ion concentration in the extracellular space: astrocytes express potassium channels at a high density. When neurons are active, they release potassium, increasing the local extracellular concentration. Because astrocytes are highly permeable to potassium, they rapidly clear the excess accumulation in the extracellular space. If this function is interfered with, the extracellular concentration of potassium will rise, leading to neuronal depolarization by the Goldman equation. Abnormal accumulation of extracellular potassium is well known to result in epileptic neuronal activity.
- Modulation of synaptic transmission: in the supraoptic nucleus of the hypothalamus, rapid changes in astrocyte morphology have been shown to affect heterosynaptic transmission between neurons.
- Vasomodulation: astrocytes may serve as intermediaries in neuronal regulation of blood flow.
- Promotion of the myelinating activity of oligodendrocytes: electrical activity in neurons causes them to release ATP, which serves as an important stimulus for myelin to form. Surprisingly, the ATP does not act directly on oligodendrocytes. Instead it causes astrocytes to secrete LIM, a regulatory protein that promotes the myelinating activity of oligodendrocytes. This suggest that astrocytes have an executive-coordinating role in the brain.
In the 1990s, following persistent study, a small group of scientists began to uncover evidence that astrocytes signal to neurons and influence their activity. First, cell experiments in petri dishes found that following an increase of the element calcium in astrocytes, there is an increase of calcium in surrounding neurons. This implied some form of communication between the two cell types. Next, scientists found that indeed the calcium increase in astrocytes directly links to changes in neuron activity. In one study of rat cells, microelectrodes measured the electrical impulses that neurons use to signal to each other. In response to the calcium increase in astrocytes, the majority of neurons tested slowed down their signaling activity. A few increased their signaling activity.
Other research is uncovering key molecules that aid the communication. Several studies indicate that following the rise of calcium, astrocytes release the amino acid glutamate, which helps them talk to the neurons. The communication flows both ways, with neurons also being able to talk to the astrocytes through their own glutamate release. Signaling molecules, such as ATP and prostaglandins, also appear to promote the cell-to-cell communication, according to other new investigations.
Determining why the astrocyte chatting occurs and whether it actually affects the neurons' ability to process information, is another area of research. Early studies hint that some of the chatting may aid memory. Adding glutamate to cell samples of astrocytes prompts them to produce special molecules that nourish neurons, known as trophic factors. Other research has found that these molecules are key to memory function. In one recent study, injections of trophic factors into the brains of rats boosted the biological mechanisms known to relate to memory and improved the rats' performance in a memory task. This all may mean that glutamate release from neurons triggers astrocytes to produce trophic factors, which then help neurons process information for memory. Scientists currently are testing this theory.
Together the research is not only making researchers rethink how the brain operates, but also how to treat it when it malfunctions. For one, if the research on astrocytes' connection to memory pans out, then the cells may make good targets for treatment of memory disorders such as Alzheimer's disease. Astrocytes' relationship to glutamate also may make them good targets for clinical intervention since several brain disorders have been tied to glutamate problems. For example, some scientists believe that when the brain is infected by the AlDS-causing HIV virus or deprived of oxygen from lack of blood flow due to a stroke, a release of excess glutamate causes neurons to die. Agents that target astrocytes might help limit the glutamate overflow and prevent the cell death.
Furthermore, studies are underway to determine whether astroglia play an instrumental role in depression, based on the link between diabetes and depression. Altered CNS glucose metabolism is seen in both these conditions, and the astroglial cells are the only cells with insulin receptors in the brain.
# Calcium waves
Astrocytes are linked by gap junctions, creating an electrically coupled syncytium.
An increase in intracellular calcium concentration can propagate outwards through this syncytium. Mechanisms of calcium wave propagation include diffusion of IP3 through gap junctions and extracellular ATP signalling. Calcium elevations are the primary known axis of activation in astrocytes, and are necessary and sufficient for some types of astrocytic glutamate release.
# Classification
There are several different ways to classify astrocytes:
## by Lineage and antigenic phenotype
These have been established by classic work by Raff et al in early 1980s on Rat optic nerves.
- Type 1: Antigenically Ran2+, GFAP+, FGFR3+, A2B5- thus resembling the "type 1 astrocyte" of the postnatal day 7 rat optic nerve. These can arise from the tripotential glial restricted precursor cells (GRP), but not from the bipotential O2A/OPC (oligodendrocyte, type 2 astrocyte precursor, also called Oligodendrocye progenitor cell) cells.
- Type 2: Antigenically A2B5+, GFAP+, FGFR3-, Ran 2-. These cells can develop in vitro from the either tripotential GRP (probably via O2A stage) or from bipotential O2A cells (which some people think may in turn have been derived from the GRP) or in vivo when the these progenitor cells are transplanted into lesion sites (but probably not in normal development, at least not in the rat optic nerve). Type-2 astrocytes are the major astrocytic component in postnatal optic nerve cultures that are generated by O2A cells grown in the presence of fetal calf serum but are not thought to exist in vivo (Fulton et al., 1992).
## by Location
- Type I: Those astrocytes are in direct contact with blood capillaries through astrocytique pod. They are actively helping neuronal metabolism and glucose delivery.
- Type II: Type II astrocytes surrounds neurons and synaptic gap. This coverage varies from 1 to 100%.
## by Anatomical Classification
- Protoplasmic: found in grey matter and have many branching processes whose end-feet envelop synapses. Some protoplasmic astrocytes are generated by multipotent subventricular zone progenitor cells (Levison and Goldman, 1993; Zerlin et al., 1995).
- Fibrous: found in white matter and have long thin unbranched processes whose end-feet envelop nodes of Ranvierand also they play an important on humans brain. Some fibrous astrocytes are generated by radial glia (Choi and Lapham, 1978; Schmechel and Rakic, 1979; Misson et al., 1988; Voigt, 1989; Goldman, 1996
## by Transporter/receptor classification
- GluT type: express glutamate transporters (EAAT1/SLC1A3 and EAAT2/SLC1A2) and respond to synaptic release of glutamate by transporter currents
- GluR type: express glutamate receptors (mostly mGluR and AMPA type) and respond to synaptic release of glutamate by channel-mediated currents and IP3-dependent Ca2+ transients
# Bergmann glia
Bergmann glia, a type of glia also known as radial epithelial cells (as named by Camillo Golgi), are astrocytes in the cerebellum that have their cell bodies in the Purkinje cell layer and processes that extend into the molecular layer, terminating with bulbous endfeet at the pial surface. Bergmann glia express high densities of glutamate transporters that limit diffusion of the neurotransmitter glutamate during its release from synaptic terminals. Besides their role in early development of the cerebellum, Bergmann glia are also required for the pruning or addition of synapses.
# Pathology
Astrocytomas are primary intracranial tumors derived from astrocytes cells of the brain. | Astrocyte
Template:Infobox Anatomy
Astrocytes (also known collectively as astroglia) are characteristic star-shaped glial cells in the brain. They perform many functions, including the formation of the blood-brain barrier, the provision of nutrients to the nervous tissue, and play a principal role in the repair and scarring process in the brain.
# Description
Astrocytes are a sub-type of the glial cells in the brain. They are also known as astrocytic glial cells. Star-shaped, their many processes envelope synapses made by neurons. Astrocytes are classically identified histologically by their expression of glial fibrillary acidic protein (GFAP). Previously in medical science, the neuronal network was considered the only important one, and astrocytes were looked upon as gap fillers. But recently they have been reconsidered and are now thought to play a number of active roles in the brain. Although they aid in the maintenance of the blood-brain barrier, they do not actually form it.
# Functions
- Structural: involved in the physical structuring of the brain.
- Metabolic support: they provide neurons with nutrients such as glucose.
- Blood-brain barrier: the astrocyte end-feet encircling endothelial cells aid in the maintenance of the blood-brain barrier.
- Transmitter reuptake and release: astrocytes express plasma membrane transporters such as glutamate transporters for several neurotransmitters, including glutamate, ATP and GABA. More recently, astrocytes were shown to release glutamate or ATP in a vesicular, Ca2+-dependent manner.
- Regulation of ion concentration in the extracellular space: astrocytes express potassium channels at a high density. When neurons are active, they release potassium, increasing the local extracellular concentration. Because astrocytes are highly permeable to potassium, they rapidly clear the excess accumulation in the extracellular space. If this function is interfered with, the extracellular concentration of potassium will rise, leading to neuronal depolarization by the Goldman equation. Abnormal accumulation of extracellular potassium is well known to result in epileptic neuronal activity.
- Modulation of synaptic transmission: in the supraoptic nucleus of the hypothalamus, rapid changes in astrocyte morphology have been shown to affect heterosynaptic transmission between neurons.[1]
- Vasomodulation: astrocytes may serve as intermediaries in neuronal regulation of blood flow.[2]
- Promotion of the myelinating activity of oligodendrocytes: electrical activity in neurons causes them to release ATP, which serves as an important stimulus for myelin to form. Surprisingly, the ATP does not act directly on oligodendrocytes. Instead it causes astrocytes to secrete LIM, a regulatory protein that promotes the myelinating activity of oligodendrocytes. This suggest that astrocytes have an executive-coordinating role in the brain.[3]
In the 1990s, following persistent study, a small group of scientists began to uncover evidence that astrocytes signal to neurons and influence their activity. First, cell experiments in petri dishes found that following an increase of the element calcium in astrocytes, there is an increase of calcium in surrounding neurons. This implied some form of communication between the two cell types. Next, scientists found that indeed the calcium increase in astrocytes directly links to changes in neuron activity. In one study of rat cells, microelectrodes measured the electrical impulses that neurons use to signal to each other. In response to the calcium increase in astrocytes, the majority of neurons tested slowed down their signaling activity. A few increased their signaling activity.
Other research is uncovering key molecules that aid the communication. Several studies indicate that following the rise of calcium, astrocytes release the amino acid glutamate, which helps them talk to the neurons. The communication flows both ways, with neurons also being able to talk to the astrocytes through their own glutamate release. Signaling molecules, such as ATP and prostaglandins, also appear to promote the cell-to-cell communication, according to other new investigations.
Determining why the astrocyte chatting occurs and whether it actually affects the neurons' ability to process information, is another area of research. Early studies hint that some of the chatting may aid memory. Adding glutamate to cell samples of astrocytes prompts them to produce special molecules that nourish neurons, known as trophic factors. Other research has found that these molecules are key to memory function. In one recent study, injections of trophic factors into the brains of rats boosted the biological mechanisms known to relate to memory and improved the rats' performance in a memory task. This all may mean that glutamate release from neurons triggers astrocytes to produce trophic factors, which then help neurons process information for memory. Scientists currently are testing this theory.
Together the research is not only making researchers rethink how the brain operates, but also how to treat it when it malfunctions. For one, if the research on astrocytes' connection to memory pans out, then the cells may make good targets for treatment of memory disorders such as Alzheimer's disease. Astrocytes' relationship to glutamate also may make them good targets for clinical intervention since several brain disorders have been tied to glutamate problems. For example, some scientists believe that when the brain is infected by the AlDS-causing HIV virus or deprived of oxygen from lack of blood flow due to a stroke, a release of excess glutamate causes neurons to die. Agents that target astrocytes might help limit the glutamate overflow and prevent the cell death.
Furthermore, studies are underway to determine whether astroglia play an instrumental role in depression, based on the link between diabetes and depression. Altered CNS glucose metabolism is seen in both these conditions, and the astroglial cells are the only cells with insulin receptors in the brain.
# Calcium waves
Astrocytes are linked by gap junctions, creating an electrically coupled syncytium.[4]
An increase in intracellular calcium concentration can propagate outwards through this syncytium. Mechanisms of calcium wave propagation include diffusion of IP3 through gap junctions and extracellular ATP signalling.[5] Calcium elevations are the primary known axis of activation in astrocytes, and are necessary and sufficient for some types of astrocytic glutamate release.[6]
# Classification
There are several different ways to classify astrocytes:
## by Lineage and antigenic phenotype
These have been established by classic work by Raff et al in early 1980s on Rat optic nerves.
- Type 1: Antigenically Ran2+, GFAP+, FGFR3+, A2B5- thus resembling the "type 1 astrocyte" of the postnatal day 7 rat optic nerve. These can arise from the tripotential glial restricted precursor cells (GRP), but not from the bipotential O2A/OPC (oligodendrocyte, type 2 astrocyte precursor, also called Oligodendrocye progenitor cell) cells.
- Type 2: Antigenically A2B5+, GFAP+, FGFR3-, Ran 2-. These cells can develop in vitro from the either tripotential GRP (probably via O2A stage) or from bipotential O2A cells (which some people think may in turn have been derived from the GRP) or in vivo when the these progenitor cells are transplanted into lesion sites (but probably not in normal development, at least not in the rat optic nerve). Type-2 astrocytes are the major astrocytic component in postnatal optic nerve cultures that are generated by O2A cells grown in the presence of fetal calf serum but are not thought to exist in vivo (Fulton et al., 1992).
## by Location
- Type I: Those astrocytes are in direct contact with blood capillaries through astrocytique pod. They are actively helping neuronal metabolism and glucose delivery.
- Type II: Type II astrocytes surrounds neurons and synaptic gap. This coverage varies from 1 to 100%.
## by Anatomical Classification
- Protoplasmic: found in grey matter and have many branching processes whose end-feet envelop synapses. Some protoplasmic astrocytes are generated by multipotent subventricular zone progenitor cells (Levison and Goldman, 1993; Zerlin et al., 1995).
- Fibrous: found in white matter and have long thin unbranched processes whose end-feet envelop nodes of Ranvier[7]and also they play an important on humans brain. Some fibrous astrocytes are generated by radial glia (Choi and Lapham, 1978; Schmechel and Rakic, 1979; Misson et al., 1988; Voigt, 1989; Goldman, 1996
## by Transporter/receptor classification
- GluT type: express glutamate transporters (EAAT1/SLC1A3 and EAAT2/SLC1A2) and respond to synaptic release of glutamate by transporter currents
- GluR type: express glutamate receptors (mostly mGluR and AMPA type) and respond to synaptic release of glutamate by channel-mediated currents and IP3-dependent Ca2+ transients
# Bergmann glia
Bergmann glia, a type of glia[8][9] also known as radial epithelial cells (as named by Camillo Golgi), are astrocytes in the cerebellum that have their cell bodies in the Purkinje cell layer and processes that extend into the molecular layer, terminating with bulbous endfeet at the pial surface. Bergmann glia express high densities of glutamate transporters that limit diffusion of the neurotransmitter glutamate during its release from synaptic terminals. Besides their role in early development of the cerebellum, Bergmann glia are also required for the pruning or addition of synapses.
# Pathology
Astrocytomas are primary intracranial tumors derived from astrocytes cells of the brain. | https://www.wikidoc.org/index.php/Astrocyte | |
716216cd0fbca7c974a7e697731283e17df03dbc | wikidoc | Atogepant | Atogepant
# 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
Atogepant is a calcitonin gene-related peptide receptor antagonist that is FDA approved for the prevention of episodic migraines. Common adverse reactions include constipation, fatigue, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Take either 10 mg, 30 mg, or 60 mg of Atogepant orally as prescribed by a doctor.
- Advise patients that Atogepant can either be taken with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Atogepant in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Atogepant in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Atogepant 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 Atogepant in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Atogepant in pediatric patients.
# Contraindications
There are no contraindications associated with Atogepant.
# Warnings
There is limited information regarding Atogepant Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials Experiance
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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. 1958 patients with migraines received Atogepant to look into the safety of Atogepant usage on patients. All patients in the study received at least one dosage of Atogepant. In the study, 839 patients were exposed to Atogepant for 6 months while 487 patients were exposed to Atogepant for 12 months.
Study 1 and 2
- 12-week, placebo-controlled clinical studies were conducted on patients to look into the adverse reactions observed in patients receiving 10 mg, 30 mg, or 60 mg of Atogepant once daily. 314 patients received 10 mg of Atogepant, 411 patients received 30 mg of Atogepant, 417 patients received 60 mg of Atogepant, and 408 patients received a placebo that had no Atogepant. The patient population was largely Caucasian (80%), and included 88% women. Constipation, nausea, and fatigue were the most common adverse reactions reported in patients (reported at least 4% and greater than placebo). Discontinuation occurred in patients that displayed nausea (0.5%), fatigue (0.5%), and constipation (0.5%).
Table 2 shows the Adverse Reactions found in patients taking Atogepant from Study 1 and Study 2.
Liver Enzyme Elevations
- 1.0% of patients taking Atogepant had a rate of transaminase elevations over 3 times the upper limit of normal. Some of these patients had asymptomatic cases which were ultimately resolved after discontinuation of Atogepant for 8 weeks.
- 1.8% of patients taking the placebo had a rate of transaminase elevations over 3 times the upper limit of normal.
- Jaundice and severe liver injury were not found in patients.
Decreases in Body Weight
- 3.8% of patients taking 10 mg of Atogepant from Study 1 and Study 2 reported a decrease in weight of at least 7%.
- 3.2% of patients taking 30 mg of Atogepant from Study 1 and Study 2 reported a decrease in weight of at least 7%.
- 4.9% of patients taking 60 mg of Atogepant from Study 1 and Study 2 reported a decrease in weight of at least 7%.
- 2.8% of patients taking the placebo from Study 1 and Study 2 reported a decrease in weight of at least 7%.
## Postmarketing Experience
There is limited information about "Postmarketing Experiance" in the drug label.
# Drug Interactions
CYP3A4 Inhibitors
- Exposure of Atogepant significantly increases with co-administration of Atogepant and itraconazole (a strong CYP3A4 inhibitor).
- 10 mg is recommended dosage of Atogepant when there is concomitant use of Atogepant with a strong CYP3A4 inhibitor.
- Concomitant use of Atogepant with either a moderate or weak CYP3A4 inhibitor requires no change in dosage of Atogepant.
CYP3A4 Inducers
- Exposure of Atogepant significantly decreases with co-administration of Atogepant and a steady state rifampin (a strong CYP3A4 inducer).
- Exposure of Atogepant significantly decreases with concomitant use of Atogepant and moderate inducers of CYP3A4.
- 30 mg or 60 mg is recommended dosage of Atogepant when there is concomitant use of Atogepant with a strong or moderate CYP3A4 inducer.
- Concomitant use of Atogepant with weak CYP3A4 inducer requires no change in dosage of Atogepant.
OATP Inhibitors
- Exposure of Atogepant significantly increases with co-administration of Atogepant and a single dose of rifampin (a OATP inhibitor).
- 10 mg or 30 mg is recommended dosage of Atogepant when there is concomitant use of Atogepant with a OATP inhibitor.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Reproduction studies done on pregnant rabbits showed a rise in adverse developmental effects such as increased incidence of fetal structural variations with increased exposure of Atogepant (0, 30, 90, or 130 mg/kg/day) during the periods of organogenesis, lactation or pregnancy. At 130 mg/kg/day, pregnant rabbits showed an increase in both skeletal variations and fetal visceral. Maternal toxicity was minimal in pregnant rabbits at 130 mg/kg/day. Adverse effects on plasma exposure and embryofetal development was 3 times for humans at the MRHD in pregnant rabbits at 90 mg/kg/day (no-effect dose). Reproduction studies done on pregnant rats showed a decrease in both skeletal ossification and fetal body weight when given either 125 and 750 mg/kg of Atogepant during the period of organogenesis. Adverse effects on plasma exposure and embryofetal development was 4 times for humans at the MRHD in pregnant rats at 15 mg/kg/day (no-effect dose). At 125 mg/kg/day, a decrease in pup body weight was found in rats during periods of gestation and lactation. At 45 mg/kg/day, the no-effect dose, adverse effects of rats on plasma exposure and pre- and postnatal development was 5 times for humans at the MRHD. Advise pregnant, female patients about the potential harms and risks in the embryo when taking Atogepant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atogepant in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Atogepant during labor and delivery.
### Nursing Mothers
No human data on the effects of Atogepant on the breastfed infant and milk production has been conducted. Studies done on lactating rats show Atogepant levels in milk is 2-fold higher than found in milk of the maternal plasma. Advise female patients about both the possible developmental and health benefits as well as potential adverse effects during nursing when taking Atogepant.
### Pediatric Use
There is no FDA guidance on the use of Atogepant with respect to pediatric populations.
### Geriatic Use
When looking at younger and elderly patients using Atogepant, no clinically significant pharmacokinetic differences were found between both groups of patients. There was not enough patients 65 years or older in age to determine if there are any response differences to Atogepant in comparison to younger patients. Decrease in frequency of decreased renal, cardiac, or hepatic function was found in elderly patients at the low end of the dosing range for Atogepant.
### Gender
There is no FDA guidance on the use of Atogepant with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Atogepant with respect to specific racial populations.
### Renal Impairment
When looking at the clearance of Atogepant, renal route of elimination plays a minor role. 10 mg of Atogepant once daily is the recommended dosage for patients with end-stage renal disease (CLcr <15 mL/min) or patients severe renal impairment (CLcr 15-29 mL/min). Patients with end-stage renal disease who are undergoing intermittent dialysis should start taking Atogepant after dialysis is completed. Patients with mild or moderate renal impairment require no change to dosage usage.
### Hepatic Impairment
Patients with mild or moderate hepatic impairment require no change to dosage usage. Patients with severe hepatic impairment should not take Atogepant.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Atogepant in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance on the use of Atogepant with respect to immunocompromised populations.
# Administration and Monitoring
### Administration
- Take recommended dosage as prescribed by the doctor with or without food.
- Take Atogepant orally and once daily.
### Monitoring
Table 1 shows Dosage Modifications for Concomitant use of Atogepant and Specific Drugs in Patients with Renal Impairment.
# IV Compatibility
There is limited information regarding the compatibility of Atogepant and IV administrations.
# Overdosage
There is limited information regarding Atogepant overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Atogepant is a calcitonin gene-related peptide receptor antagonist.
## Structure
- Atogepant is a calcitonin gene-related peptide receptor antagonist for oral administration. It has an empirical formula of C29H23F6N5O3 and a molecular weight of 603.5 g/mol.
- The chemical name is (3'S)-N--2'-oxo-1',2',5,7- tetrahydrospiropyridine-6,3'-pyrrolopyridine]-3-carboxamide.
## Pharmacodynamics
Cardiac Electrophysiology
- Atogepant does not prolong the QT interval at 5 times the maximum recommended dosage to any clinically relevant extent.
## Pharmacokinetics
Absorption
- The absorption of Atogepant is around 1 to 2 hours with peak plasma concentrations.
- 170 mg is the max dose-proportional pharmacokinetics found in Atogepant with no accumulation.
Effect of Food
- The effect of food was not significant in patients eating a high-fat meal.
- Patients who eat a high-fat meal showed a decrease in the AUC by 18% which resulted in no changes in median time to maximum Atogepant plasma concentration.
- Patients who eat a high-fat meal showed a decrease in the Cmax by 22% which resulted in no changes in median time to maximum Atogepant plasma concentration.
Distribution
- No concentration dependency of the binding of Atogepant to the plasma protein when looking at a range of 0.1 to 10 µM.
- 4.7% is the unbound fraction of Atogepant in human plasma.
- 292 L is the mean apparent volume of distribution for Atogepant.
Elimination
Metabolism
- CYP3A4 plays a primary role in the elimination of Atogepant during metabolism.
- The primary components that make up the human plasma was M23 and Atogepant.
Excretion
- 11 hours is the elimination half-life found in Atogepant.
- 19 L/hr is the mean apparent oral clearance found in Atogepant.
- In feces, after oral administration of 50 mg 14C-Atogepant, 42% of Atogepant was found in which all was found unchanged.
- In urine, after oral administration of 50 mg 14C-Atogepant, 5% of Atogepant was found in which all was found unchanged.
Specific Population
Patients with Renal Impairment
- Renal route of elimination does not play a significant role in Atogepant clearance.
- Pharmacokinetics for patients with mild or moderate renal impairment has shown no significant differences when using Atogepant.
- 10 mg of Atogepant is the recommended dosage for patients either with severe renal impairment or end-stage renal disease.
Patients with Hepatic Impairment
- A 24% increase in total exposure of Atogepant was reported in patients with pre-existing mild hepatic impairment.
- A 15% increase in total exposure of Atogepant was reported in patients with moderate hepatic impairment.
- A 38% increase in total exposure of Atogepant was reported in patients with severe hepatic impairment.
- Patients should avoid Atogepant treatment if they have severe hepatic impairment.
Other Specific Populations
- No dosage changes in Atogepant is required based on a patients sex, race, body weight, or age.
Drug Interactions
In Vitro Studies:
Enzymes
- CYPs 3A4, 2B6, 2C8, 2D6, 1A2, 2C9, and 2C19 are not inhibited by Atogepant.
- UGT1A1 and MAO-A are not inhibited by Atogepant.
- MAO-A, CYP450s, or UGT1A1 inhibition is not clinically significant when looking at Atogepant as a perpetrator of drug-drug interactions.
- CYP2B6, CYP3A4, or CYP1A2 are not induced by Atogepant.
Transporters
- A substrate of OATP1B1, P-gp, OAT1, OATP1B3, and BCRP is Atogepant.
- Concomitant use of OATP inhibitors and Atogepant should have dosage adjustments based on clinical studies.
- Increase in Atogepant exposure is not expected with co-administration of either P-gp inhibitors or BCRP inhibitors and Atogepant.
- OCT2, MATE1, or OAT3 substrate is not Atogepant.
- Transporters such as NTCP, BSEP, BCRP, OAT1, OAT3, MRP4, P-gp, or MRP3 are not inhibited by Atogepant.
- OATP1B3, MATE1, OATP1B1, and OCT1 are weakly inhibited by Atogepant.
In Vivo Studies:
CYP3A4 Inhibitors
- AUC significantly increased by 5.5-fold in exposure of Atogepant with co-administration of Atogepant and itraconazole (a strong CYP3A4 inhibitor)
- Cmax significantly increased by 2.15-fold in exposure of Atogepant with co-administration of Atogepant and itraconazole (a strong CYP3A4 inhibitor).
- A 1.7 fold increase of Atogepant AUC occurred with co-administration of Atogepant and moderate CYP3A4 inhibitors.
- A 1.1 fold increase of Atogepant AUC occurred with co-administration of Atogepant and weak CYP3A4 inhibitors.
- Co-administration of Atogepant with either weak or moderate CYP3A4 inhibitors can create changes in Atogepant exposure which is not clinically significant.
CYP3A4 Inducers
- A 60% decrease in Atogepant AUC was reported in patients with co-administration of Atogepant and rifampin (a strong CYP3A4 inducer).
- A 30% decrease in Atogepant Cmax was reported in patients with co-administration of Atogepant and rifampin (a strong CYP3A4 inducer).
- Decrease in exposure of Atogepant may occur due to moderate inducers of CYP3A4.
- Concomitant use of Atogepant and weak inducers of CYP3A4 are not expected to have a clinically significant interaction.
BCRP/OATP/P-gp Inhibitors
- AUC of Atogepant increased 2.85-fold in patients with co-administration of Atogepant and a single dose of rifampin (an OATP inhibitor).
- Cmax of Atogepant increased 2.23-fold in patients with co-administration of Atogepant and a single dose of rifampin (an OATP inhibitor).
- AUC of Atogepant increased 26% in patients with co-administration of Atogepant and quinidine (a P-gp inhibitor). Exposure of Atogepant is not clinically significant for co-administration of Atogepant and P-gp inhibitors.
- Cmax of Atogepant increased 4% in patients with co-administration of Atogepant and quinidine (a P-gp inhibitor). Exposure of Atogepant is not clinically significant for co-administration of Atogepant and P-gp inhibitors.
- Exposure of Atogepant increased 1.2-fold with co-administration of Atogepant and BCRP inhibitors as reported in PBPK modeling. This increase in exposure of Atogepant may not be clinically significant.
Other Drug Interaction Evaluations
- Pharmacokinetic interactions were not deemed significant in either Atogepant or co-administered oral contraceptive components. Oral contraceptive components include estradiol and levonorgestrel, famotidine, esomeprazole, acetaminophen, naproxen, or sumatriptan.
## Nonclinical Toxicology
Carcinogenicity
- No signs of drug-related tumors in either mice (0, 5, 20, or 75 mg/kg/day in males; 0, 5, 30, 160 mg/kg/day in females) or rats (0, 10, 20, or 100 mg/kg in males; 0, 25, 65, or 200 mg/kg in females) that were given different dosages of Atogepant.
- At the highest dosage given in mice, plasma exposure was 8 times higher in mice compared to humans when given 60 mg/day.
- At the highest dosage given in rats, plasma exposure was 20-35 times higher in rats compared to humans when given 60 mg/day.
Mutagenicity
- Vitro and Vivo assays both showed that Atogepant was negative.
Impairment of Fertility
- No adverse reactions were seen in rats reproductive performance or fertility when given either 0, 5, 20, or 125 mg/kg/day of Atogepant.
- At the highest dosage given to rats, plasma exposure was was 15 times higher in rats compared to humans when given 60 mg/day.
# Clinical Studies
Study 1
- This study was a randomized, multicenter, double-blind, placebo-controlled study that looked into patients with at least a 1-year history of migraine with or without aura to test the efficacy of Atogepant. Study 1 was a randomized 1:1:1:1 trial where patients either received 10 mg of Atogepant, 30 mg of Atogepant, 60 mg of Atogepant, or a placebo containing no Atogepant. 910 patients made up the study where 222 patients were part of the 10 mg group, 230 patients were part of the 30 mg group, 235 patients were part of the 60 mg group, and 223 patients were part of the placebo group. The study lasted 12 weeks for all patients part of the study. The patient population was largely Caucasian (83%),included 89% women, and had a mean age of 42 years old. Acute headache treatments were allowed for all patients in this study when necessary. Medications that played a role in the CGRP pathway were not permitted. Transient ischemic attacks, myocardial infarction, or strokes found in patients within 6 months prior to screening were not part of this study.
- One goal of Study 1 is to see if there would be change during a 12 week treatment plan to the baseline in mean monthly migraine days. Another goal of this study was to see change from baseline in mean monthly acute medication use days and the change from baseline in mean monthly Activity Impairment in Migraine-Diary as well as Performance of Daily Activities domain scores. The study also looked into the change from baseline in mean monthly headache days and the proportion of patients achieving at least a 50% reduction from baseline in mean monthly migraine days. Finally, the study looked into the change from baseline at Week 12 for Migraine Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR) domain scores.
Table 1 shows the Data Reported from Patients toward Study 1's goals.
Figure 1 shows Mean Change from Baseline in Mean Monthly Migraine Days.
Figure 2 shows Distribution of Change from Baseline in Mean Monthly Migraine Days in the treatment group for this Study.
Study 2
- This study was also a randomized, multicenter, double-blind, placebo-controlled study that looked into patients with at least a 1-year history of migraine with or without aura to test the efficacy of Atogepant. Study 2 was a randomized 1:2:2:2 trial where patients either received 10 mg of Atogepant, 30 mg of Atogepant, 60 mg of Atogepant, or a placebo containing no Atogepant. 652 patients made up the study where 94 patients were part of the 10 mg group, 185 patients were part of the 30 mg group, 187 patients were part of the 60 mg group, and 186 patients were part of the placebo group. The study lasted 12 weeks for all patients part of the study. The patient population was largely Caucasian (76%),included 87% women, and had a mean age of 40 years old. Acute headache treatments were allowed for all patients in this study when necessary. Medications that played a role in the CGRP pathway were not permitted. Transient ischemic attacks, myocardial infarction, or strokes found in patients within 6 months prior to screening were not part of this study.
- The goal of Study 2 was to see change during a 12 week trial from baseline in mean monthly migraine day. 83% patients were able to complete the entirety of the 12 weeks of treatment received during this study. All 3 groups that received any Atogepant showed greater reduction in mean monthly migraine days than the placebo received.
Table 4 shows the Data Reported from Patients toward Study 2's goals.
Figure 3 shows The Mean Change from Baseline in Mean Monthly Migraine Days in this Study.
Figure 4 shows the Distribution of Change from Baseline in Mean Monthly Migraine Days in the treatment group for this Study.
# How Supplied
- 30 Tablet bottles of 10 mg of Atogepant.
- 30 Tablet bottles of 30 mg of Atogepant.
- 30 Tablet bottles of 60 mg of Atogepant.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Drug Interactions
- Some drugs that are co-administered with Atogepant may change the dosage amount of Atogepant used in patients.
- Advise patients to report any over-the-counter medications, other prescription medications, grapefruit juice, or herbal products to the prescriber before taking Atogepant.
Atogepant Package Insert:
# Precautions with Alcohol
Alcohol-Atogepant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Qulipta
# Look-Alike Drug Names
There is limited information regarding Atogepant Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Atogepant
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra
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# Overview
Atogepant is a calcitonin gene-related peptide receptor antagonist that is FDA approved for the prevention of episodic migraines. Common adverse reactions include constipation, fatigue, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Take either 10 mg, 30 mg, or 60 mg of Atogepant orally as prescribed by a doctor.
- Advise patients that Atogepant can either be taken with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Atogepant in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Atogepant in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Atogepant 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 Atogepant in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Atogepant in pediatric patients.
# Contraindications
There are no contraindications associated with Atogepant.
# Warnings
There is limited information regarding Atogepant Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials Experiance
- Because clinical trials are conducted under widely varying conditions and durations of follow up, 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. 1958 patients with migraines received Atogepant to look into the safety of Atogepant usage on patients. All patients in the study received at least one dosage of Atogepant. In the study, 839 patients were exposed to Atogepant for 6 months while 487 patients were exposed to Atogepant for 12 months.
Study 1 and 2
- 12-week, placebo-controlled clinical studies were conducted on patients to look into the adverse reactions observed in patients receiving 10 mg, 30 mg, or 60 mg of Atogepant once daily. 314 patients received 10 mg of Atogepant, 411 patients received 30 mg of Atogepant, 417 patients received 60 mg of Atogepant, and 408 patients received a placebo that had no Atogepant. The patient population was largely Caucasian (80%), and included 88% women. Constipation, nausea, and fatigue were the most common adverse reactions reported in patients (reported at least 4% and greater than placebo). Discontinuation occurred in patients that displayed nausea (0.5%), fatigue (0.5%), and constipation (0.5%).
Table 2 shows the Adverse Reactions found in patients taking Atogepant from Study 1 and Study 2.
Liver Enzyme Elevations
- 1.0% of patients taking Atogepant had a rate of transaminase elevations over 3 times the upper limit of normal. Some of these patients had asymptomatic cases which were ultimately resolved after discontinuation of Atogepant for 8 weeks.
- 1.8% of patients taking the placebo had a rate of transaminase elevations over 3 times the upper limit of normal.
- Jaundice and severe liver injury were not found in patients.
Decreases in Body Weight
- 3.8% of patients taking 10 mg of Atogepant from Study 1 and Study 2 reported a decrease in weight of at least 7%.
- 3.2% of patients taking 30 mg of Atogepant from Study 1 and Study 2 reported a decrease in weight of at least 7%.
- 4.9% of patients taking 60 mg of Atogepant from Study 1 and Study 2 reported a decrease in weight of at least 7%.
- 2.8% of patients taking the placebo from Study 1 and Study 2 reported a decrease in weight of at least 7%.
## Postmarketing Experience
There is limited information about "Postmarketing Experiance" in the drug label.
# Drug Interactions
CYP3A4 Inhibitors
- Exposure of Atogepant significantly increases with co-administration of Atogepant and itraconazole (a strong CYP3A4 inhibitor).
- 10 mg is recommended dosage of Atogepant when there is concomitant use of Atogepant with a strong CYP3A4 inhibitor.
- Concomitant use of Atogepant with either a moderate or weak CYP3A4 inhibitor requires no change in dosage of Atogepant.
CYP3A4 Inducers
- Exposure of Atogepant significantly decreases with co-administration of Atogepant and a steady state rifampin (a strong CYP3A4 inducer).
- Exposure of Atogepant significantly decreases with concomitant use of Atogepant and moderate inducers of CYP3A4.
- 30 mg or 60 mg is recommended dosage of Atogepant when there is concomitant use of Atogepant with a strong or moderate CYP3A4 inducer.
- Concomitant use of Atogepant with weak CYP3A4 inducer requires no change in dosage of Atogepant.
OATP Inhibitors
- Exposure of Atogepant significantly increases with co-administration of Atogepant and a single dose of rifampin (a OATP inhibitor).
- 10 mg or 30 mg is recommended dosage of Atogepant when there is concomitant use of Atogepant with a OATP inhibitor.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Reproduction studies done on pregnant rabbits showed a rise in adverse developmental effects such as increased incidence of fetal structural variations with increased exposure of Atogepant (0, 30, 90, or 130 mg/kg/day) during the periods of organogenesis, lactation or pregnancy. At 130 mg/kg/day, pregnant rabbits showed an increase in both skeletal variations and fetal visceral. Maternal toxicity was minimal in pregnant rabbits at 130 mg/kg/day. Adverse effects on plasma exposure and embryofetal development was 3 times for humans at the MRHD in pregnant rabbits at 90 mg/kg/day (no-effect dose). Reproduction studies done on pregnant rats showed a decrease in both skeletal ossification and fetal body weight when given either 125 and 750 mg/kg of Atogepant during the period of organogenesis. Adverse effects on plasma exposure and embryofetal development was 4 times for humans at the MRHD in pregnant rats at 15 mg/kg/day (no-effect dose). At 125 mg/kg/day, a decrease in pup body weight was found in rats during periods of gestation and lactation. At 45 mg/kg/day, the no-effect dose, adverse effects of rats on plasma exposure and pre- and postnatal development was 5 times for humans at the MRHD. Advise pregnant, female patients about the potential harms and risks in the embryo when taking Atogepant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atogepant in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Atogepant during labor and delivery.
### Nursing Mothers
No human data on the effects of Atogepant on the breastfed infant and milk production has been conducted. Studies done on lactating rats show Atogepant levels in milk is 2-fold higher than found in milk of the maternal plasma. Advise female patients about both the possible developmental and health benefits as well as potential adverse effects during nursing when taking Atogepant.
### Pediatric Use
There is no FDA guidance on the use of Atogepant with respect to pediatric populations.
### Geriatic Use
When looking at younger and elderly patients using Atogepant, no clinically significant pharmacokinetic differences were found between both groups of patients. There was not enough patients 65 years or older in age to determine if there are any response differences to Atogepant in comparison to younger patients. Decrease in frequency of decreased renal, cardiac, or hepatic function was found in elderly patients at the low end of the dosing range for Atogepant.
### Gender
There is no FDA guidance on the use of Atogepant with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Atogepant with respect to specific racial populations.
### Renal Impairment
When looking at the clearance of Atogepant, renal route of elimination plays a minor role. 10 mg of Atogepant once daily is the recommended dosage for patients with end-stage renal disease (CLcr <15 mL/min) or patients severe renal impairment (CLcr 15-29 mL/min). Patients with end-stage renal disease who are undergoing intermittent dialysis should start taking Atogepant after dialysis is completed. Patients with mild or moderate renal impairment require no change to dosage usage.
### Hepatic Impairment
Patients with mild or moderate hepatic impairment require no change to dosage usage. Patients with severe hepatic impairment should not take Atogepant.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Atogepant in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance on the use of Atogepant with respect to immunocompromised populations.
# Administration and Monitoring
### Administration
- Take recommended dosage as prescribed by the doctor with or without food.
- Take Atogepant orally and once daily.
### Monitoring
Table 1 shows Dosage Modifications for Concomitant use of Atogepant and Specific Drugs in Patients with Renal Impairment.
# IV Compatibility
There is limited information regarding the compatibility of Atogepant and IV administrations.
# Overdosage
There is limited information regarding Atogepant overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Atogepant is a calcitonin gene-related peptide receptor antagonist.
## Structure
- Atogepant is a calcitonin gene-related peptide receptor antagonist for oral administration. It has an empirical formula of C29H23F6N5O3 and a molecular weight of 603.5 g/mol.
- The chemical name is (3'S)-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2'-oxo-1',2',5,7- tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide.
## Pharmacodynamics
Cardiac Electrophysiology
- Atogepant does not prolong the QT interval at 5 times the maximum recommended dosage to any clinically relevant extent.
## Pharmacokinetics
Absorption
- The absorption of Atogepant is around 1 to 2 hours with peak plasma concentrations.
- 170 mg is the max dose-proportional pharmacokinetics found in Atogepant with no accumulation.
Effect of Food
- The effect of food was not significant in patients eating a high-fat meal.
- Patients who eat a high-fat meal showed a decrease in the AUC by 18% which resulted in no changes in median time to maximum Atogepant plasma concentration.
- Patients who eat a high-fat meal showed a decrease in the Cmax by 22% which resulted in no changes in median time to maximum Atogepant plasma concentration.
Distribution
- No concentration dependency of the binding of Atogepant to the plasma protein when looking at a range of 0.1 to 10 µM.
- 4.7% is the unbound fraction of Atogepant in human plasma.
- 292 L is the mean apparent volume of distribution for Atogepant.
Elimination
Metabolism
- CYP3A4 plays a primary role in the elimination of Atogepant during metabolism.
- The primary components that make up the human plasma was M23 and Atogepant.
Excretion
- 11 hours is the elimination half-life found in Atogepant.
- 19 L/hr is the mean apparent oral clearance found in Atogepant.
- In feces, after oral administration of 50 mg 14C-Atogepant, 42% of Atogepant was found in which all was found unchanged.
- In urine, after oral administration of 50 mg 14C-Atogepant, 5% of Atogepant was found in which all was found unchanged.
Specific Population
Patients with Renal Impairment
- Renal route of elimination does not play a significant role in Atogepant clearance.
- Pharmacokinetics for patients with mild or moderate renal impairment has shown no significant differences when using Atogepant.
- 10 mg of Atogepant is the recommended dosage for patients either with severe renal impairment or end-stage renal disease.
Patients with Hepatic Impairment
- A 24% increase in total exposure of Atogepant was reported in patients with pre-existing mild hepatic impairment.
- A 15% increase in total exposure of Atogepant was reported in patients with moderate hepatic impairment.
- A 38% increase in total exposure of Atogepant was reported in patients with severe hepatic impairment.
- Patients should avoid Atogepant treatment if they have severe hepatic impairment.
Other Specific Populations
- No dosage changes in Atogepant is required based on a patients sex, race, body weight, or age.
Drug Interactions
In Vitro Studies:
Enzymes
- CYPs 3A4, 2B6, 2C8, 2D6, 1A2, 2C9, and 2C19 are not inhibited by Atogepant.
- UGT1A1 and MAO-A are not inhibited by Atogepant.
- MAO-A, CYP450s, or UGT1A1 inhibition is not clinically significant when looking at Atogepant as a perpetrator of drug-drug interactions.
- CYP2B6, CYP3A4, or CYP1A2 are not induced by Atogepant.
Transporters
- A substrate of OATP1B1, P-gp, OAT1, OATP1B3, and BCRP is Atogepant.
- Concomitant use of OATP inhibitors and Atogepant should have dosage adjustments based on clinical studies.
- Increase in Atogepant exposure is not expected with co-administration of either P-gp inhibitors or BCRP inhibitors and Atogepant.
- OCT2, MATE1, or OAT3 substrate is not Atogepant.
- Transporters such as NTCP, BSEP, BCRP, OAT1, OAT3, MRP4, P-gp, or MRP3 are not inhibited by Atogepant.
- OATP1B3, MATE1, OATP1B1, and OCT1 are weakly inhibited by Atogepant.
In Vivo Studies:
CYP3A4 Inhibitors
- AUC significantly increased by 5.5-fold in exposure of Atogepant with co-administration of Atogepant and itraconazole (a strong CYP3A4 inhibitor)
- Cmax significantly increased by 2.15-fold in exposure of Atogepant with co-administration of Atogepant and itraconazole (a strong CYP3A4 inhibitor).
- A 1.7 fold increase of Atogepant AUC occurred with co-administration of Atogepant and moderate CYP3A4 inhibitors.
- A 1.1 fold increase of Atogepant AUC occurred with co-administration of Atogepant and weak CYP3A4 inhibitors.
- Co-administration of Atogepant with either weak or moderate CYP3A4 inhibitors can create changes in Atogepant exposure which is not clinically significant.
CYP3A4 Inducers
- A 60% decrease in Atogepant AUC was reported in patients with co-administration of Atogepant and rifampin (a strong CYP3A4 inducer).
- A 30% decrease in Atogepant Cmax was reported in patients with co-administration of Atogepant and rifampin (a strong CYP3A4 inducer).
- Decrease in exposure of Atogepant may occur due to moderate inducers of CYP3A4.
- Concomitant use of Atogepant and weak inducers of CYP3A4 are not expected to have a clinically significant interaction.
BCRP/OATP/P-gp Inhibitors
- AUC of Atogepant increased 2.85-fold in patients with co-administration of Atogepant and a single dose of rifampin (an OATP inhibitor).
- Cmax of Atogepant increased 2.23-fold in patients with co-administration of Atogepant and a single dose of rifampin (an OATP inhibitor).
- AUC of Atogepant increased 26% in patients with co-administration of Atogepant and quinidine (a P-gp inhibitor). Exposure of Atogepant is not clinically significant for co-administration of Atogepant and P-gp inhibitors.
- Cmax of Atogepant increased 4% in patients with co-administration of Atogepant and quinidine (a P-gp inhibitor). Exposure of Atogepant is not clinically significant for co-administration of Atogepant and P-gp inhibitors.
- Exposure of Atogepant increased 1.2-fold with co-administration of Atogepant and BCRP inhibitors as reported in PBPK modeling. This increase in exposure of Atogepant may not be clinically significant.
Other Drug Interaction Evaluations
- Pharmacokinetic interactions were not deemed significant in either Atogepant or co-administered oral contraceptive components. Oral contraceptive components include estradiol and levonorgestrel, famotidine, esomeprazole, acetaminophen, naproxen, or sumatriptan.
## Nonclinical Toxicology
Carcinogenicity
- No signs of drug-related tumors in either mice (0, 5, 20, or 75 mg/kg/day in males; 0, 5, 30, 160 mg/kg/day in females) or rats (0, 10, 20, or 100 mg/kg in males; 0, 25, 65, or 200 mg/kg in females) that were given different dosages of Atogepant.
- At the highest dosage given in mice, plasma exposure was 8 times higher in mice compared to humans when given 60 mg/day.
- At the highest dosage given in rats, plasma exposure was 20-35 times higher in rats compared to humans when given 60 mg/day.
Mutagenicity
- Vitro and Vivo assays both showed that Atogepant was negative.
Impairment of Fertility
- No adverse reactions were seen in rats reproductive performance or fertility when given either 0, 5, 20, or 125 mg/kg/day of Atogepant.
- At the highest dosage given to rats, plasma exposure was was 15 times higher in rats compared to humans when given 60 mg/day.
# Clinical Studies
Study 1
- This study was a randomized, multicenter, double-blind, placebo-controlled study that looked into patients with at least a 1-year history of migraine with or without aura to test the efficacy of Atogepant. Study 1 was a randomized 1:1:1:1 trial where patients either received 10 mg of Atogepant, 30 mg of Atogepant, 60 mg of Atogepant, or a placebo containing no Atogepant. 910 patients made up the study where 222 patients were part of the 10 mg group, 230 patients were part of the 30 mg group, 235 patients were part of the 60 mg group, and 223 patients were part of the placebo group. The study lasted 12 weeks for all patients part of the study. The patient population was largely Caucasian (83%),included 89% women, and had a mean age of 42 years old. Acute headache treatments were allowed for all patients in this study when necessary. Medications that played a role in the CGRP pathway were not permitted. Transient ischemic attacks, myocardial infarction, or strokes found in patients within 6 months prior to screening were not part of this study.
- One goal of Study 1 is to see if there would be change during a 12 week treatment plan to the baseline in mean monthly migraine days. Another goal of this study was to see change from baseline in mean monthly acute medication use days and the change from baseline in mean monthly Activity Impairment in Migraine-Diary as well as Performance of Daily Activities domain scores. The study also looked into the change from baseline in mean monthly headache days and the proportion of patients achieving at least a 50% reduction from baseline in mean monthly migraine days. Finally, the study looked into the change from baseline at Week 12 for Migraine Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR) domain scores.
Table 1 shows the Data Reported from Patients toward Study 1's goals.
Figure 1 shows Mean Change from Baseline in Mean Monthly Migraine Days.
Figure 2 shows Distribution of Change from Baseline in Mean Monthly Migraine Days in the treatment group for this Study.
Study 2
- This study was also a randomized, multicenter, double-blind, placebo-controlled study that looked into patients with at least a 1-year history of migraine with or without aura to test the efficacy of Atogepant. Study 2 was a randomized 1:2:2:2 trial where patients either received 10 mg of Atogepant, 30 mg of Atogepant, 60 mg of Atogepant, or a placebo containing no Atogepant. 652 patients made up the study where 94 patients were part of the 10 mg group, 185 patients were part of the 30 mg group, 187 patients were part of the 60 mg group, and 186 patients were part of the placebo group. The study lasted 12 weeks for all patients part of the study. The patient population was largely Caucasian (76%),included 87% women, and had a mean age of 40 years old. Acute headache treatments were allowed for all patients in this study when necessary. Medications that played a role in the CGRP pathway were not permitted. Transient ischemic attacks, myocardial infarction, or strokes found in patients within 6 months prior to screening were not part of this study.
- The goal of Study 2 was to see change during a 12 week trial from baseline in mean monthly migraine day. 83% patients were able to complete the entirety of the 12 weeks of treatment received during this study. All 3 groups that received any Atogepant showed greater reduction in mean monthly migraine days than the placebo received.
Table 4 shows the Data Reported from Patients toward Study 2's goals.
Figure 3 shows The Mean Change from Baseline in Mean Monthly Migraine Days in this Study.
Figure 4 shows the Distribution of Change from Baseline in Mean Monthly Migraine Days in the treatment group for this Study.
# How Supplied
- 30 Tablet bottles of 10 mg of Atogepant.
- 30 Tablet bottles of 30 mg of Atogepant.
- 30 Tablet bottles of 60 mg of Atogepant.
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Drug Interactions
- Some drugs that are co-administered with Atogepant may change the dosage amount of Atogepant used in patients.
- Advise patients to report any over-the-counter medications, other prescription medications, grapefruit juice, or herbal products to the prescriber before taking Atogepant.
Atogepant Package Insert:
# Precautions with Alcohol
Alcohol-Atogepant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Qulipta
# Look-Alike Drug Names
There is limited information regarding Atogepant Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Atogepant | |
f6e02a1efbb8294c17bba7d6a33a77f3cb5002df | wikidoc | Atomidine | Atomidine
Atomidine is a yellow-gold liquid that provides iodine supplementation in a non-poisonous form through a special process where iodine is compounded in a solution that liberates the element in an atomic or nascent state. It is readily utilized by the human body. Edgar Cayce called it “atomic iodine” or Atomidine and said it is more active and less toxic and less irritating to the system than molecular iodine. Thus Atomidine is more suitable for internal use in small quantities in addition to its effectiveness as an external antiseptic.
What is the nature of the process that transforms ordinary iodine into such a valuable, non-toxic state? Basically a solution of iodine trichloride is treated with several herbal compounds. The result is Atomidine, which contains approximately 1/100 grain of iodine in each drop of the solution, supplying in a single drop approximately four times the minimum daily requirement of iodine. The Atomidine that Edgar Cayce recommended in over 2,000 readings was not “electrified” although the man that brought Atomidine to Cayce’s awareness, Dr. Sunker Bisey, did experiment with an electrified solution.
Atomidine existed in various forms and had been called a variety of names, including Beslin and Alphaiodine, since the beginning of the 20th century. Prior to 1910, its forerunner appeared as a crude, thick, black liquid supposedly developed by an East Indian shaman, and was used as a household remedy for fevers. In 1910 it was used as a last resort to treat Dr. Bisey who was dying of a severe malaria infection. Dr. Bisey made a miraculous recovery. As a Hindu scientist, chemist and consulting engineer and friend of Mahatma Gandhi, Dr. Bisey was so impressed with the potential of the iodine compound that he subjected it to thorough chemical analysis and research. The result was “Beslin” that stood for “best liquid iodine”, which was marketed in England in 1913.
Dr. Bisey settled in the United States in 1917, establishing the American Beslin Corporation in Delaware. In 1926 Laboratoire Durveaux purchased the Beslin Corporation. The New York-based company engaged in clinical studies and collection of medical data and testimonials on Beslin. The use of Beslin in both liquid and ointment form was expanded to the fields of dentistry and veterinary medicine.
In 1931 Dr Bisey, then 64 years old, traveled to Virginia Beach, Virginia, to consult with Edgar Cayce, the famous “Sleeping Prophet,” regarding the preparation and distribution of Atomidine, as his product would come to be called when Dr. Bisey formed his own Atomidine Company in 1932. Cayce’s psychic readings, given while he was in a self-induced trance state, had long indicated that iodine would be very beneficial to the system if its poisonous qualities could be removed. Prior to this, experiments in rendering iodine non-poisonous by people who had readings from Edgar Cayce had not been successful. The processes Cayce outlined in the readings proved to be too expensive.
In Dr. Bisey’s readings, Cayce found the Atomidine formula satisfactory. At that time Cayce also suggested a modification in the preparation procedure that involved treating the iodine by a specific electrical charging process that Cayce outlined in detail. Dr. Bisey succeeded in completing this process experimentally; however “electrified Atomidine” was never marketed by Dr. Bisey, and was never part of the Atomidine formula. Dr. Bisey had several other readings from Cayce dealing with distribution of the Atomidine.
Dr. Bisey died in 1935 and his son, Harold, ran the company until 1948, with Schieffelin and Company of New York manufacturing the Atomidine. In 1948 the Atomidine Company was turned over to Dr. Bisey’s son-in-law of Mt. Vernon, New York who felt the iodine supplement was extremely valuable, even though sales were falling off. He continued to insure Atomidine’s availability until 1974 when he sold the formula to The Heritage Store at of Virginia Beach, Virginia. Heritage has been providing Cayce products since 1969 and continues to produce the original Atomidine to this day.
Similar products are made in different ways by different manufacturers, each with different interpretations of the Cayce readings. For example, two companies which make an Iodine product are Baar under the name Atomic Iodine and Cayce Concepts. under the name Detoxified Iodine. The Baar product is 1% iodine-trichloride dissolved in water; while the Cayce Concepts product is 1% iodine dissolved in alcohol. Neither is an exact formulation of the product recommended in the Edgar Cayce readings, although both have been electrified.
The Cayce reading for 358-1, direction to Sunkar A. Bisey has been attempted and verified by John Brookshire. Magnascent.com The two readings 358-1 and 358-2 produce two very different products. 358-2 is a weaker effect, it energizes the molecule of iodine. 358-1 breaks the diatomic bond producing iodine in the Atomic State, nascent iodine. An electromagnetic field is used to produces nascent iodine, in a consumable form. It is currently being made in a tincture of iodine, not the saline solution of Bisey, but the nascent iodine is that described by Schieffelin and Company. A US Patent is pending for a consumable form of nascent iodine. The original product of Bisey could be taken 100 drops in a day in the 1930's. It was extremily safe and useful according Schieffelin and Company documents. Iodine trichloride is recommended for external use only by Baar.
Critics of Cayce claim that the chemistry behind the creation of Atomidine, and the alleged health benefits, are pseudoscience. | Atomidine
Atomidine is a yellow-gold liquid that provides iodine supplementation in a non-poisonous form through a special process where iodine is compounded in a solution that liberates the element in an atomic or nascent state. It is readily utilized by the human body. Edgar Cayce called it “atomic iodine” or Atomidine and said it is more active and less toxic and less irritating to the system than molecular iodine. Thus Atomidine is more suitable for internal use in small quantities in addition to its effectiveness as an external antiseptic.
What is the nature of the process that transforms ordinary iodine into such a valuable, non-toxic state? Basically a solution of iodine trichloride is treated with several herbal compounds. The result is Atomidine, which contains approximately 1/100 grain of iodine in each drop of the solution, supplying in a single drop approximately four times the minimum daily requirement of iodine. The Atomidine that Edgar Cayce recommended in over 2,000 readings was not “electrified” although the man that brought Atomidine to Cayce’s awareness, Dr. Sunker Bisey, did experiment with an electrified solution.
Atomidine existed in various forms and had been called a variety of names, including Beslin and Alphaiodine, since the beginning of the 20th century. Prior to 1910, its forerunner appeared as a crude, thick, black liquid supposedly developed by an East Indian shaman, and was used as a household remedy for fevers. In 1910 it was used as a last resort to treat Dr. Bisey who was dying of a severe malaria infection. Dr. Bisey made a miraculous recovery. As a Hindu scientist, chemist and consulting engineer and friend of Mahatma Gandhi, Dr. Bisey was so impressed with the potential of the iodine compound that he subjected it to thorough chemical analysis and research. The result was “Beslin” that stood for “best liquid iodine”, which was marketed in England in 1913.
Dr. Bisey settled in the United States in 1917, establishing the American Beslin Corporation in Delaware. In 1926 Laboratoire Durveaux purchased the Beslin Corporation. The New York-based company engaged in clinical studies and collection of medical data and testimonials on Beslin. The use of Beslin in both liquid and ointment form was expanded to the fields of dentistry and veterinary medicine.
In 1931 Dr Bisey, then 64 years old, traveled to Virginia Beach, Virginia, to consult with Edgar Cayce, the famous “Sleeping Prophet,” regarding the preparation and distribution of Atomidine, as his product would come to be called when Dr. Bisey formed his own Atomidine Company in 1932. Cayce’s psychic readings, given while he was in a self-induced trance state, had long indicated that iodine would be very beneficial to the system if its poisonous qualities could be removed. Prior to this, experiments in rendering iodine non-poisonous by people who had readings from Edgar Cayce had not been successful. The processes Cayce outlined in the readings proved to be too expensive.
In Dr. Bisey’s readings, Cayce found the Atomidine formula satisfactory. At that time Cayce also suggested a modification in the preparation procedure that involved treating the iodine by a specific electrical charging process that Cayce outlined in detail. Dr. Bisey succeeded in completing this process experimentally; however “electrified Atomidine” was never marketed by Dr. Bisey, and was never part of the Atomidine formula. Dr. Bisey had several other readings from Cayce dealing with distribution of the Atomidine.
Dr. Bisey died in 1935 and his son, Harold, ran the company until 1948, with Schieffelin and Company of New York manufacturing the Atomidine. In 1948 the Atomidine Company was turned over to Dr. Bisey’s son-in-law of Mt. Vernon, New York who felt the iodine supplement was extremely valuable, even though sales were falling off. He continued to insure Atomidine’s availability until 1974 when he sold the formula to The Heritage Store [1] at of Virginia Beach, Virginia. Heritage has been providing Cayce products since 1969 and continues to produce the original Atomidine to this day.
Similar products are made in different ways by different manufacturers, each with different interpretations of the Cayce readings. For example, two companies which make an Iodine product are Baar[2] under the name Atomic Iodine and Cayce Concepts.[3] under the name Detoxified Iodine. The Baar product is 1% iodine-trichloride dissolved in water; while the Cayce Concepts product is 1% iodine dissolved in alcohol. Neither is an exact formulation of the product recommended in the Edgar Cayce readings, although both have been electrified.
The Cayce reading for 358-1, direction to Sunkar A. Bisey has been attempted and verified by John Brookshire. Magnascent.com The two readings 358-1 and 358-2 produce two very different products. 358-2 is a weaker effect, it energizes the molecule of iodine. 358-1 breaks the diatomic bond producing iodine in the Atomic State, nascent iodine. An electromagnetic field is used to produces nascent iodine, in a consumable form. It is currently being made in a tincture of iodine, not the saline solution of Bisey, but the nascent iodine is that described by Schieffelin and Company. A US Patent is pending for a consumable form of nascent iodine. The original product of Bisey could be taken 100 drops in a day in the 1930's. It was extremily safe and useful according Schieffelin and Company documents. Iodine trichloride is recommended for external use only by Baar.
Critics of Cayce claim that the chemistry behind the creation of Atomidine, and the alleged health benefits, are pseudoscience.[4] | https://www.wikidoc.org/index.php/Atomidine | |
455ee1970b456995fa987cbed3791cec30239863 | wikidoc | Atrial MI | Atrial MI
# Overview
In approximately 10% of patients with acute myocardial infarction involving the ventricular territory, an atrial infarct also occurs. An atrial infarct can manifest itself in atrial rhytm disturbances such as atrial fibrillation. Because the atria may be of minor consequences hemodynamically, an atrial infarct may be missed.
On the ECG, an atrial infarct manifests by rhythm changes and/or change of the P-Ta segment (sometimes called PTA (P - atriale T) segment or PR or PQ or PTp (P - T wave of P wave) segment). This is the part between the end of the P wave and the Q. The ST segment indicates an infarct in the ventricle, the P-Ta segment indicates an infarct in the atria.
Diagnostic criteria for an atrial infarct include:
- P-Ta elevation >0.5mm in V5 and V6 with reciprocal depression in V1 and V2
- P-Ta elevation >0.5mm in I and depression in II and III
- >1.5mm P-Ta depression in precordial leads
- >1.2mm P-Ta depression in I,II or III in combination with atrial arrhytmias
Several diagnostic criteria are in use, and this is just an example of one. An important differential diagnosis of PTa segment elevation or depression is pericarditis. | Atrial MI
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
In approximately 10% of patients with acute myocardial infarction involving the ventricular territory, an atrial infarct also occurs. An atrial infarct can manifest itself in atrial rhytm disturbances such as atrial fibrillation. Because the atria may be of minor consequences hemodynamically, an atrial infarct may be missed.
On the ECG, an atrial infarct manifests by rhythm changes and/or change of the P-Ta segment (sometimes called PTA (P - atriale T) segment or PR or PQ or PTp (P - T wave of P wave) segment). This is the part between the end of the P wave and the Q. The ST segment indicates an infarct in the ventricle, the P-Ta segment indicates an infarct in the atria.
Diagnostic criteria for an atrial infarct include:
- P-Ta elevation >0.5mm in V5 and V6 with reciprocal depression in V1 and V2
- P-Ta elevation >0.5mm in I and depression in II and III
- >1.5mm P-Ta depression in precordial leads
- >1.2mm P-Ta depression in I,II or III in combination with atrial arrhytmias
Several diagnostic criteria are in use, and this is just an example of one. An important differential diagnosis of PTa segment elevation or depression is pericarditis.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Atrial_MI | |
5382e854f1677ef22b2504cb44a1eebec791147c | wikidoc | Audiology | Audiology
Audiology (from Latin: audire, "to hear"; and from Greek: and λόγος, logos, "knowledge") is the branch of Science that studies hearing, balance and related disorders. Its practitioners, who treat those with hearing loss and proactively prevent related damage are audiologists. Employing various testing strategies (e.g. hearing tests, otoacoustic emission measurements, videonystagmography, and electrophysiologic tests), audiology aims to determine whether someone can hear within the normal range, and if not, which portions of hearing (high, middle, or low frequencies) are affected and to what degree. If an audiologist determines that a hearing loss or vestibular abnormality is present he or she will provide recommendations to a patient as to what options (e.g. hearing aids, cochlear implants, surgery, appropriate medical referrals) may be of assistance.
In addition to testing hearing, audiologists can also work with a wide range of clientele in rehabilitation (cochlear implants and/or hearing aids), paediatric populations and assessment of the vestibular system.
# History
The use of the terms "Audiology" and "Audiologist" in publications has been traced back only as far as 1946. The original creator of the term remains unknown, but Berger identified possible originators as Mayer BA Schier, Willard B Hargrave, Stanley Nowak, Norton Canfield, or Raymond Carhart. The first US university course for audiologists was offered by Carhart at Northwestern University, in 1946.
Audiology was born to address the hearing damage from World War II veterans.
# Audiologist
Audiologists are licensed professionals who hold a masters or doctoral degree (Doctor of Audiology (Au.D.) or Ph.D. in the hearing sciences) as well as state licensure and national board certification. Presently, a doctoral degree is the entry level degree to become to be a practising Audiologist. Audiologists who earned the Master's degree prior to the change in licensing standards are not required to earn a doctorate to continue practising in the field. Currently, audiologists have a clinical/educational background that emphasizes diagnostic testing, amplification technology, hearing science, and assistive device fitting. Audiologists may also specialize in pediatric diagnostics/amplification, cochlear implants, educational audiology, intraoperative neurophysiological monitoring, vestibular and balance issues, and/or industrial hearing conservation. Audiologists can also evaluate and fit patients for hearing aids as treatment for various forms of hearing loss.
Audiologists are also involved in the prevention of hearing loss and other communication disorders. Hearing Conservation programs in industry and government strive to prevent noise induced hearing loss through education and Audiologist intervention. Audiologists are often in charge of Newborn Hearing Screening programs designed to identify hearing loss within the first 3 months of life.
## United States
In the United States, 50 states license Audiologists and they all require a graduate clinical degree. Starting in 2007, the Doctor of Audiology (Au.D.) will be the entry level degree for clinical practice. Other requirements include passing a national exam offered by Praxis Series of the Educational Testing Service, at least 375 hours of supervised clinical experience, and a full year mentored fellowship or supervised externship. All states have continuing education renewal requirements that must be met to stay licensed. Audiologists can also earn a certificate from the American Speech-Language-Hearing Association or seek board certification through the American Board of Audiology. Most states also require a Hearing Aid Dispenser License to enable the Audiologist to dispense hearing aids, though legislation is currently underway in many states which would not require this extra step. It would allow Audiologists to dispense under their Audiology license. Currently there are 67 AuD. or programs in united states:
Distance Au.D. Programs:
- Arizona School of Health Sciences
- University of Florida
Residential Au.D. Programs:
## Australia
In Australia Audiologists must hold a Masters in Audiology, alternatively Bachelor's degree from overseas certified by the vetasses. As per the law of the land currently to practise as an Audiologist one doesn't need to be a member of any professional body. But to dispense hearing aids to eligible pensioners and eligible war veterans one must have 2 years clinical experience and be registered with an approved body such as Audiology Australia or the Australian College of Audiology (ACAud).
In India, an Audiologist must hold a Bachelors/Masters Degree in Audiology and be registered with an approved body such as Indian Speech and Hearing Association (ISHA)or Rehabilitaion Council of India (RCI).
Hearing aid dispensers (Hearing Instrument Specialists, Hearing Aid Dealers) are not to be confused with Audiologists. Hearing aid dispensers must pass a state licensing written and practical examination in fitting hearing aids. A Board Certified dispenser must have two years experience and pass a National Competency Examination. However, no college education is required. Hearing aid dispensers work on a commission. Prior to 1988, hearing instrument dispensers fit patients referred to them by Audiologists and physicians who wrote a prescriptions for hearing aids.
# United Kingdom
There are currently three routes to becoming a Registered Audiologist:
· BSc in Audiology
· MSc in Audiology
· Fast track conversion Diploma for those with a BSc in other relevant science subject, available at Southampton, Manchester, UCL, London and Edinburgh
There are 9 United Kingdom educational institutions offering degrees in Audiology:
- University of Aston
- University of Bristol
- De Montfort University
- University of Leeds
- University of Manchester
- Queen Margaret University
- University of Southampton
- University of Wales Swansea
- University College London
Post Graduate Diploma
Entry qualification:- A 2.1 undergraduate degree in a relevant Science degree or previous experience as an audiologist through the old BAAT training route.
Structure of the course:- One-year university based course followed by a one-year full-time salaried supervised clinical practice placement, working under the guidance of a qualified audiologist. A national training scheme and logbook is a requirement and requires competence-based assessments to be undertaken. The in-service training period is currently under review and may get extend to 3 years.
MSc in Audiology
Entry qualifications:- Entry requirements are a good relevant science degree , preferable some knowledge of physics or behavioural science and a proven interest or experience in Audiology. Excellent interpersonal and communication skills and an interest in direct patient care are also essential.
Training posts are via the NHS Regional Scheme or British Academy of Audiology Some NHS Audiology Departments employ trainee clinical scientist directly.
Structure of the Course
One year full-time MSc in Audiology can be undertaken at Southampton University, University College London or Manchester University.
This is then followed by 18-24 months supervised in-service clinical placement culminating in a written, practical and oral examination to obtain the BAA Certificate of Audiological Competency. Successful completion of the M.Sc practical training also includes a portfolio of clinical training, research and personal development leading to the Association of Clinical Scientists Certificate of Attainment required for Registration to the Health Professions Council.
Postgraduate diploma students and MSc students follow the same academic course, the only difference being that the MSc students take an extra three months to complete an additional dissertation. The CAC scheme (only available to MSc students) resulting in "clinical scientist" status is likely to be replaced by the diploma/BSc in-service training year and an additional higher training certificate available to all students.
# India
Audiology and Speech Pathology in India was started by a group of dedicated professionals like Dr. N Rathna, Dr. S Nikam, Mr Ramesh Oza and Dr. Vijay Shah. The first Audiology & Speech Language Therapy program was started in 1966 at T.N.Medical College and BYL Nair Ch.Hospital in Mumbai. In the same year, Government of India established All India Institute of Speech and Hearing (www.aiishmsyore.com) which has become the country's leading Institute in the field of communication disorders. There are currently 20 Universities in India which provide Speech Pathology and Audiology programs. These programs are accredited by Rehabilitation council of India. Majority of these institutes provide excellent multidisciplinary clinical setup for persons with communication disorders. For a complete list of Institutes visit the website of Indo-International Society of Communication and Hearing Sciences (IISCHS www.iischs.com).
To practice audiology, professionals need to have either Bachelors/Masters degree in Audiology and be registered with Indian Speech and Hearing Association (ISHA) or Rehabilitation Council of India (RCI). There are around 100 private clinics in India providing speech and hearing services. Apart from these clinics, Widex - one of the most innovative producers of hearing aids have opened state of the art Senso Hearing Centres in major cities in India.
Internationally recognised degree, unique multilingual/multicultural background, excellent communication in English has increased the global demand of Indian Audiologists considering the shortage of these graduates especially in western countries. There is a rapidly growing community of qualified and skilled Indian Speech-Language Pathologists and Audiologists across the world (mainly in North America, Singapore and Australia). Indo-International Society of Communication and Hearing Sciences (IISCHS www.iischs.com) provides a web-based platform for this rapidly growing Indian community. This Society was founded by Sharad Govil & Arvind K.N in 2003.
# Malaysia
There are only 3 Malaysian educational institutions offering degrees in Audiology:
- University Kebangsaan Malaysia
- University Science Malaysia
- International Islamic University Malaysia | Audiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Audiology (from Latin: audire, "to hear"; and from Greek: and λόγος, logos, "knowledge") is the branch of Science that studies hearing, balance and related disorders. Its practitioners, who treat those with hearing loss and proactively prevent related damage are audiologists. Employing various testing strategies (e.g. hearing tests, otoacoustic emission measurements, videonystagmography, and electrophysiologic tests), audiology aims to determine whether someone can hear within the normal range, and if not, which portions of hearing (high, middle, or low frequencies) are affected and to what degree. If an audiologist determines that a hearing loss or vestibular abnormality is present he or she will provide recommendations to a patient as to what options (e.g. hearing aids, cochlear implants, surgery, appropriate medical referrals) may be of assistance.
In addition to testing hearing, audiologists can also work with a wide range of clientele in rehabilitation (cochlear implants and/or hearing aids), paediatric populations and assessment of the vestibular system.
# History
The use of the terms "Audiology" and "Audiologist" in publications has been traced back only as far as 1946. The original creator of the term remains unknown, but Berger[1] identified possible originators as Mayer BA Schier, Willard B Hargrave, Stanley Nowak, Norton Canfield, or Raymond Carhart. The first US university course for audiologists was offered by Carhart at Northwestern University, in 1946.[2]
Audiology was born to address the hearing damage from World War II veterans.
# Audiologist
Audiologists are licensed professionals who hold a masters or doctoral degree (Doctor of Audiology (Au.D.) or Ph.D. in the hearing sciences) as well as state licensure and national board certification. Presently, a doctoral degree is the entry level degree to become to be a practising Audiologist. Audiologists who earned the Master's degree prior to the change in licensing standards are not required to earn a doctorate to continue practising in the field. Currently, audiologists have a clinical/educational background that emphasizes diagnostic testing, amplification technology, hearing science, and assistive device fitting. Audiologists may also specialize in pediatric diagnostics/amplification, cochlear implants, educational audiology, intraoperative neurophysiological monitoring, vestibular and balance issues, and/or industrial hearing conservation. Audiologists can also evaluate and fit patients for hearing aids as treatment for various forms of hearing loss.
Audiologists are also involved in the prevention of hearing loss and other communication disorders. Hearing Conservation programs in industry and government strive to prevent noise induced hearing loss through education and Audiologist intervention. Audiologists are often in charge of Newborn Hearing Screening programs designed to identify hearing loss within the first 3 months of life.
## United States
In the United States, 50 states license Audiologists and they all require a graduate clinical degree. Starting in 2007, the Doctor of Audiology (Au.D.) will be the entry level degree for clinical practice. Other requirements include passing a national exam offered by Praxis Series of the Educational Testing Service, at least 375 hours of supervised clinical experience, and a full year mentored fellowship or supervised externship. All states have continuing education renewal requirements that must be met to stay licensed. Audiologists can also earn a certificate from the American Speech-Language-Hearing Association or seek board certification through the American Board of Audiology. Most states also require a Hearing Aid Dispenser License to enable the Audiologist to dispense hearing aids, though legislation is currently underway in many states which would not require this extra step. It would allow Audiologists to dispense under their Audiology license. Currently there are 67 AuD. or programs in united states:
Distance Au.D. Programs:
- Arizona School of Health Sciences
- University of Florida
Residential Au.D. Programs:
## Australia
In Australia Audiologists must hold a Masters in Audiology, alternatively Bachelor's degree from overseas certified by the vetasses. As per the law of the land currently to practise as an Audiologist one doesn't need to be a member of any professional body. But to dispense hearing aids to eligible pensioners and eligible war veterans one must have 2 years clinical experience and be registered with an approved body such as Audiology Australia or the Australian College of Audiology (ACAud).
In India, an Audiologist must hold a Bachelors/Masters Degree in Audiology and be registered with an approved body such as Indian Speech and Hearing Association (ISHA)or Rehabilitaion Council of India (RCI).
Hearing aid dispensers (Hearing Instrument Specialists, Hearing Aid Dealers) are not to be confused with Audiologists. Hearing aid dispensers must pass a state licensing written and practical examination in fitting hearing aids. A Board Certified dispenser must have two years experience and pass a National Competency Examination. However, no college education is required. Hearing aid dispensers work on a commission. Prior to 1988, hearing instrument dispensers fit patients referred to them by Audiologists and physicians who wrote a prescriptions for hearing aids.
# United Kingdom
There are currently three routes to becoming a Registered Audiologist:
· BSc in Audiology
· MSc in Audiology
· Fast track conversion Diploma for those with a BSc in other relevant science subject, available at Southampton, Manchester, UCL, London and Edinburgh
There are 9 United Kingdom educational institutions offering degrees in Audiology:
- University of Aston [2]
- University of Bristol [3]
- De Montfort University [4]
- University of Leeds [5]
- University of Manchester [6]
- Queen Margaret University [7]
- University of Southampton [8]
- University of Wales Swansea [9]
- University College London [10]
Post Graduate Diploma
Entry qualification:- A 2.1 undergraduate degree in a relevant Science degree or previous experience as an audiologist through the old BAAT training route.
Structure of the course:- One-year university based course followed by a one-year full-time salaried supervised clinical practice placement, working under the guidance of a qualified audiologist. A national training scheme and logbook is a requirement and requires competence-based assessments to be undertaken. The in-service training period is currently under review and may get extend to 3 years.
MSc in Audiology
Entry qualifications:- Entry requirements are a good relevant science degree [usually 2:1], preferable some knowledge of physics or behavioural science and a proven interest or experience in Audiology. Excellent interpersonal and communication skills and an interest in direct patient care are also essential.
Training posts are via the NHS Regional Scheme [11] or British Academy of Audiology [12] Some NHS Audiology Departments employ trainee clinical scientist directly.
Structure of the Course
One year full-time MSc in Audiology can be undertaken at Southampton University, University College London or Manchester University.
This is then followed by 18-24 months supervised in-service clinical placement culminating in a written, practical and oral examination to obtain the BAA Certificate of Audiological Competency. Successful completion of the M.Sc practical training also includes a portfolio of clinical training, research and personal development leading to the Association of Clinical Scientists Certificate of Attainment required for Registration to the Health Professions Council.
Postgraduate diploma students and MSc students follow the same academic course, the only difference being that the MSc students take an extra three months to complete an additional dissertation. The CAC scheme (only available to MSc students) resulting in "clinical scientist" status is likely to be replaced by the diploma/BSc in-service training year and an additional higher training certificate available to all students.
# India
Audiology and Speech Pathology in India was started by a group of dedicated professionals like Dr. N Rathna, Dr. S Nikam, Mr Ramesh Oza and Dr. Vijay Shah. The first Audiology & Speech Language Therapy program was started in 1966 at T.N.Medical College and BYL Nair Ch.Hospital in Mumbai. In the same year, Government of India established All India Institute of Speech and Hearing (www.aiishmsyore.com) which has become the country's leading Institute in the field of communication disorders. There are currently 20 Universities in India which provide Speech Pathology and Audiology programs. These programs are accredited by Rehabilitation council of India. Majority of these institutes provide excellent multidisciplinary clinical setup for persons with communication disorders. For a complete list of Institutes visit the website of Indo-International Society of Communication and Hearing Sciences (IISCHS www.iischs.com).
To practice audiology, professionals need to have either Bachelors/Masters degree in Audiology and be registered with Indian Speech and Hearing Association (ISHA) or Rehabilitation Council of India (RCI). There are around 100 private clinics in India providing speech and hearing services. Apart from these clinics, Widex - one of the most innovative producers of hearing aids have opened state of the art Senso Hearing Centres in major cities in India.
Internationally recognised degree, unique multilingual/multicultural background, excellent communication in English has increased the global demand of Indian Audiologists considering the shortage of these graduates especially in western countries. There is a rapidly growing community of qualified and skilled Indian Speech-Language Pathologists and Audiologists across the world (mainly in North America, Singapore and Australia). Indo-International Society of Communication and Hearing Sciences (IISCHS www.iischs.com) provides a web-based platform for this rapidly growing Indian community. This Society was founded by Sharad Govil & Arvind K.N in 2003.
# Malaysia
There are only 3 Malaysian educational institutions offering degrees in Audiology:
- University Kebangsaan Malaysia
- University Science Malaysia
- International Islamic University Malaysia | https://www.wikidoc.org/index.php/Audiology | |
f52e960c84649020ce9b79313336640d8ccb4afd | wikidoc | Aura-Soma | Aura-Soma
Aura-Soma is a method of chromotherapy and a divination system based on colour, devised by British pharmacist and chiropodist Vicky Wall. It shares similarities with other forms of divination such as tarot, the I Ching and the Kabbalah, and many of the concepts from Jungian psychology and other studies of mythology have also been related to the system. While not claiming healing in the sense of Acupuncture or other remedial systems, practitioners regard it as able to help identify the answer to what lies behind disease (referred to as dis-ease).
The central idea of Aura-Soma is that colour is a unifying universal language which relates to all other theologies and schools of psychology. It is part of the underlying order of the universe. Colour is a means by which connections can be made, with each colour relating to a different aspect of life. Practitioners attach great spiritual significance and psychological connotations to colour combinations chosen by an individual.
In traditional systems, such as the Chakras, colour is related to the different parts of the body and their underlying physical structure. Each of these physical attributes in turn is related to emotional, mental and spiritual states.
Colour combinations are represented by two-tone bottles known as equilibrium bottles. These bottles are made from two colours of organic oil and water (usually two different colours, but some bottles are monotone). Each bottle represents a series of symbolic, spiritual, mental, emotional and physical concepts defined by its two colours. The bottles are numbered from 0 to 105 (currently, more are being regularly added), and each has a name. The bottles are named after associated series of figures, such as the major arcana of the Tarot and the Seven Archangels.
# History
The first Aura-Soma Equilibrium bottle was brought forth by Vicky Wall in 1983. She was 66 years old at the time and had become clinically blind. Wall claimed she could see auras around people, plants and animals and also that she had retained this ability even after the loss of her vision. Ms. Wall developed the coloured bottle system and asserted that the selection by the user may reveal their gifts, challenges and opportunities.
Over time the colour care system has come to include pomanders, oils, essences and sprays, all colour-related. These items are not held to have strict medical use, they are symbolic in nature. The theory being that if the practitioner can draw the state of mind of a client out through colour, then the application of appropriate colour in the life of the client can also have a restorative or healing psychosomatic effect.
Aura-Soma is looked upon by its practitioners as a constantly developing system. New bottles and methods are added to the system on an infrequent basis. In addition it is thought to reflect what is emerging for the collective as well as individuals.
After the initial start in 1983, Aura-Soma spread from the UK, becoming established in Denmark, Germany, the United States, Australia, Italy, Ireland, Japan, Korea, China and South America.
# Practice
The standard divination process for Aura-Soma is based on the equilibrium bottles. The user picks four bottles one after another while faced with the full selection to choose from, and the practitioner then interprets the meaning of their selection. The order in which they are chosen is important:
- The first bottle represents the self, or a description of the user's current state of being
- The second represents the user's hidden gifts as well as their biggest obstacles
- The third represents their present energy, which gives a method which can be used to overcome their obstacles
- The fourth represents the energy that they are drawing toward them; the future that they are trying to create for themselves though overcoming the obstacles.
Afterwards, the user picks one of the four bottles which they use as an ointment, by shaking the bottle and applying the fusion of the oil and water to the parts of their body whose Chakras correspond to the colours of the bottle. This aids them with one area of disease which will help them achieve the outcome of the four bottle spread. Since much emphasis is on the obstacle, the second bottle is usually chosen.
While sounding superficially like the processes of other systems like Tarot, practitioners of Aura-Soma do not regard it as fortune-telling, but instead to be more like a counselling method, similar to the Lüscher color test, Rorschach inkblot test and other similar psychological methods of accessing the unconscious mind as separate to the conscious mind. Aura-Soma is not, however, a science or branch of psychology.
# Practitioners and Teachers
There is an Aura-Soma Code of Practice that is regulated by the Art & Science International Academy of Colour Therapeutics (ASIACT). ASIACT maintains a practitioner register and issues certificates to those who work according to this code. Each certificate is valid for two years. A current certificate shows that the practitioner is continuing to be updated in the Aura-Soma system and works according to the practices set out by the Academy.
Practitioner training currently comprises 4 levels. Levels 1, 2 and 3 each involve attendance at an accredited course. Each level involves broader and more detailed instruction in Aura-Soma. Level 4 involves the completion of a piece of original research on colour, together with presentation of a required number of case records and researched responses to colour related questions. A practitioner's level of training is featured on their certificate.
Students may become practitioners at any time after the completion of Level 2, regulated by laid down guidelines. At Level 4 the practitioner has demonstrated experience of working with Aura-Soma and understanding of the principles of Aura-Soma and may develop a full public practice. Practitioners and teachers can be found at the ASIACT website.
The bottle system is now governed by a central company (called Aura-Soma Products LTD) and the term 'Aura-Soma' is a registered trademark of that company. It is currently managed by Mike Booth. | Aura-Soma
Aura-Soma is a method of chromotherapy and a divination system based on colour, devised by British pharmacist and chiropodist Vicky Wall. It shares similarities with other forms of divination such as tarot, the I Ching and the Kabbalah, and many of the concepts from Jungian psychology and other studies of mythology have also been related to the system. While not claiming healing in the sense of Acupuncture or other remedial systems, practitioners regard it as able to help identify the answer to what lies behind disease (referred to as dis-ease).
The central idea of Aura-Soma is that colour is a unifying universal language which relates to all other theologies and schools of psychology.[1] It is part of the underlying order of the universe. Colour is a means by which connections can be made, with each colour relating to a different aspect of life. Practitioners attach great spiritual significance and psychological connotations to colour combinations chosen by an individual.
In traditional systems, such as the Chakras, colour is related to the different parts of the body and their underlying physical structure. Each of these physical attributes in turn is related to emotional, mental and spiritual states.
Colour combinations are represented by two-tone bottles known as equilibrium bottles. These bottles are made from two colours of organic oil and water (usually two different colours, but some bottles are monotone).[2] Each bottle represents a series of symbolic, spiritual, mental, emotional and physical concepts defined by its two colours. The bottles are numbered from 0 to 105 (currently, more are being regularly added), and each has a name. The bottles are named after associated series of figures, such as the major arcana of the Tarot and the Seven Archangels.
# History
The first Aura-Soma Equilibrium bottle was brought forth by Vicky Wall in 1983. She was 66 years old at the time and had become clinically blind.[3] Wall claimed she could see auras around people, plants and animals and also that she had retained this ability even after the loss of her vision. Ms. Wall developed the coloured bottle system and asserted that the selection by the user may reveal their gifts, challenges and opportunities.
Over time the colour care system has come to include pomanders, oils, essences and sprays, all colour-related. These items are not held to have strict medical use, they are symbolic in nature. The theory being that if the practitioner can draw the state of mind of a client out through colour, then the application of appropriate colour in the life of the client can also have a restorative or healing psychosomatic effect.
Aura-Soma is looked upon by its practitioners as a constantly developing system. New bottles and methods are added to the system on an infrequent basis. In addition it is thought to reflect what is emerging for the collective as well as individuals.
After the initial start in 1983, Aura-Soma spread from the UK, becoming established in Denmark, Germany, the United States, Australia, Italy, Ireland, Japan, Korea, China and South America.
# Practice
The standard divination process for Aura-Soma is based on the equilibrium bottles. The user picks four bottles one after another while faced with the full selection to choose from,[4] and the practitioner then interprets the meaning of their selection. The order in which they are chosen is important:
- The first bottle represents the self, or a description of the user's current state of being
- The second represents the user's hidden gifts as well as their biggest obstacles
- The third represents their present energy, which gives a method which can be used to overcome their obstacles
- The fourth represents the energy that they are drawing toward them; the future that they are trying to create for themselves though overcoming the obstacles.
Afterwards, the user picks one of the four bottles which they use as an ointment, by shaking the bottle and applying the fusion of the oil and water to the parts of their body whose Chakras correspond to the colours of the bottle. This aids them with one area of disease which will help them achieve the outcome of the four bottle spread. Since much emphasis is on the obstacle, the second bottle is usually chosen.
While sounding superficially like the processes of other systems like Tarot, practitioners of Aura-Soma do not regard it as fortune-telling, but instead to be more like a counselling method, similar to the Lüscher color test, Rorschach inkblot test and other similar psychological methods of accessing the unconscious mind as separate to the conscious mind. Aura-Soma is not, however, a science or branch of psychology.
# Practitioners and Teachers
There is an Aura-Soma Code of Practice that is regulated by the Art & Science International Academy of Colour Therapeutics (ASIACT). ASIACT maintains a practitioner register and issues certificates to those who work according to this code. Each certificate is valid for two years. A current certificate shows that the practitioner is continuing to be updated in the Aura-Soma system and works according to the practices set out by the Academy.
Practitioner training currently comprises 4 levels. Levels 1, 2 and 3 each involve attendance at an accredited course. Each level involves broader and more detailed instruction in Aura-Soma. Level 4 involves the completion of a piece of original research on colour, together with presentation of a required number of case records and researched responses to colour related questions. A practitioner's level of training is featured on their certificate.
Students may become practitioners at any time after the completion of Level 2, regulated by laid down guidelines. At Level 4 the practitioner has demonstrated experience of working with Aura-Soma and understanding of the principles of Aura-Soma and may develop a full public practice. Practitioners and teachers can be found at the ASIACT website.
The bottle system is now governed by a central company (called Aura-Soma Products LTD) and the term 'Aura-Soma' is a registered trademark of that company. It is currently managed by Mike Booth. | https://www.wikidoc.org/index.php/Aura-Soma | |
e12b382cec25a4b5be733da81699e69621c53011 | wikidoc | Auranofin | Auranofin
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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
Auranofin is a antirheumatic, gold compound and musculoskeletal agent that is FDA approved for the treatment of adults with active classical or definite rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, rash, diarrhea, indigestion, loss of appetite, nausea, stomatitis, conjunctivitis, proteinuria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- RIDAURA (auranofin) is indicated in the management of adults with active classical or definite rheumatoid arthritis (ARA criteria) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of full doses of one or more nonsteroidal anti-inflammatory drugs. RIDAURA should be added to a comprehensive baseline program, including non-drug therapies.
- Unlike anti-inflammatory drugs, RIDAURA does not produce an immediate response. Therapeutic effects may be seen after three to four months of treatment, although improvement has not been seen in some patients before six months.
- When cartilage and bone damage has already occurred, gold cannot reverse structural damage to joints caused by previous disease. The greatest potential benefit occurs in patients with active synovitis, particularly in its early stage.
- In controlled clinical trials comparing RIDAURA with injectable gold, RIDAURA was associated with fewer dropouts due to adverse reactions, while injectable gold was associated with fewer dropouts for inadequate or poor therapeutic effect. Physicians should consider these findings when deciding on the use of RIDAURA in patients who are candidates for chrysotherapy.
### Dosing Information
- The usual adult dosage of RIDAURA (auranofin) is 6 mg daily, given either as 3 mg twice daily or 6 mg once daily. Initiation of therapy at dosages exceeding 6 mg daily is not recommended because it is associated with an increased incidence of diarrhea. If response is inadequate after six months, an increase to 9 mg (3 mg three times daily) may be tolerated. If response remains inadequate after a three-month trial of 9 mg daily, RIDAURA therapy should be discontinued. Safety at dosages exceeding 9 mg daily has not been studied.
- In controlled clinical studies, patients on injectable gold have been transferred to RIDAURA (auranofin) by discontinuing the injectable agent and starting oral therapy with RIDAURA, 6 mg daily. When patients are transferred to RIDAURA, they should be informed of its adverse reaction profile, in particular the gastrointestinal reactions. (See PRECAUTIONS— INFORMATION FOR PATIENTS.) At six months, control of disease activity of patients transferred to RIDAURA and those maintained on the injectable agent was not different. Data beyond six months are not available.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Auranofin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Auranofin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Auranofin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Auranofin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Auranofin in pediatric patients.
# Contraindications
- RIDAURA (auranofin) is contraindicated in patients with a history of any of the following gold-induced disorders: anaphylactic reactions, necrotizing enterocolitis, pulmonary fibrosis, exfoliative dermatitis, bone marrow aplasia or other severe hematologic disorders.
# Warnings
- Danger signs of possible gold toxicity include fall in hemoglobin, leukopenia below 4,000 WBC/cu mm, granulocytes below 1,500/cu mm, decrease in platelets below 150,000/cu mm, proteinuria, hematuria, pruritus, rash, stomatitis or persistent diarrhea.
- Thrombocytopenia has occurred in 1–3% of patients treated with RIDAURA (auranofin), some of whom developed bleeding. The thrombocytopenia usually appears to be peripheral in origin and is usually reversible upon withdrawal of RIDAURA. Its onset bears no relationship to the duration of RIDAURA therapy and its course may be rapid. While patients' platelet counts should normally be monitored at least monthly, the occurrence of a precipitous decline in platelets or a platelet count less than 100,000/cu mm or signs and symptoms (e.g., purpura, ecchymoses or petechiae) suggestive of thrombocytopenia indicates a need to immediately withdraw RIDAURA and other therapies with the potential to cause thrombocytopenia, and to obtain additional platelet counts. No additional RIDAURA should be given unless the thrombocytopenia resolves and further studies show it was not due to gold therapy.
- Proteinuria has developed in 3-9% of patients treated with RIDAURA. If clinically significant proteinuria or microscopic hematuria is found, RIDAURA and other therapies with the potential to cause proteinuria or microscopic hematuria should be stopped immediately.
### PRECAUTIONS
- The safety of concomitant use of RIDAURA (auranofin) with injectable gold, hydroxychloroquine, penicillamine, immunosuppressive agents (e.g., cyclophosphamide, azathioprine, or methotrexate) or high doses of corticosteroids has not been established.
- Medical problems that might affect the signs or symptoms used to detect RIDAURA toxicity should be under control before starting RIDAURA (auranofin).
- The potential benefits of using RIDAURA in patients with progressive renal disease, significant hepatocellular disease, inflammatory bowel disease, skin rash or history of bone marrow depression should be weighed against 1) the potential risks of gold toxicity on organ systems previously compromised or with decreased reserve, and 2) the difficulty in quickly detecting and correctly attributing the toxic effect.
- The following adverse reactions have been reported with the use of gold preparations and require modification of RIDAURA treatment or additional monitoring. See ADVERSE REACTIONS for the approximate incidence of those reactions specifically reported with RIDAURA.
- Gastrointestinal reactions reported with gold therapy include diarrhea/loose stools, nausea, vomiting, anorexia and abdominal cramps. The most common reaction to RIDAURA is diarrhea/ loose stools reported in approximately 50% of the patients. This is generally manageable by reducing the dosage (e.g., from 6 mg daily to 3 mg) and in only 6% of the patients is it necessary to discontinue RIDAURA (auranofin) permanently. Ulcerative enterocolitis is a rare serious gold reaction. Therefore, patients with gastrointestinal symptoms should be monitored for the appearance of gastrointestinal bleeding.
- Dermatitis is the most common reaction to injectable gold therapy and the second most common reaction to RIDAURA. Any eruption, especially if pruritic, that develops during treatment should be considered a gold reaction until proven otherwise. Pruritus often exists before dermatitis becomes apparent, and therefore should be considered to be a warning signal of a cutaneous reaction. Gold dermatitis may be aggravated by exposure to sunlight or an actinic rash may develop. The most serious form of cutaneous reaction reported with injectable gold is generalized exfoliative dermatitis.
- Stomatitis, another common gold reaction, may be manifested by shallow ulcers on the buccal membranes, on the borders of the tongue, and on the palate or in the pharynx. Stomatitis may occur as the only adverse reaction or with a dermatitis. Sometimes diffuse glossitis or gingivitis develops. A metallic taste may precede these oral mucous membrane reactions and should be considered a warning signal.
- Gold can produce a nephrotic syndrome or glomerulitis with proteinuria and hematuria. These renal reactions are usually relatively mild and subside completely if recognized early and treatment is discontinued. They may become severe and chronic if treatment is continued after the onset of the reaction. Therefore it is important to perform urinalyses regularly and to discontinue treatment promptly if proteinuria or hematuria develops.
- Blood dyscrasias including leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have all been reported as reactions to injectable gold and RIDAURA. These reactions may occur separately or in combination at anytime during treatment. Because they have potentially serious consequences, blood dyscrasias should be constantly watched for through regular monitoring (at least monthly) of the formed elements of the blood throughout treatment.
- Rare reactions attributed to gold include cholestatic jaundice; gold bronchitis and interstitial pneumonitis and fibrosis; peripheral neuropathy; partial or complete hair loss; fever.
- Patients should be advised of the possibility of toxicity from RIDAURA and of the signs and symptoms that they should report promptly. (Patient information sheets are available.)
- Women of childbearing potential should be warned of the potential risks of RIDAURA therapy during pregnancy (See PRECAUTIONS— PREGNANCY).
- CBC with differential, platelet count, urinalysis, and renal and liver function tests should be performed prior to RIDAURA (auranofin) therapy to establish a baseline and to identify any preexisting conditions.
- CBC with differential, platelet count and urinalysis should then be monitored at least monthly; other parameters should be monitored as appropriate.
# Adverse Reactions
## Clinical Trials Experience
- The adverse reactions incidences listed below are based on observations of 1) 4,784 RIDAURA treated patients in clinical trials (2,474 U.S., 2,310 foreign), of whom 2,729 were treated more than one year and 573 for more than three years; and 2) postmarketing experience. The highest incidence is during the first six months of treatment; however, reactions can occur after many months of therapy. With rare exceptions, all patients were on concomitant nonsteroidal anti-inflammatory therapy; some of them were also taking low dosages of corticosteroids.
### Reactions occurring in more than 1% of RIDAURA-treated patients
- Loose stools or diarrhea (47%); abdominal pain (14%); nausea with or without vomiting (10%); constipation; anorexia*; flatulence*; dyspepsia*; dysgeusia.
- Rash (24%); pruritus (17%); hair loss; urticaria.
- Stomatitis (13%); conjunctivitis*; glossitis.
- Anemia, leukopenia, thrombocytopenia, eosinophilia
- Proteinuria, hematuria
- Elevated liver enzymes.
- Reactions marked with an asterisk occurred in 3-9% of the patients. The other reactions listed occurred in 1-3%.
### Reactions occurring in less than 1% of RIDAURA-treated patients
- Dysphagia, gastrointestinal bleeding, melena, positive stool for occult blood, ulcerative enterocolitis
- Angioedema.
- Gingivitis†.
- Aplastic anemia; neutropenia; agranulocytosis; pure red cell aplasia; pancytopenia.
- Jaundice.
- Interstitial pneumonitis.
- Peripheral neuropathy.
- Gold deposits in the lens or cornea unassociated clinically with eye disorders or visual impairment.
- † Reactions marked with a dagger occurred in 0.1-1% of the patients. The other reactions listed occurred in less than 0.1%.
### Reactions reported with injectable gold preparations, but not with RIDAURA (auranofin) (based on clinical trials and on postmarketing experience)
- Generalized exfoliative dermatitis.
## Postmarketing Experience
There is limited information regarding Auranofin Postmarketing Experience in the drug label.
# Drug Interactions
- In a single patient-report, there is the suggestion that concurrent administration of RIDAURA and phenytoin may have increased phenytoin blood levels.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Use of RIDAURA (auranofin) by pregnant women is not recommended. Furthermore, women of childbearing potential should be warned of the potential risks of RIDAURA therapy during pregnancy. (See below.)
- Pregnant rabbits given auranofin at doses of 0.5, 3 or 6 mg/kg/day (4.2 to 50 times the human dose) had impaired food intake, decreased maternal weights, decreased fetal weights and an increase above controls in the incidence of resorptions, abortions and congenital abnormalities, mainly abdominal defects such as gastroschisis and umbilical hernia. Pregnant rats given auranofin at a dose of 5 mg/kg/day (42 times the human dose) had an increase above controls in the incidence of resorptions and a decrease in litter size and weight linked to maternal toxicity. No such effects were found in rats given 2.5 mg/kg/day (21 times the human dose).
- Pregnant mice given auranofin at a dose of 5 mg/kg/day (42 times the human dose) had no teratogenic effects.
- There are no adequate and well-controlled RIDAURA studies 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 Auranofin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Auranofin during labor and delivery.
### Nursing Mothers
- Nursing during RIDAURA therapy is not recommended.
- Following auranofin administration to rats and mice, gold is excreted in milk. Following the administration of injectable gold, gold appears in the milk of nursing women; human data on auranofin are not available.
### Pediatric Use
- RIDAURA (auranofin) is not recommended for use in pediatric patients because its safety and effectiveness have not been established.
### Geriatic Use
There is no FDA guidance on the use of Auranofin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Auranofin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Auranofin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Auranofin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Auranofin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Auranofin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Auranofin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Gastrointestinal reactions reported with gold therapy include diarrhea/loose stools, nausea, vomiting, anorexia and abdominal cramps. The most common reaction to RIDAURA is diarrhea/ loose stools reported in approximately 50% of the patients. This is generally manageable by reducing the dosage (e.g., from 6 mg daily to 3 mg) and in only 6% of the patients is it necessary to discontinue RIDAURA (auranofin) permanently. Ulcerative enterocolitis is a rare serious gold reaction. Therefore, patients with gastrointestinal symptoms should be monitored for the appearance of gastrointestinal bleeding.
- Blood dyscrasias including leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have all been reported as reactions to injectable gold and RIDAURA. These reactions may occur separately or in combination at anytime during treatment. Because they have potentially serious consequences, blood dyscrasias should be constantly watched for through regular monitoring (at least monthly) of the formed elements of the blood throughout treatment.
- CBC with differential, platelet count, urinalysis, and renal and liver function tests should be performed prior to RIDAURA (auranofin) therapy to establish a baseline and to identify any preexisting conditions.
- CBC with differential, platelet count and urinalysis should then be monitored at least monthly; other parameters should be monitored as appropriate.
# IV Compatibility
There is limited information regarding IV Compatibility of Auranofin in the drug label.
# Overdosage
- The acute oral LD50 for auranofin is 310 mg/kg in adult mice and 265 mg/ kg in adult rats. The minimum lethal dose in rats is 30 mg/kg.
- In case of acute overdosage, immediate induction of emesis or gastric lavage and appropriate supportive therapy are recommended.
- RIDAURA overdosage experience is limited. A 50-year-old female, previously on 6 mg RIDAURA daily, took 27 mg (9 capsules) daily for 10 days and developed an encephalopathy and peripheral neuropathy. RIDAURA was discontinued and she eventually recovered.
- There has been no experience with treating RIDAURA overdosage with modalities such as chelating agents. However, they have been used with injectable gold and may be considered for RIDAURA overdosage.
# Pharmacology
## Mechanism of Action
- The mechanism of action of RIDAURA (auranofin) is not understood. In patients with adult rheumatoid arthritis, RIDAURA may modify disease activity as manifested by synovitis and associated symptoms, and reflected by laboratory parameters such as ESR. There is no substantial evidence, however, that gold-containing compounds induce remission of rheumatoid arthritis.
## Structure
- RIDAURA (auranofin) is available in oral form as capsules containing 3 mg auranofin.
- Auranofin is (2,3,4,6-tetra-O-acetyl-1-thio-ß-D-glucopyranosato-S-) (triethyl–phosphine) gold.
- Auranofin contains 29% gold and has the following chemical structure:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Auranofin in the drug label.
## Pharmacokinetics
- Pharmacokinetic studies were performed in rheumatoid arthritis patients, not in normal volunteers. Auranofin is rapidly metabolized and intact auranofin has never been detected in the blood. Thus, studies of the pharmacokinetics of auranofin have involved measurement of gold concentrations. Approximately 25% of the gold in auranofin is absorbed.
- The mean terminal plasma half-life of auranofin gold at steady state was 26 days (range 21 to 31 days; n=5). The mean terminal body half-life was 80 days (range 42 to 128; n=5). Approximately 60% of the absorbed gold (15% of the administered dose) from a single dose of auranofin is excreted in urine; the remainder is excreted in the feces.
- In clinical studies, steady state blood-gold concentrations are achieved in about three months. In patients on 6 mg auranofin/day, mean steady state blood-gold concentrations were 0.68 ±0.45 mcg/mL (n=63 patients). In blood, approximately 40% of auranofin gold is associated with red cells, and 60% associated with serum proteins. In contrast, 99% of injectable gold is associated with serum proteins.
- Mean blood-gold concentrations are proportional to dose; however, no correlation between blood-gold concentrations and safety or efficacy has been established.
## Nonclinical Toxicology
- In a 24-month study in rats, animals treated with auranofin at 0.4, 1.0 or 2.5 mg/kg/day orally (3, 8 or 21 times the human dose) or gold sodium thiomalate at 2 or 6 mg/kg injected twice weekly (4 or 12 times the human dose) were compared to untreated control animals.
- There was a significant increase in the frequency of renal tubular cell karyomegaly and cytomegaly and renal adenoma in the animals treated with 1.0 or 2.5 mg/kg/day of auranofin and 2 or 6 mg/kg twice weekly of gold sodium thiomalate. Malignant renal epithelial tumors were seen in the 1.0 mg/kg/day and the 2.5 mg/kg/day auranofin and in the 6 mg/kg twice weekly gold sodium thiomalate–treated animals.
- In a 12-month study, rats treated with auranofin at 23 mg/kg/day (192 times the human dose) developed tumors of the renal tubular epithelium, whereas those treated with 3.6 mg/ kg/day (30 times the human dose) did not.
- In an 18-month study in mice given oral auranofin at doses of 1, 3 and 9 mg/kg/day (8, 24 and 72 times the human dose), there was no statistically significant increase above controls in the instances of tumors.
- In the mouse lymphoma forward mutation assay, auranofin at high concentrations (313 to 700 ng/mL) induced increases in the mutation frequencies in the presence of a rat liver microsomal preparation. Auranofin produced no mutation effects in the Ames test (Salmonella), in the in vitro assay (Forward and Reverse Mutation Inducement Assay with Saccharomyces), in the in vitro transformation of BALB/T3 cell mouse assay or in the Dominant Lethal Assay.
# Clinical Studies
There is limited information regarding Clinical Studies of Auranofin in the drug label.
# How Supplied
Capsules, containing 3 mg auranofin, in bottles of 60.
NDC 65483-093-06
REVISED January 2011
©2007 Prometheus Laboratories Inc.
All rights reserved.
RIDAURA is a registered trademark of Prometheus Laboratories Inc.
Manufactured for:
Prometheus Laboratories Inc.
San Diego, CA 92121-4203
RI002E
## Storage
- Store between 15° and 30°C (59° and 86°F). Dispense in a tight, light-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
3 mg NDC 65483-093-06
Ridaura®
Auranofin Capsules
60 Capsules
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Auranofin in the drug label.
# Precautions with Alcohol
- Alcohol-Auranofin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ridaura®
# Look-Alike Drug Names
There is limited information regarding Auranofin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Auranofin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
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# Black Box Warning
# Overview
Auranofin is a antirheumatic, gold compound and musculoskeletal agent that is FDA approved for the treatment of adults with active classical or definite rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, rash, diarrhea, indigestion, loss of appetite, nausea, stomatitis, conjunctivitis, proteinuria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- RIDAURA (auranofin) is indicated in the management of adults with active classical or definite rheumatoid arthritis (ARA criteria) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of full doses of one or more nonsteroidal anti-inflammatory drugs. RIDAURA should be added to a comprehensive baseline program, including non-drug therapies.
- Unlike anti-inflammatory drugs, RIDAURA does not produce an immediate response. Therapeutic effects may be seen after three to four months of treatment, although improvement has not been seen in some patients before six months.
- When cartilage and bone damage has already occurred, gold cannot reverse structural damage to joints caused by previous disease. The greatest potential benefit occurs in patients with active synovitis, particularly in its early stage.
- In controlled clinical trials comparing RIDAURA with injectable gold, RIDAURA was associated with fewer dropouts due to adverse reactions, while injectable gold was associated with fewer dropouts for inadequate or poor therapeutic effect. Physicians should consider these findings when deciding on the use of RIDAURA in patients who are candidates for chrysotherapy.
### Dosing Information
- The usual adult dosage of RIDAURA (auranofin) is 6 mg daily, given either as 3 mg twice daily or 6 mg once daily. Initiation of therapy at dosages exceeding 6 mg daily is not recommended because it is associated with an increased incidence of diarrhea. If response is inadequate after six months, an increase to 9 mg (3 mg three times daily) may be tolerated. If response remains inadequate after a three-month trial of 9 mg daily, RIDAURA therapy should be discontinued. Safety at dosages exceeding 9 mg daily has not been studied.
- In controlled clinical studies, patients on injectable gold have been transferred to RIDAURA (auranofin) by discontinuing the injectable agent and starting oral therapy with RIDAURA, 6 mg daily. When patients are transferred to RIDAURA, they should be informed of its adverse reaction profile, in particular the gastrointestinal reactions. (See PRECAUTIONS— INFORMATION FOR PATIENTS.) At six months, control of disease activity of patients transferred to RIDAURA and those maintained on the injectable agent was not different. Data beyond six months are not available.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Auranofin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Auranofin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Auranofin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Auranofin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Auranofin in pediatric patients.
# Contraindications
- RIDAURA (auranofin) is contraindicated in patients with a history of any of the following gold-induced disorders: anaphylactic reactions, necrotizing enterocolitis, pulmonary fibrosis, exfoliative dermatitis, bone marrow aplasia or other severe hematologic disorders.
# Warnings
- Danger signs of possible gold toxicity include fall in hemoglobin, leukopenia below 4,000 WBC/cu mm, granulocytes below 1,500/cu mm, decrease in platelets below 150,000/cu mm, proteinuria, hematuria, pruritus, rash, stomatitis or persistent diarrhea.
- Thrombocytopenia has occurred in 1–3% of patients treated with RIDAURA (auranofin), some of whom developed bleeding. The thrombocytopenia usually appears to be peripheral in origin and is usually reversible upon withdrawal of RIDAURA. Its onset bears no relationship to the duration of RIDAURA therapy and its course may be rapid. While patients' platelet counts should normally be monitored at least monthly, the occurrence of a precipitous decline in platelets or a platelet count less than 100,000/cu mm or signs and symptoms (e.g., purpura, ecchymoses or petechiae) suggestive of thrombocytopenia indicates a need to immediately withdraw RIDAURA and other therapies with the potential to cause thrombocytopenia, and to obtain additional platelet counts. No additional RIDAURA should be given unless the thrombocytopenia resolves and further studies show it was not due to gold therapy.
- Proteinuria has developed in 3-9% of patients treated with RIDAURA. If clinically significant proteinuria or microscopic hematuria is found, RIDAURA and other therapies with the potential to cause proteinuria or microscopic hematuria should be stopped immediately.
### PRECAUTIONS
- The safety of concomitant use of RIDAURA (auranofin) with injectable gold, hydroxychloroquine, penicillamine, immunosuppressive agents (e.g., cyclophosphamide, azathioprine, or methotrexate) or high doses of corticosteroids has not been established.
- Medical problems that might affect the signs or symptoms used to detect RIDAURA toxicity should be under control before starting RIDAURA (auranofin).
- The potential benefits of using RIDAURA in patients with progressive renal disease, significant hepatocellular disease, inflammatory bowel disease, skin rash or history of bone marrow depression should be weighed against 1) the potential risks of gold toxicity on organ systems previously compromised or with decreased reserve, and 2) the difficulty in quickly detecting and correctly attributing the toxic effect.
- The following adverse reactions have been reported with the use of gold preparations and require modification of RIDAURA treatment or additional monitoring. See ADVERSE REACTIONS for the approximate incidence of those reactions specifically reported with RIDAURA.
- Gastrointestinal reactions reported with gold therapy include diarrhea/loose stools, nausea, vomiting, anorexia and abdominal cramps. The most common reaction to RIDAURA is diarrhea/ loose stools reported in approximately 50% of the patients. This is generally manageable by reducing the dosage (e.g., from 6 mg daily to 3 mg) and in only 6% of the patients is it necessary to discontinue RIDAURA (auranofin) permanently. Ulcerative enterocolitis is a rare serious gold reaction. Therefore, patients with gastrointestinal symptoms should be monitored for the appearance of gastrointestinal bleeding.
- Dermatitis is the most common reaction to injectable gold therapy and the second most common reaction to RIDAURA. Any eruption, especially if pruritic, that develops during treatment should be considered a gold reaction until proven otherwise. Pruritus often exists before dermatitis becomes apparent, and therefore should be considered to be a warning signal of a cutaneous reaction. Gold dermatitis may be aggravated by exposure to sunlight or an actinic rash may develop. The most serious form of cutaneous reaction reported with injectable gold is generalized exfoliative dermatitis.
- Stomatitis, another common gold reaction, may be manifested by shallow ulcers on the buccal membranes, on the borders of the tongue, and on the palate or in the pharynx. Stomatitis may occur as the only adverse reaction or with a dermatitis. Sometimes diffuse glossitis or gingivitis develops. A metallic taste may precede these oral mucous membrane reactions and should be considered a warning signal.
- Gold can produce a nephrotic syndrome or glomerulitis with proteinuria and hematuria. These renal reactions are usually relatively mild and subside completely if recognized early and treatment is discontinued. They may become severe and chronic if treatment is continued after the onset of the reaction. Therefore it is important to perform urinalyses regularly and to discontinue treatment promptly if proteinuria or hematuria develops.
- Blood dyscrasias including leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have all been reported as reactions to injectable gold and RIDAURA. These reactions may occur separately or in combination at anytime during treatment. Because they have potentially serious consequences, blood dyscrasias should be constantly watched for through regular monitoring (at least monthly) of the formed elements of the blood throughout treatment.
- Rare reactions attributed to gold include cholestatic jaundice; gold bronchitis and interstitial pneumonitis and fibrosis; peripheral neuropathy; partial or complete hair loss; fever.
- Patients should be advised of the possibility of toxicity from RIDAURA and of the signs and symptoms that they should report promptly. (Patient information sheets are available.)
- Women of childbearing potential should be warned of the potential risks of RIDAURA therapy during pregnancy (See PRECAUTIONS— PREGNANCY).
- CBC with differential, platelet count, urinalysis, and renal and liver function tests should be performed prior to RIDAURA (auranofin) therapy to establish a baseline and to identify any preexisting conditions.
- CBC with differential, platelet count and urinalysis should then be monitored at least monthly; other parameters should be monitored as appropriate.
# Adverse Reactions
## Clinical Trials Experience
- The adverse reactions incidences listed below are based on observations of 1) 4,784 RIDAURA treated patients in clinical trials (2,474 U.S., 2,310 foreign), of whom 2,729 were treated more than one year and 573 for more than three years; and 2) postmarketing experience. The highest incidence is during the first six months of treatment; however, reactions can occur after many months of therapy. With rare exceptions, all patients were on concomitant nonsteroidal anti-inflammatory therapy; some of them were also taking low dosages of corticosteroids.
### Reactions occurring in more than 1% of RIDAURA-treated patients
- Loose stools or diarrhea (47%); abdominal pain (14%); nausea with or without vomiting (10%); constipation; anorexia*; flatulence*; dyspepsia*; dysgeusia.
- Rash (24%); pruritus (17%); hair loss; urticaria.
- Stomatitis (13%); conjunctivitis*; glossitis.
- Anemia, leukopenia, thrombocytopenia, eosinophilia
- Proteinuria, hematuria
- Elevated liver enzymes.
- Reactions marked with an asterisk occurred in 3-9% of the patients. The other reactions listed occurred in 1-3%.
### Reactions occurring in less than 1% of RIDAURA-treated patients
- Dysphagia, gastrointestinal bleeding, melena, positive stool for occult blood, ulcerative enterocolitis
- Angioedema.
- Gingivitis†.
- Aplastic anemia; neutropenia; agranulocytosis; pure red cell aplasia; pancytopenia.
- Jaundice.
- Interstitial pneumonitis.
- Peripheral neuropathy.
- Gold deposits in the lens or cornea unassociated clinically with eye disorders or visual impairment.
- † Reactions marked with a dagger occurred in 0.1-1% of the patients. The other reactions listed occurred in less than 0.1%.
### Reactions reported with injectable gold preparations, but not with RIDAURA (auranofin) (based on clinical trials and on postmarketing experience)
- Generalized exfoliative dermatitis.
## Postmarketing Experience
There is limited information regarding Auranofin Postmarketing Experience in the drug label.
# Drug Interactions
- In a single patient-report, there is the suggestion that concurrent administration of RIDAURA and phenytoin may have increased phenytoin blood levels.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Use of RIDAURA (auranofin) by pregnant women is not recommended. Furthermore, women of childbearing potential should be warned of the potential risks of RIDAURA therapy during pregnancy. (See below.)
- Pregnant rabbits given auranofin at doses of 0.5, 3 or 6 mg/kg/day (4.2 to 50 times the human dose) had impaired food intake, decreased maternal weights, decreased fetal weights and an increase above controls in the incidence of resorptions, abortions and congenital abnormalities, mainly abdominal defects such as gastroschisis and umbilical hernia. Pregnant rats given auranofin at a dose of 5 mg/kg/day (42 times the human dose) had an increase above controls in the incidence of resorptions and a decrease in litter size and weight linked to maternal toxicity. No such effects were found in rats given 2.5 mg/kg/day (21 times the human dose).
- Pregnant mice given auranofin at a dose of 5 mg/kg/day (42 times the human dose) had no teratogenic effects.
- There are no adequate and well-controlled RIDAURA studies 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 Auranofin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Auranofin during labor and delivery.
### Nursing Mothers
- Nursing during RIDAURA therapy is not recommended.
- Following auranofin administration to rats and mice, gold is excreted in milk. Following the administration of injectable gold, gold appears in the milk of nursing women; human data on auranofin are not available.
### Pediatric Use
- RIDAURA (auranofin) is not recommended for use in pediatric patients because its safety and effectiveness have not been established.
### Geriatic Use
There is no FDA guidance on the use of Auranofin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Auranofin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Auranofin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Auranofin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Auranofin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Auranofin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Auranofin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Gastrointestinal reactions reported with gold therapy include diarrhea/loose stools, nausea, vomiting, anorexia and abdominal cramps. The most common reaction to RIDAURA is diarrhea/ loose stools reported in approximately 50% of the patients. This is generally manageable by reducing the dosage (e.g., from 6 mg daily to 3 mg) and in only 6% of the patients is it necessary to discontinue RIDAURA (auranofin) permanently. Ulcerative enterocolitis is a rare serious gold reaction. Therefore, patients with gastrointestinal symptoms should be monitored for the appearance of gastrointestinal bleeding.
- Blood dyscrasias including leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have all been reported as reactions to injectable gold and RIDAURA. These reactions may occur separately or in combination at anytime during treatment. Because they have potentially serious consequences, blood dyscrasias should be constantly watched for through regular monitoring (at least monthly) of the formed elements of the blood throughout treatment.
- CBC with differential, platelet count, urinalysis, and renal and liver function tests should be performed prior to RIDAURA (auranofin) therapy to establish a baseline and to identify any preexisting conditions.
- CBC with differential, platelet count and urinalysis should then be monitored at least monthly; other parameters should be monitored as appropriate.
# IV Compatibility
There is limited information regarding IV Compatibility of Auranofin in the drug label.
# Overdosage
- The acute oral LD50 for auranofin is 310 mg/kg in adult mice and 265 mg/ kg in adult rats. The minimum lethal dose in rats is 30 mg/kg.
- In case of acute overdosage, immediate induction of emesis or gastric lavage and appropriate supportive therapy are recommended.
- RIDAURA overdosage experience is limited. A 50-year-old female, previously on 6 mg RIDAURA daily, took 27 mg (9 capsules) daily for 10 days and developed an encephalopathy and peripheral neuropathy. RIDAURA was discontinued and she eventually recovered.
- There has been no experience with treating RIDAURA overdosage with modalities such as chelating agents. However, they have been used with injectable gold and may be considered for RIDAURA overdosage.
# Pharmacology
## Mechanism of Action
- The mechanism of action of RIDAURA (auranofin) is not understood. In patients with adult rheumatoid arthritis, RIDAURA may modify disease activity as manifested by synovitis and associated symptoms, and reflected by laboratory parameters such as ESR. There is no substantial evidence, however, that gold-containing compounds induce remission of rheumatoid arthritis.
## Structure
- RIDAURA (auranofin) is available in oral form as capsules containing 3 mg auranofin.
- Auranofin is (2,3,4,6-tetra-O-acetyl-1-thio-ß-D-glucopyranosato-S-) (triethyl–phosphine) gold.
- Auranofin contains 29% gold and has the following chemical structure:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Auranofin in the drug label.
## Pharmacokinetics
- Pharmacokinetic studies were performed in rheumatoid arthritis patients, not in normal volunteers. Auranofin is rapidly metabolized and intact auranofin has never been detected in the blood. Thus, studies of the pharmacokinetics of auranofin have involved measurement of gold concentrations. Approximately 25% of the gold in auranofin is absorbed.
- The mean terminal plasma half-life of auranofin gold at steady state was 26 days (range 21 to 31 days; n=5). The mean terminal body half-life was 80 days (range 42 to 128; n=5). Approximately 60% of the absorbed gold (15% of the administered dose) from a single dose of auranofin is excreted in urine; the remainder is excreted in the feces.
- In clinical studies, steady state blood-gold concentrations are achieved in about three months. In patients on 6 mg auranofin/day, mean steady state blood-gold concentrations were 0.68 ±0.45 mcg/mL (n=63 patients). In blood, approximately 40% of auranofin gold is associated with red cells, and 60% associated with serum proteins. In contrast, 99% of injectable gold is associated with serum proteins.
- Mean blood-gold concentrations are proportional to dose; however, no correlation between blood-gold concentrations and safety or efficacy has been established.
## Nonclinical Toxicology
- In a 24-month study in rats, animals treated with auranofin at 0.4, 1.0 or 2.5 mg/kg/day orally (3, 8 or 21 times the human dose) or gold sodium thiomalate at 2 or 6 mg/kg injected twice weekly (4 or 12 times the human dose) were compared to untreated control animals.
- There was a significant increase in the frequency of renal tubular cell karyomegaly and cytomegaly and renal adenoma in the animals treated with 1.0 or 2.5 mg/kg/day of auranofin and 2 or 6 mg/kg twice weekly of gold sodium thiomalate. Malignant renal epithelial tumors were seen in the 1.0 mg/kg/day and the 2.5 mg/kg/day auranofin and in the 6 mg/kg twice weekly gold sodium thiomalate–treated animals.
- In a 12-month study, rats treated with auranofin at 23 mg/kg/day (192 times the human dose) developed tumors of the renal tubular epithelium, whereas those treated with 3.6 mg/ kg/day (30 times the human dose) did not.
- In an 18-month study in mice given oral auranofin at doses of 1, 3 and 9 mg/kg/day (8, 24 and 72 times the human dose), there was no statistically significant increase above controls in the instances of tumors.
- In the mouse lymphoma forward mutation assay, auranofin at high concentrations (313 to 700 ng/mL) induced increases in the mutation frequencies in the presence of a rat liver microsomal preparation. Auranofin produced no mutation effects in the Ames test (Salmonella), in the in vitro assay (Forward and Reverse Mutation Inducement Assay with Saccharomyces), in the in vitro transformation of BALB/T3 cell mouse assay or in the Dominant Lethal Assay.
# Clinical Studies
There is limited information regarding Clinical Studies of Auranofin in the drug label.
# How Supplied
Capsules, containing 3 mg auranofin, in bottles of 60.
NDC 65483-093-06
REVISED January 2011
©2007 Prometheus Laboratories Inc.
All rights reserved.
RIDAURA is a registered trademark of Prometheus Laboratories Inc.
Manufactured for:
Prometheus Laboratories Inc.
San Diego, CA 92121-4203
RI002E
## Storage
- Store between 15° and 30°C (59° and 86°F). Dispense in a tight, light-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
3 mg NDC 65483-093-06
Ridaura®
Auranofin Capsules
60 Capsules
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Auranofin in the drug label.
# Precautions with Alcohol
- Alcohol-Auranofin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ridaura®
# Look-Alike Drug Names
There is limited information regarding Auranofin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Auranofin | |
7074e4c3958ea592ea4cb782f66e177bd86ebb01 | wikidoc | Austenite | Austenite
Austenite (or gamma phase iron) is a metallic non-magnetic solid solution of iron and an alloying element. In plain-carbon steel, austenite exists above the critical eutectoid temperature of 1000 K (about 727 °C); other alloys of steel have different eutectoid temperatures. It is named after Sir William Chandler Roberts-Austen (1843-1902).
# Behavior in Plain-Carbon Steel
As austenite cools, it often transforms into a mixture of ferrite and cementite as dissolved carbon falls out of solution. Depending on alloy composition and rate of cooling, pearlite may form. If the rate of cooling is very fast, the alloy may experience a slight lattice distortion known as martensitic transformation, instead of transforming into a mixture. In this industrially very important case, the carbon is not allowed to blend out in the remaining melt due to the cooling speed, but is captured inside the FCC-structure of austenite, creating tension in the crystal when the alloy cools. The result is hard martensite. The rate of cooling determines the relative proportions of these materials and therefore the mechanical properties (e.g. hardness, tensile strength) of the steel. Quenching (to induce martensitic transformation), followed by tempering will transform some of the brittle martensite into bainite. If a low-hardenability steel is quenched, a significant amount of austenite will be retained in the microstructure.
# Stabilization
The addition of certain alloying elements, such as manganese and nickel, can stabilize the austenitic structure, facilitating heat-treatment of low-alloy steels. In the extreme case of austenitic stainless steel, much higher alloy content makes this structure stable even at room temperature. On the other hand, such elements as silicon, molybdenum, and chromium tend to de-stabilize austenite, raising the eutectoid temperature.
# Austenite transformation and Curie point
In many magnetic alloys, the Curie point, the temperature at which magnetic materials cease to behave magnetically, occurs at nearly the same temperature as the austenite transformation. This behavior is attributed to the paramagnetic nature of austenite, while both martensite and ferrite are strongly ferromagnetic.
# Thermo-optical emission
A blacksmith causes phase changes in the iron-carbon system in order to control the material's mechanical properties, often using the annealing, quenching, and tempering processes. In this context, the color of light emitted by the workpiece is an approximate gauge of temperature, with the transition from red to orange corresponding to the formation of austenite in medium- and high-carbon steel.
Maximum carbon solubility in austenite is 2.03% C at 1420 K (1147 °C). | Austenite
Austenite (or gamma phase iron) is a metallic non-magnetic solid solution of iron and an alloying element. In plain-carbon steel, austenite exists above the critical eutectoid temperature of 1000 K (about 727 °C); other alloys of steel have different eutectoid temperatures. It is named after Sir William Chandler Roberts-Austen (1843-1902).
# Behavior in Plain-Carbon Steel
As austenite cools, it often transforms into a mixture of ferrite and cementite as dissolved carbon falls out of solution. Depending on alloy composition and rate of cooling, pearlite may form. If the rate of cooling is very fast, the alloy may experience a slight lattice distortion known as martensitic transformation, instead of transforming into a mixture. In this industrially very important case, the carbon is not allowed to blend out in the remaining melt due to the cooling speed, but is captured inside the FCC-structure of austenite, creating tension in the crystal when the alloy cools. The result is hard martensite. The rate of cooling determines the relative proportions of these materials and therefore the mechanical properties (e.g. hardness, tensile strength) of the steel. Quenching (to induce martensitic transformation), followed by tempering will transform some of the brittle martensite into bainite. If a low-hardenability steel is quenched, a significant amount of austenite will be retained in the microstructure.
# Stabilization
The addition of certain alloying elements, such as manganese and nickel, can stabilize the austenitic structure, facilitating heat-treatment of low-alloy steels. In the extreme case of austenitic stainless steel, much higher alloy content makes this structure stable even at room temperature. On the other hand, such elements as silicon, molybdenum, and chromium tend to de-stabilize austenite, raising the eutectoid temperature.
# Austenite transformation and Curie point
In many magnetic alloys, the Curie point, the temperature at which magnetic materials cease to behave magnetically, occurs at nearly the same temperature as the austenite transformation. This behavior is attributed to the paramagnetic nature of austenite, while both martensite and ferrite are strongly ferromagnetic.
# Thermo-optical emission
A blacksmith causes phase changes in the iron-carbon system in order to control the material's mechanical properties, often using the annealing, quenching, and tempering processes. In this context, the color of light emitted by the workpiece is an approximate gauge of temperature, with the transition from red to orange corresponding to the formation of austenite in medium- and high-carbon steel.
Maximum carbon solubility in austenite is 2.03% C at 1420 K (1147 °C). | https://www.wikidoc.org/index.php/Austenite | |
3861c8033072f52f3d986bb586d2435f21637a5b | wikidoc | Autoclave | Autoclave
An autoclave is a pressurized device designed to heat aqueous solutions above their boiling point to achieve sterilization. It was invented by Charles Chamberland in 1879. The term autoclave is also used to describe an industrial machine in which elevated temperature and pressure are used in processing materials.
# Introduction
Under ordinary circumstances (at standard pressure), liquid water cannot be heated above 100 °C in an open vessel. Further heating results in boiling, but does not raise the temperature of the liquid water. However, when water is heated in a sealed vessel such as an autoclave, it is possible to heat liquid water to a much higher temperature. As the container is heated the pressure rises due to the constant volume of the container (see the ideal gas law). The boiling point of the water is raised because the amount of energy needed to form steam against the higher pressure is increased.
This works well on solid objects; when autoclaving hollow objects, however, (hypodermic needles, tools, etc.), it is important to ensure that all of the trapped air inside the hollow compartments is removed. Autoclaves may achieve air removal by downward displacement, super atmospheric, transatmospheric or sub-atmospheric pulses.
Autoclaves are widely used in microbiology, medicine, veterinary science, dentistry, podiatry and metallurgy. The large carbon-fiber composite parts for the Boeing 787, such as wing and fuselage parts, are cured in large autoclaves.
# Autoclaves in medicine
A medical autoclave is a device that uses steam to sterilize equipment and other objects. This means that all bacteria, viruses, fungi, and spores are inactivated. However, in 2003 scientists discovered a single-celled organism, Strain 121, that survives traditional autoclave temperatures. Prions, like those associated with Creutzfeldt-Jakob disease, also may not be destroyed by autoclaving at the typical 121 degrees Celsius for 15 minutes or 134 degrees Celsius for 3 minutes, but can be destroyed with a longer sterilisation cycle of 134 degrees Celsius for 18 minutes.
Autoclaves are found in many medical settings and other places that need to ensure sterility of an object. They were once more common, but many procedures today use single-use items rather than sterilized, reusable items. This first happened with hypodermic needles, but today many surgical instruments (such as forceps, needle holders, and scalpel handles) are commonly single-use items rather than reusable. See waste autoclave.
Because damp heat is used, heat-labile products (such as some plastics) cannot be sterilised this way or they will melt. Some paper or other products that may be damaged by the steam must also be sterilized another way. In all autoclaves, items should always be separated to allow the steam to penetrate the load evenly.
Autoclaving is often used to sterilize medical waste prior to disposal in the standard municipal solid waste stream. This application has grown as an alternative to incineration due to environmental and health concerns raised by combustion byproducts from incinerators, especially from the small units which were commonly operated at individual hospitals. Incineration or a similar thermal oxidation process is still generally mandated for pathological waste and other very toxic and/or infectious medical wastes.
# Chemiclave
Unlike the humid environment produced by conventional steam, the unsaturated chemical vapor method is a low-humidity process. No time-consuming drying phase is needed, because nothing gets wet. The heat-up time is shorter than for most steam sterilizers, and the heaters stay on between cycles to minimize warm-up time and increase the instrument turnover.
# Autoclave quality assurance
There are physical, chemical, and biological indicators that can be used to ensure an autoclave reaches the correct temperature for the correct amount of time.
Chemical indicators can be found on medical packaging and autoclave tape, and these change color once the correct conditions have been met. This color change indicates that the object inside the package, or under the tape, has been autoclaved sufficiently. Biological indicators include attest devices. These contain spores of a heat-resistant bacterium, Geobacillus stearothermophilus. If the autoclave does not reach the right temperature, the spores will germinate, and their metabolism will change the color of a pH-sensitive chemical. Physical indicators often consist of an alloy designed to melt only after being subjected to 121°C or 249°F for 15 minutes. If the alloy melts, the change will be visible.
In addition to these indicators, autoclaves have timers, temperature and pressure gauges that can be viewed from the outside.
There are certain plastics that can withstand repeated temperature cycling greater than the 121°C or 249°F required for the autoclaving process. PFA is an example.
Some computer-controlled autoclaves use an F0 (F-naught) value to control the sterilization cycle. F0 values are set as the number of minutes of equivalent sterilization at 121°C or 249°F (e.g: F0 = 15 min.). Since exact temperature control is difficult, the temperature is monitored, and the sterilization time adjusted accordingly. | Autoclave
Template:Infobox laboratory equipment
An autoclave is a pressurized device designed to heat aqueous solutions above their boiling point to achieve sterilization. It was invented by Charles Chamberland in 1879.[1] The term autoclave is also used to describe an industrial machine in which elevated temperature and pressure are used in processing materials.
# Introduction
Under ordinary circumstances (at standard pressure), liquid water cannot be heated above 100 °C in an open vessel. Further heating results in boiling, but does not raise the temperature of the liquid water. However, when water is heated in a sealed vessel such as an autoclave, it is possible to heat liquid water to a much higher temperature. As the container is heated the pressure rises due to the constant volume of the container (see the ideal gas law). The boiling point of the water is raised because the amount of energy needed to form steam against the higher pressure is increased.
This works well on solid objects; when autoclaving hollow objects, however, (hypodermic needles, tools, etc.), it is important to ensure that all of the trapped air inside the hollow compartments is removed. Autoclaves may achieve air removal by downward displacement, super atmospheric, transatmospheric or sub-atmospheric pulses.
Autoclaves are widely used in microbiology, medicine, veterinary science, dentistry, podiatry and metallurgy. The large carbon-fiber composite parts for the Boeing 787, such as wing and fuselage parts, are cured in large autoclaves.[2]
# Autoclaves in medicine
A medical autoclave is a device that uses steam to sterilize equipment and other objects. This means that all bacteria, viruses, fungi, and spores are inactivated. However, in 2003 scientists discovered a single-celled organism, Strain 121, that survives traditional autoclave temperatures.[2] Prions, like those associated with Creutzfeldt-Jakob disease, also may not be destroyed by autoclaving at the typical 121 degrees Celsius for 15 minutes or 134 degrees Celsius for 3 minutes, but can be destroyed with a longer sterilisation cycle of 134 degrees Celsius for 18 minutes.
Autoclaves are found in many medical settings and other places that need to ensure sterility of an object. They were once more common, but many procedures today use single-use items rather than sterilized, reusable items. This first happened with hypodermic needles, but today many surgical instruments (such as forceps, needle holders, and scalpel handles) are commonly single-use items rather than reusable. See waste autoclave.
Because damp heat is used, heat-labile products (such as some plastics) cannot be sterilised this way or they will melt. Some paper or other products that may be damaged by the steam must also be sterilized another way. In all autoclaves, items should always be separated to allow the steam to penetrate the load evenly.
Autoclaving is often used to sterilize medical waste prior to disposal in the standard municipal solid waste stream. This application has grown as an alternative to incineration due to environmental and health concerns raised by combustion byproducts from incinerators, especially from the small units which were commonly operated at individual hospitals. Incineration or a similar thermal oxidation process is still generally mandated for pathological waste and other very toxic and/or infectious medical wastes.
# Chemiclave
Unlike the humid environment produced by conventional steam, the unsaturated chemical vapor method is a low-humidity process. No time-consuming drying phase is needed, because nothing gets wet. The heat-up time is shorter than for most steam sterilizers, and the heaters stay on between cycles to minimize warm-up time and increase the instrument turnover.
# Autoclave quality assurance
There are physical, chemical, and biological indicators that can be used to ensure an autoclave reaches the correct temperature for the correct amount of time.
Chemical indicators can be found on medical packaging and autoclave tape, and these change color once the correct conditions have been met. This color change indicates that the object inside the package, or under the tape, has been autoclaved sufficiently. Biological indicators include attest devices. These contain spores of a heat-resistant bacterium, Geobacillus stearothermophilus. If the autoclave does not reach the right temperature, the spores will germinate, and their metabolism will change the color of a pH-sensitive chemical. Physical indicators often consist of an alloy designed to melt only after being subjected to 121°C or 249°F for 15 minutes. If the alloy melts, the change will be visible.
In addition to these indicators, autoclaves have timers, temperature and pressure gauges that can be viewed from the outside.
There are certain plastics that can withstand repeated temperature cycling greater than the 121°C or 249°F required for the autoclaving process. PFA is an example.
Some computer-controlled autoclaves use an F0 (F-naught) value to control the sterilization cycle. F0 values are set as the number of minutes of equivalent sterilization at 121°C or 249°F (e.g: F0 = 15 min.). Since exact temperature control is difficult, the temperature is monitored, and the sterilization time adjusted accordingly. | https://www.wikidoc.org/index.php/Autoclavation | |
449848fb5a7b4baefe0963ee82cf99ba32c199ae | wikidoc | Autotaxin | Autotaxin
Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (E-NPP 2), is an enzyme that in humans is encoded by the ENPP2 gene.
# Function
Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2), is a secreted enzyme important for generating the lipid signaling molecule lysophosphatidic acid (LPA). Autotaxin has lysophospholipase D activity that converts lysophosphatidylcholine into LPA.
Autotaxin was originally identified as a tumor cell-motility-stimulating factor; later it was shown to be LPA (which signals through lysophospholipid receptors), the lipid product of the reaction catalyzed by autotaxin, which is responsible for its effects on cell-proliferation.
The protein encoded by this gene functions as a phosphodiesterase. Autotaxin is secreted and further processed to make the biologically active form. Several alternatively spliced transcript variants have been identified. Autotaxin is able to cleave the phosphodiester bond between the α and the β position of triphosphate nucleotides, acting as an ectonucleotide phosphodiesterase producing pyrophosphate, as most members of the ENPP family. Importantly, autotaxin also acts as phospholipase, catalyzing the removal of the head group of various lysolipids. The physiological function of autotaxin is the production of the signalling lipid lysophosphatidic acid (LPA) in extracellular fluids. LPA evokes growth factor-like responses including stimulation of cell proliferation and chemotaxis. This gene product stimulates the motility of tumor cells, has angiogenic properties, and its expression is up-regulated in several kinds of tumours. Also, autotaxin and LPA are involved in numerous inflammatory-driven diseases such as asthma and arthritis. Physiologically, LPA helps promote wound healing responses to tissue damage. Under normal circumstances, LPA negatively regulates autotaxin transcription, but in the context of wound repair, cytokines induce autotaxin expression to increase overall LPA concentrations.
It has been shown that autotaxin's function can be regulated by certain steroids, namely bile acids.
# As a drug target
Various small molecule inhibitors of autotaxin have been developed for clinical applications. A specific inhibitor against idiopathic pulmonary fibrosis showed promising results in a phase II trial that ended in May 2018. A DNA aptamer inhibitor of Autotaxin has also been described.
# Structure
The crystal structures rat and mouse autotaxin have been solved. In each case, the apo structure have been solved along with product or inhibitor bound complexes. Both proteins consist of 4 domains, 2 N-terminal somatomedin-B-like (SMB) domains which may be involved in cell-surface localisation. The catalytic domain follows and contains a deep hydrophobic pocket in which the lipid substrate binds. At the C-terminus is the inactive nuclease domain which may function to aid protein stability. | Autotaxin
Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (E-NPP 2), is an enzyme that in humans is encoded by the ENPP2 gene.[1][2]
# Function
Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2), is a secreted enzyme important for generating the lipid signaling molecule lysophosphatidic acid (LPA). Autotaxin has lysophospholipase D activity that converts lysophosphatidylcholine into LPA.
Autotaxin was originally identified as a tumor cell-motility-stimulating factor; later it was shown to be LPA (which signals through lysophospholipid receptors), the lipid product of the reaction catalyzed by autotaxin, which is responsible for its effects on cell-proliferation.
The protein encoded by this gene functions as a phosphodiesterase. Autotaxin is secreted and further processed to make the biologically active form. Several alternatively spliced transcript variants have been identified. Autotaxin is able to cleave the phosphodiester bond between the α and the β position of triphosphate nucleotides, acting as an ectonucleotide phosphodiesterase producing pyrophosphate, as most members of the ENPP family. Importantly, autotaxin also acts as phospholipase, catalyzing the removal of the head group of various lysolipids. The physiological function of autotaxin is the production of the signalling lipid lysophosphatidic acid (LPA) in extracellular fluids. LPA evokes growth factor-like responses including stimulation of cell proliferation and chemotaxis. This gene product stimulates the motility of tumor cells, has angiogenic properties, and its expression is up-regulated in several kinds of tumours.[2] Also, autotaxin and LPA are involved in numerous inflammatory-driven diseases such as asthma and arthritis.[3] Physiologically, LPA helps promote wound healing responses to tissue damage. Under normal circumstances, LPA negatively regulates autotaxin transcription, but in the context of wound repair, cytokines induce autotaxin expression to increase overall LPA concentrations.[4]
It has been shown that autotaxin's function can be regulated by certain steroids, namely bile acids.[5]
# As a drug target
Various small molecule inhibitors of autotaxin have been developed for clinical applications. A specific inhibitor against idiopathic pulmonary fibrosis showed promising results in a phase II trial that ended in May 2018.[6] A DNA aptamer inhibitor of Autotaxin has also been described.[7]
# Structure
The crystal structures rat[8] and mouse autotaxin[9] have been solved. In each case, the apo structure have been solved along with product or inhibitor bound complexes. Both proteins consist of 4 domains, 2 N-terminal somatomedin-B-like (SMB) domains which may be involved in cell-surface localisation. The catalytic domain follows and contains a deep hydrophobic pocket in which the lipid substrate binds. At the C-terminus is the inactive nuclease domain which may function to aid protein stability. | https://www.wikidoc.org/index.php/Autotaxin | |
e6b968050cde2e8377f0b6d5fdfc9ec2460be064 | wikidoc | Autotroph | Autotroph
An autotroph (from the Greek autos = self and trophe = nutrition) is an organism that produces complex organic compounds from simple inorganic molecules using energy from light or inorganic chemical reactions.
Autotrophs are the producers in a food chain. Plants and other organisms which carry out photosynthesis are photoautotrophs (or phototrophs). Bacteria which derive energy from oxidizing inorganic compounds (such as hydrogen sulfide, ammonium and ferrous iron) are chemoautotrophs, and include the lithotrophs.
Autotrophs are fundamental to the food chains of all plant ecosystems. They take energy from the environment (in the form of sunlight or inorganic chemicals) and use it to create carbon-based organic molecules. Other organisms, called heterotrophs, take in autotrophs as food to carry out such functions. Thus, heterotrophs — animals, fungi, as well as most bacteria and protozoa — depend on autotrophs for the energy and raw materials they need. This mechanism is called primary production in the sea. Heterotrophs obtain energy by breaking down organic molecules obtained in food. Carnivorous animals ultimately rely on autotrophs because the energy and organic building blocks obtained from their prey comes from autotrophs they preyed upon.
There are some species(species come from the ground or the soil) of organisms that require organic compounds as a source of carbon, but are able to use light or inorganic compounds as a source of energy. Such organisms are not defined as autotrophic, but rather as heterotrophic. An organism that obtains carbon from organic compounds but obtains energy from light is called a photoheterotroph, while an organism that obtains carbon from organic compounds but obtains energy from the oxidation of inorganic compounds is termed a chemoheterotroph.
- Heterotrophic
- Mixotrophic
- Primary nutritional groups
- Saprotrophic | Autotroph
An autotroph (from the Greek autos = self and trophe = nutrition) is an organism that produces complex organic compounds from simple inorganic molecules using energy from light or inorganic chemical reactions.
Autotrophs are the producers in a food chain. Plants and other organisms which carry out photosynthesis are photoautotrophs (or phototrophs). Bacteria which derive energy from oxidizing inorganic compounds (such as hydrogen sulfide, ammonium and ferrous iron) are chemoautotrophs, and include the lithotrophs.
Autotrophs are fundamental to the food chains of all plant ecosystems. They take energy from the environment (in the form of sunlight or inorganic chemicals) and use it to create carbon-based organic molecules. Other organisms, called heterotrophs, take in autotrophs as food to carry out such functions. Thus, heterotrophs — animals, fungi, as well as most bacteria and protozoa — depend on autotrophs for the energy and raw materials they need. This mechanism is called primary production in the sea. Heterotrophs obtain energy by breaking down organic molecules obtained in food. Carnivorous animals ultimately rely on autotrophs because the energy and organic building blocks obtained from their prey comes from autotrophs they preyed upon.
There are some species(species come from the ground or the soil) of organisms that require organic compounds as a source of carbon, but are able to use light or inorganic compounds as a source of energy. Such organisms are not defined as autotrophic, but rather as heterotrophic. An organism that obtains carbon from organic compounds but obtains energy from light is called a photoheterotroph, while an organism that obtains carbon from organic compounds but obtains energy from the oxidation of inorganic compounds is termed a chemoheterotroph.
- Heterotrophic
- Mixotrophic
- Primary nutritional groups
- Saprotrophic | https://www.wikidoc.org/index.php/Autotroph | |
bb6cc2195761ea9fdab583651361f533073d8d19 | wikidoc | Auxospore | Auxospore
In certain species of diatoms, auxospores are specialised cells that are produced at key stages in their cell cycle or life history. Auxospores typically play a role in growth processes, sexual reproduction or dormancy.
Auxospores are involved in re-establishing the normal size in diatoms because successive mitotic cell divisions leads to a decrease in cell size. This occurs because each daughter cell produced by cell division inherits one of the two valves that make up the silica cell wall, and then grows a smaller valve within it. Consequently, each division cycle decreases the average size of diatom cells in a population. When its size becomes too small, a dividing diatom cell produces an auxospore to expand its cell size back to that which is normal for vegetative cells.
Auxospores can also play a role in sexual reproduction in diatoms, and may be formed after haploid gametes fuse to form a diploid zygote.
Finally, auxospores can be produced by diatoms to act as dormant stages, sometimes referred to as "resting spores". These are used to survive periods of time that are unfavourable to growth, such as winter or while nutrients are depleted. | Auxospore
In certain species of diatoms, auxospores are specialised cells that are produced at key stages in their cell cycle or life history. Auxospores typically play a role in growth processes, sexual reproduction or dormancy[1].
Auxospores are involved in re-establishing the normal size in diatoms because successive mitotic cell divisions leads to a decrease in cell size. This occurs because each daughter cell produced by cell division inherits one of the two valves that make up the silica cell wall, and then grows a smaller valve within it. Consequently, each division cycle decreases the average size of diatom cells in a population. When its size becomes too small, a dividing diatom cell produces an auxospore to expand its cell size back to that which is normal for vegetative cells[2].
Auxospores can also play a role in sexual reproduction in diatoms, and may be formed after haploid gametes fuse to form a diploid zygote[3].
Finally, auxospores can be produced by diatoms to act as dormant stages, sometimes referred to as "resting spores". These are used to survive periods of time that are unfavourable to growth, such as winter or while nutrients are depleted[1]. | https://www.wikidoc.org/index.php/Auxospore | |
9a768b4774705f3401364ae10f739af73334b6b7 | wikidoc | Avisodomy | Avisodomy
# Background
Avisodomy is the act of a human engaging in sexual activity that involves a bird. Due to the size difference between the species, any act involving penetration is usually fatal to the bird.
R.E.L. Masters, in his book (1962) describes it and other zoosadistic acts under "related perversions" as follows:
According to de Sade, a variant of this bestial pleasure with the goose was to be found in the parisian brothels of his day. Known as avisodomy, it was accomplished, as described by the Marquis, in this way: " ... the girl holds the bird's (turkey's) neck locked between her thighs, you have her ass straight ahead of you for prospect, and she cuts the bird's throat the same moment you discharge.
Some descriptions of this act feature the perpetrator breaking the bird's neck as the moment of orgasm approaches.
# Other references
- One of the tracks on Whitehouse's album Erector is titled "Avisodomy".
- An episode of South Park entitled Chickenlover, wherein an unknown perpetrator molests the town's chickens.
- David Lynch's cartoon series Dumbland features a character described as a "one armed duck fucker".
- In Mario Vargas Llosa's novel, La Ciudad y los Perros (1962), one of the characters, a cadet nicknamed Boa, engages in sexual acts with hens to satisfy his libido.
- In the Rob Zombie's film, The Devil's Rejects (2005), when a character enquires about purchasing a chicken. | Avisodomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Avisodomy is the act of a human engaging in sexual activity that involves a bird. Due to the size difference between the species, any act involving penetration is usually fatal to the bird.[citation needed]
R.E.L. Masters, in his book (1962) describes it and other zoosadistic acts under "related perversions" as follows:
According to de Sade, a variant of this bestial pleasure with the goose was to be found in the parisian brothels of his day. Known as avisodomy, it was accomplished, as described by the Marquis, in this way: " ... the girl holds the bird's (turkey's) neck locked between her thighs, you have her ass straight ahead of you for prospect, and she cuts the bird's throat the same moment you discharge.
Some descriptions of this act feature the perpetrator breaking the bird's neck as the moment of orgasm approaches.
# Other references
- One of the tracks on Whitehouse's album Erector is titled "Avisodomy".
- An episode of South Park entitled Chickenlover, wherein an unknown perpetrator molests the town's chickens.
- David Lynch's cartoon series Dumbland features a character described as a "one armed duck fucker".
- In Mario Vargas Llosa's novel, La Ciudad y los Perros (1962), one of the characters, a cadet nicknamed Boa, engages in sexual acts with hens to satisfy his libido.
- In the Rob Zombie's film, The Devil's Rejects (2005), when a character enquires about purchasing a chicken. | https://www.wikidoc.org/index.php/Avisodomy | |
dd0a308b72861b0addf75c2d9381661edfda5891 | wikidoc | Avolition | Avolition
# Overview
Avolition is a psychological state characterized by general lack of desire, motivation, and persistence. Commonly seen in patients with schizophrenia, those suffering from avolition will not start or complete any major tasks. This differs from anhedonia, where patients generally find task completion pleasureless.
It is the reduction, difficulty, or inability to initiate and/or persist in goal-directed behavior; it is quite often mistaken for apparent disinterest.
Avolition refers to the lack of initiative, or loss in drive and motivation to pursue realistic goals. Avolition is one of the four (affective flattening, alogia, anhedronia) main 'negative' symptoms of Schizophrenia.
DSM IV criteria for schizophrenia or schizo-affective disorder:
Characteristic symptoms are two (or more) of the following, each present for a significant portion
-f time during a 1-month period: delusions, hallucinations, disorganized speech (e.g., frequent derailment or incoherence), grossly disorganized or catatonic behavior, negative symptoms, i.e., affective flattening, alogia, or avolition. | Avolition
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Avolition is a psychological state characterized by general lack of desire, motivation, and persistence. Commonly seen in patients with schizophrenia, those suffering from avolition will not start or complete any major tasks. This differs from anhedonia, where patients generally find task completion pleasureless.
It is the reduction, difficulty, or inability to initiate and/or persist in goal-directed behavior; it is quite often mistaken for apparent disinterest.
Avolition refers to the lack of initiative, or loss in drive and motivation to pursue realistic goals. Avolition is one of the four (affective flattening, alogia, anhedronia) main 'negative' symptoms of Schizophrenia. [1]
DSM IV criteria for schizophrenia or schizo-affective disorder:
Characteristic symptoms are two (or more) of the following, each present for a significant portion
of time during a 1-month period: delusions, hallucinations, disorganized speech (e.g., frequent derailment or incoherence), grossly disorganized or catatonic behavior, negative symptoms, i.e., affective flattening, alogia, or avolition. [2] | https://www.wikidoc.org/index.php/Avolition | |
4515a6a579a3b4526e4f3ba709bae49210f15827 | wikidoc | Ayahuasca | Ayahuasca
Ayahuasca (Quechua, pronounced Template:IPA) is any of various psychoactive infusions or decoctions prepared from the Banisteriopsis spp. vine, native to the Amazon Rainforest (which is also called ayahuasca). The resulting drinks are pharmacologically complex and used for shamanic, folk-medicinal, and religious purposes.
## Preparation
Sections of vine are macerated and boiled alone or with leaves from any of a large number of other plants, including Psychotria viridis (chakruna in Quechua) or Diplopterys cabrerana (also known as chaliponga). The resulting brew contains MAO inhibiting harmala alkaloids and the powerful hallucinogenic alkaloid N,N-dimethyltryptamine (DMT), a psychedelic which is active orally only when combined with an MAOI. Harmala alkaloids in Banisteriopsis caapi serve as MAOIs in Ayahuasca. Western brews sometimes substitute plant sources such as Syrian Rue or other harmala containing plants in lieu of the Banisteriopsis caapi vine, but the vine itself is always central to traditional usage.
Brews are also made with no DMT-containing plants; sometimes they are made with plants such as Justicia pectoralis, Brugmansia and sometimes made with no plants other than the ayahuasca vine itself. Tobacco is a common additive in traditional brews. The potency of this brew varies radically from one batch to the next, both in strength and psychoactive effect, based mainly on the skill of the shaman or brewer, as well as other admixtures sometimes added. Natural variations in plant alkaloid content and profiles also affect the final concentration of alkaloids in the brew, and the physical act of cooking may also serve to modify the alkaloid profile of harmala alkaloids.
Individual polymorphisms in the cytochrome P450-2D6 enzyme affects the ability of individuals to metabolize harmine. Some natural tolerance to the regular use of Ayahuasca (say, once weekly) may be seen as an upregulation of the serotonergic system. A phase 1 pharmacokinetic study on Ayahuasca (as Hoasca) with 15 volunteers was conducted in 1993, during the Hoasca Project. A review of the Hoasca Project has been published.
# Names
- "caapi", "cipó," "hoasca" or "daime" in Brazil
- "yagé" or "yajé" (both pronounced Template:IPA) in Colombia; popularized in English by the beat generation writers William S. Burroughs and Allen Ginsberg in The Yage Letters.
- "ayahuasca" or "ayawaska" in Ecuador, Bolivia and Peru, also to a lesser extent in Brazil ("vine of the dead" or "vine of souls": in Quechua, aya means "spirit," "ancestor," or "dead person," while waska means "vine" or "rope"). The name is properly that of the plant B. caapi, one of the primary sources of beta-carbolines for the brew.
- "natem" amongst the indigenous Shuar people of Peru.
The spelling ayahuasca is the hispanicized version of the name; many Quechua or Aymara speakers would prefer the spelling ayawaska. In the central Andeans of Perú, Ayacwasca means: "Ayac" (spirit or dead) and "Wasca" (vine, cord or rope)
# Usage
Ayahuasca is used largely as a religious sacrament, no matter which culture it is associated with. Those whose usage of ayahuasca is performed in non-traditional contexts often align themselves with the philosophies and cosmologies associated with ayahuasca shamanism, as practiced among indigenous peoples like the Urarina of Peruvian Amazonia.
While non-native users know of the spiritual applications of ayahuasca, a less well-known traditional usage focuses on the medicinal properties of ayahuasca. Its purgative properties are highly important (many refer to it as la Purga, "the purge"). The intense vomiting and occasional diarrhea it induces can clear the body of worms and other tropical parasites, and harmala alkaloids themselves have been shown to be anthelmintic. Thus, this action is twofold; a direct action on the parasites by these harmala alkaloids (particularly harmine in ayahuasca) works to kill the parasites, and parasites are expelled through the increased intestinal motility that is caused by these alkaloids.
Dietary taboos are almost always associated with the use of Ayahuasca; in the rainforest, these tend towards the purification of one's self- abstaining from spicy and heavily seasoned foods, fat, salt, caffeine, acidic foods (such as citrus) and sex before, after, or both before and after a ceremony. A diet low in foods containing tyramine is recommended, as the interaction of tyramine and MAOIs can lead to a hypertensive crisis. This extreme dietary specificity is largely a modern one, as most tyramine is produced as food ages, and is therefore not usually a problem in traditional South American cultures. These dietary restrictions have developed as a means of making ayahuasca ingestion easier on the body, as well as having strong traditional and spiritual significance.
Today, the name 'ayahuasca' can mean a variety of botanical concoctions containing one or more MAOIs and DMT or one of its chemical analogues. The synthetic pharmahuasca is sometimes called ayahuasca as well. In this usage, the DMT is generally considered the main psychoactive active ingredient, while the MAOI merely preserves the psychoactivity of orally ingested DMT, which would otherwise be destroyed in the gut before it could be absorbed in the body. Most ayahuasqueros and others working with the brew claim the B. caapi vine to be the defining ingredient; according to them, it is not ayahuasca unless B. caapi is in the brew. The vine is considered to be the "spirit" of ayahuasca, the gatekeeper and guide to the otherworldly realms.
In some areas, it is even said that the chakruna or chaliponga admixtures are added only to make the brew taste sweeter. This is a strong indicator of the often wildly divergent intentions and cultural differences between the native ayahuasca-using cultures and psychedelics enthusiasts in other countries.
In modern Europe and North America, ayahuasca analogues are often prepared using non-traditional plants which contain the same alkaloids. For example, seeds of the Syrian rue plant are often used as a substitute for the ayawaska vine, and the DMT-rich Mimosa hostilis is used in place of chakruna. Australia has several indigenous plants which are popular among modern ayahuasqueros there, such as various DMT-rich species of Acacia.
In modern Western culture, entheogen users sometimes base concoctions on Ayahuasca. When doing so, most often Rue or B. caapi are used with an alternative form of the DMT molecule, such as psilocin, or a non-DMT based hallucinogen such as mescaline. Nicknames such as Psilohuasca, Mush-rue-asca, or 'Shroom-a-huasca, for mushroom based mixtures, or Pedrohuasca (from the San Pedro Cactus, which contains mescaline) are often given to such brews. Such nicknames are by many considered inappropriate and culturally insensitive seeing as "huasca" means "vine" and none of the above are vines, nor do the psychedelic experimentalist trappings of such concoctions bear any resemblance to the medicinal use of Ayahuasca in its original cultural context. This is usually only done by experienced entheogen users who are more familiar with the chemicals and plants being used, as the uninformed combination of various neuro-chemicals can be dangerous.
It seems unlikely that Ayahuasca could ever emerge as a "street-drug", given the difficulty of making the tea and the intense experience it provides. Most Western users employ it almost exclusively for spiritual purposes, in line with both traditional, animist usage and organized churches such as the União do Vegetal (or UDV). A diet is almost always followed before use, including a day of fasting, to rid the body of tyramines and other contraindicated chemicals; a "dieta" is often followed as well, to spiritually cleanse the body before and after the experience. Most recreational drug users have never even heard of Ayahuasca, or the possibility of alterations to the shamanic brew.
## Introduction to the West
Ayahuasca is mentioned in the writings of some of the earliest missionaries to South America, but it wasn't for some time that it became commonly known in the West. The early missionary reports generally claim it as demonic, and great efforts were made by the Roman Catholic Church to stamp it out.
When originally researched in the 20th century, the active chemical constituent of B. caapi was called telepathine, but it was found to be identical to a chemical already isolated from Peganum harmala and given the name harmaline.
William Burroughs sought yagé (still considered to be "telepathine") in the 1950s while traveling through South America, in the hopes that it could relieve or cure opiate addiction. The Yage Letters, written between Burroughs and Allen Ginsberg were probably the first major introduction of Ayahuasca to the West.
Ayahuasca was made more widely known by Terence and Dennis McKenna's experiences with Amazonian tribes as detailed in the book Invisible Landscape, which they co-authored. Their journey to the rainforest to search for Ayahuasca was spurred by their reading of Burroughs and Ginsberg. Dennis later extensively studied the pharmacology, botany, and chemistry of ayahuasca and oo-koo-he, which were the subjects of his master's thesis.
In Brazil, a number of modern religious movements based on the use of ayahuasca have emerged, the most famous of them being Santo Daime and the União do Vegetal (or UDV), usually in an animistic context that may be shamanistic or, more often (as with Santo Daime and the UDV), integrated with Christianity. Both Santo Daime and União do Vegetal now have members and churches throughout the world.
Similarly, the US and Europe have started to see new religious groups develop in relation to increased ayahuasca use. PaDeva, an American Wiccan group, has become the first incorporated legal church which holds the use of ayahuasca central to their beliefs.
Several notable celebrities have publicly discussed their use of ayahuasca, including Sting, Tori Amos, and Paul Simon (who wrote the song Spirit Voices about his experience with the brew in the Amazon).
Some Westerners have teamed up with shamans in the Amazon rainforest regions, forming Ayahuasca healing retreats that claim to be able to cure mental and physical illness and allow communication with the spirit world. Though both anecdotal reports and scientific studies affirm that ritualized use of ayahuasca may improve mental and physical health, the monoamine oxidase inhibitor (MAOI) component of the brew is a powerful compound that interacts with many foods that some Westerners would not consider dangerous, from liver to Vegemite. Therefore, observing strict dietary restrictions is required before taking ayahuasca.
## "Ayahuasca tourism"
"Ayahuasca tourists" is a slighting term for those who quest for a transcendent experience through using ayahuasca and usually implies insincere Westerners who want a taste of an exotic ritual. Not all Westerners who have teamed up with Amazonian shamans are considered "ayahuasca tourists", or provide modified services directed specifically to Westerners. Genuine pilgrims from Colombia, Argentina, or Mexico also come for ayahuasca healing.
People such as these include many explorers of consciousness, writers, researchers, medical doctors, journalists, amateur anthropologists and ethno botanists, alongside vision quest seekers, and knowledge seekers who take part in ayahuasca retreats. The retreats offer the encounter with ayahuasca as an opportunity to re-balance and re-centre their lives, to clear emotional blocks, in a way that has to do with healing and personal evolution.
## Initiation
Usually a visitor who wishes to becomes a "dietero" or "dietera" that is, a male or female apprentice-shaman learning the way of the teacher plants undergoes a rigorous initiation. This can involve spending a year in the jungle. This initiation challenges and trains the initiate through extreme circumstances covering isolation, deprivation from utilities available in civilization and its conveniences, enduring radical weather of heavy rains, storms, intense heat, insects and solitude.
# Modern descriptions
Wade Davis (author of The Serpent and The Rainbow) describes the traditional mixture as tough in his book One River: "The smell and acrid taste was that of the entire jungle ground up and mixed with bile."
Writer Kira Salak describes her personal experiences with ayahuasca in the March 2006 issue of magazine. The article includes a candid description of how ayahuasca cured her depression, as well as provides detailed information about the brew. Here is an excerpt from the article about Dr. Charles Grob's landmark findings:
The taking of ayahuasca has been associated with a long list of documented cures: the disappearance of everything from metastasized colorectal cancer to cocaine addiction, even after just a ceremony or two. It has been medically proven to be nonaddictive and safe to ingest. Yet Western scientists have all but ignored it for decades, reluctant to risk their careers by researching a substance containing the outlawed DMT. Only in the past decade, and then only by a handful of researchers, has ayahuasca begun to be studied. At the vanguard of this research is Charles Grob, M.D., a professor of psychiatry and pediatrics at UCLA’s School of Medicine.
In 1993 Dr. Grob launched the Hoasca Project, the first in-depth study of the physical and psychological effects of ayahuasca on humans. His team went to Brazil, where the plant mixture can be taken legally, to study members of a church, the União do Vegetal (UDV), who use ayahuasca as a sacrament, and compared them to a control group that had never ingested the substance. The studies found that all the ayahuasca-using UDV members had experienced remission without recurrence of their addictions, depression, or anxiety disorders. Unlike most common anti-depressants, which Grob says can create such high levels of serotonin that cells may actually compensate by losing many of their serotonin receptors, the Hoasca Project showed that ayahuasca strongly enhances the body’s ability to absorb the serotonin that’s naturally there. 'Ayahuasca is perhaps a far more sophisticated and effective way to treat depression than SSRIs ,' Grob concludes, adding that the use of SSRIs is 'a rather crude way' of doing it. And ayahuasca, he insists, has great potential as a long-term solution.
# Plant constituents
## Traditional
Traditional Ayahuasca brews are always made with Banisteriopsis caapi as an MAOI, although DMT sources and other admixtures vary from region to region. There are several varieties of caapi, often known as different "colors", with varying effects, potencies, and uses.
DMT admixtures:
- Psychotria viridis (Chakruna) - leaves
- Diplopterys cabrerana (Chaliponga, Banisteriopsis rusbyana) - leaves
- Psychotria carthagensis (Amyruca) - leaves
Other common admixtures:
- Justicia pectoralis
- Brugmansia (Toé)
- Nicotiana rustica (Mapacho, variety of tobacco)
- Ilex guayusa, a relative of yerba mate
## Western Ayahuasca analogs
Although traditional plant materials are often used, sources with similar chemical constituents are often substituted for the traditional ingredients.
MAOI:
- Harmal (Peganum harmala, Syrian Rue) - seeds
- Passion flower
- medicinal MAOIs
DMT admixture sources:
- Acacia maidenii (Maiden's Wattle), Acacia phlebophylla, and other Acacias, most commonly employed in Australia - bark
- Anadenanthera peregrina, A. colubrina, A. excelsa, A. macrocarpa
- Mimosa hostilis (Jurema) - root bark - not traditionally employed with ayahuasca by any existing cultures, though likely it was in the past. Popular in Europe and North America.
# Legal status
Internationally, DMT is a Schedule I drug under the Convention on Psychotropic Substances. The Commentary on the Convention on Psychotropic Substances notes, however, that the plant itself is excluded from international control:
A fax from the Secretary of the International Narcotics Control Board to the Netherlands Ministry of Public Health sent in 2001 goes on to state that "Consequently, preparations (e.g.decoctions) made of these plants, including ayahuasca, are not under international control and, therefore, not subject to any of the articles of the 1971 Convention."
The legal status of these plants in the United States is somewhat questionable. Ayahuasca plants and preparations are legal as they contain no scheduled chemicals. However, brews made using DMT containing plants are illegal since DMT is a Schedule I drug. That said, some people are challenging this, using arguments similar to those used by peyotist religious sects, such as the Native American Church. A court case allowing União do Vegetal to use the tea for religious purposes in the United States, Gonzales v. O Centro Espirita Beneficente Uniao do Vegetal, was heard by the U.S. Supreme Court on November 1, 2005; the decision, released February 21, 2006, allows the UDV to use the tea in its ceremonies pursuant to the Religious Freedom Restoration Act.
Religious use in Brazil was legalized after two official inquiries into the tea in the mid-1980s, which concluded that ayahuasca is not a recreational drug and has valid spiritual uses. (More on the legal status of ayahuasca can be found in the Erowid vault on the legality of ayahuasca.)
In France, Santo Daime won a court case allowing them to use the tea in early 2005; however, they were not allowed an exception for religious purposes, but rather for the simple reason that they did not perform chemical extractions to end up with pure DMT and harmala and the plants used were not scheduled. Four months after the court victory, the common ingredients of Ayahuasca as well as harmala were declared stupéfiants, or narcotic schedule I substances, making the tea and its ingredients illegal to use or possess. See and Template:Fr icon for more information. | Ayahuasca
Ayahuasca (Quechua, pronounced Template:IPA) is any of various psychoactive infusions or decoctions prepared from the Banisteriopsis spp. vine, native to the Amazon Rainforest (which is also called ayahuasca). The resulting drinks are pharmacologically complex and used for shamanic, folk-medicinal, and religious purposes.
## Preparation
Sections of vine are macerated and boiled alone or with leaves from any of a large number of other plants, including Psychotria viridis (chakruna in Quechua) or Diplopterys cabrerana (also known as chaliponga). The resulting brew contains MAO inhibiting harmala alkaloids and the powerful hallucinogenic alkaloid N,N-dimethyltryptamine (DMT), a psychedelic which is active orally only when combined with an MAOI. Harmala alkaloids in Banisteriopsis caapi serve as MAOIs in Ayahuasca. Western brews sometimes substitute plant sources such as Syrian Rue or other harmala containing plants in lieu of the Banisteriopsis caapi vine, but the vine itself is always central to traditional usage.
Brews are also made with no DMT-containing plants; sometimes they are made with plants such as Justicia pectoralis, Brugmansia and sometimes made with no plants other than the ayahuasca vine itself. Tobacco is a common additive in traditional brews. The potency of this brew varies radically from one batch to the next, both in strength and psychoactive effect, based mainly on the skill of the shaman or brewer, as well as other admixtures sometimes added. Natural variations in plant alkaloid content and profiles also affect the final concentration of alkaloids in the brew, and the physical act of cooking may also serve to modify the alkaloid profile of harmala alkaloids.[1][2]
Individual polymorphisms in the cytochrome P450-2D6 enzyme affects the ability of individuals to metabolize harmine.[3] Some natural tolerance to the regular use of Ayahuasca (say, once weekly) may be seen as an upregulation of the serotonergic system.[4] A phase 1 pharmacokinetic study on Ayahuasca (as Hoasca) with 15 volunteers was conducted in 1993, during the Hoasca Project.[5] A review of the Hoasca Project has been published.[6]
# Names
- "caapi", "cipó," "hoasca" or "daime" in Brazil
- "yagé" or "yajé" (both pronounced Template:IPA) in Colombia; popularized in English by the beat generation writers William S. Burroughs and Allen Ginsberg in The Yage Letters.
- "ayahuasca" or "ayawaska" in Ecuador, Bolivia and Peru, also to a lesser extent in Brazil ("vine of the dead" or "vine of souls": in Quechua, aya means "spirit," "ancestor," or "dead person," while waska means "vine" or "rope"). The name is properly that of the plant B. caapi, one of the primary sources of beta-carbolines for the brew.
- "natem" amongst the indigenous Shuar people of Peru.
The spelling ayahuasca is the hispanicized version of the name; many Quechua or Aymara speakers would prefer the spelling ayawaska. In the central Andeans of Perú, Ayacwasca means: "Ayac" (spirit or dead) and "Wasca" (vine, cord or rope)
# Usage
Ayahuasca is used largely as a religious sacrament, no matter which culture it is associated with. Those whose usage of ayahuasca is performed in non-traditional contexts often align themselves with the philosophies and cosmologies associated with ayahuasca shamanism, as practiced among indigenous peoples like the Urarina of Peruvian Amazonia.
While non-native users know of the spiritual applications of ayahuasca, a less well-known traditional usage focuses on the medicinal properties of ayahuasca. Its purgative properties are highly important (many refer to it as la Purga, "the purge"). The intense vomiting and occasional diarrhea it induces can clear the body of worms and other tropical parasites,[7] and harmala alkaloids themselves have been shown to be anthelmintic[8]. Thus, this action is twofold; a direct action on the parasites by these harmala alkaloids (particularly harmine in ayahuasca) works to kill the parasites, and parasites are expelled through the increased intestinal motility that is caused by these alkaloids.
Dietary taboos are almost always associated with the use of Ayahuasca; in the rainforest, these tend towards the purification of one's self- abstaining from spicy and heavily seasoned foods, fat, salt, caffeine, acidic foods (such as citrus) and sex before, after, or both before and after a ceremony. A diet low in foods containing tyramine is recommended, as the interaction of tyramine and MAOIs can lead to a hypertensive crisis. This extreme dietary specificity is largely a modern one, as most tyramine is produced as food ages, and is therefore not usually a problem in traditional South American cultures. These dietary restrictions have developed as a means of making ayahuasca ingestion easier on the body, as well as having strong traditional and spiritual significance.
Today, the name 'ayahuasca' can mean a variety of botanical concoctions containing one or more MAOIs and DMT or one of its chemical analogues. The synthetic pharmahuasca is sometimes called ayahuasca as well. In this usage, the DMT is generally considered the main psychoactive active ingredient, while the MAOI merely preserves the psychoactivity of orally ingested DMT, which would otherwise be destroyed in the gut before it could be absorbed in the body. Most ayahuasqueros and others working with the brew claim the B. caapi vine to be the defining ingredient; according to them, it is not ayahuasca unless B. caapi is in the brew. The vine is considered to be the "spirit" of ayahuasca, the gatekeeper and guide to the otherworldly realms.
In some areas, it is even said that the chakruna or chaliponga admixtures are added only to make the brew taste sweeter. This is a strong indicator of the often wildly divergent intentions and cultural differences between the native ayahuasca-using cultures and psychedelics enthusiasts in other countries.
In modern Europe and North America, ayahuasca analogues are often prepared using non-traditional plants which contain the same alkaloids. For example, seeds of the Syrian rue plant are often used as a substitute for the ayawaska vine, and the DMT-rich Mimosa hostilis is used in place of chakruna. Australia has several indigenous plants which are popular among modern ayahuasqueros there, such as various DMT-rich species of Acacia.
In modern Western culture, entheogen users sometimes base concoctions on Ayahuasca. When doing so, most often Rue or B. caapi are used with an alternative form of the DMT molecule, such as psilocin, or a non-DMT based hallucinogen such as mescaline. Nicknames such as Psilohuasca, Mush-rue-asca, or 'Shroom-a-huasca, for mushroom based mixtures, or Pedrohuasca (from the San Pedro Cactus, which contains mescaline) are often given to such brews. Such nicknames are by many considered inappropriate and culturally insensitive seeing as "huasca" means "vine" and none of the above are vines, nor do the psychedelic experimentalist trappings of such concoctions bear any resemblance to the medicinal use of Ayahuasca in its original cultural context. This is usually only done by experienced entheogen users who are more familiar with the chemicals and plants being used, as the uninformed combination of various neuro-chemicals can be dangerous.
It seems unlikely that Ayahuasca could ever emerge as a "street-drug", given the difficulty of making the tea and the intense experience it provides. Most Western users employ it almost exclusively for spiritual purposes, in line with both traditional, animist usage and organized churches such as the União do Vegetal (or UDV). A diet is almost always followed before use, including a day of fasting, to rid the body of tyramines and other contraindicated chemicals; a "dieta" is often followed as well, to spiritually cleanse the body before and after the experience. Most recreational drug users have never even heard of Ayahuasca, or the possibility of alterations to the shamanic brew.
## Introduction to the West
Ayahuasca is mentioned in the writings of some of the earliest missionaries to South America, but it wasn't for some time that it became commonly known in the West. The early missionary reports generally claim it as demonic, and great efforts were made by the Roman Catholic Church to stamp it out.
When originally researched in the 20th century, the active chemical constituent of B. caapi was called telepathine, but it was found to be identical to a chemical already isolated from Peganum harmala and given the name harmaline.
William Burroughs sought yagé (still considered to be "telepathine") in the 1950s while traveling through South America, in the hopes that it could relieve or cure opiate addiction. The Yage Letters, written between Burroughs and Allen Ginsberg were probably the first major introduction of Ayahuasca to the West.
Ayahuasca was made more widely known by Terence and Dennis McKenna's experiences with Amazonian tribes as detailed in the book Invisible Landscape, which they co-authored. Their journey to the rainforest to search for Ayahuasca was spurred by their reading of Burroughs and Ginsberg. Dennis later extensively studied the pharmacology, botany, and chemistry of ayahuasca and oo-koo-he, which were the subjects of his master's thesis.
In Brazil, a number of modern religious movements based on the use of ayahuasca have emerged, the most famous of them being Santo Daime and the União do Vegetal (or UDV), usually in an animistic context that may be shamanistic or, more often (as with Santo Daime and the UDV), integrated with Christianity. Both Santo Daime and União do Vegetal now have members and churches throughout the world.
Similarly, the US and Europe have started to see new religious groups develop in relation to increased ayahuasca use. PaDeva, an American Wiccan group, has become the first incorporated legal church which holds the use of ayahuasca central to their beliefs.
Several notable celebrities have publicly discussed their use of ayahuasca, including Sting, Tori Amos, and Paul Simon (who wrote the song Spirit Voices about his experience with the brew in the Amazon).
Some Westerners have teamed up with shamans in the Amazon rainforest regions, forming Ayahuasca healing retreats that claim to be able to cure mental and physical illness and allow communication with the spirit world. Though both anecdotal reports and scientific studies affirm that ritualized use of ayahuasca may improve mental and physical health,[9] the monoamine oxidase inhibitor (MAOI) component of the brew is a powerful compound that interacts with many foods that some Westerners would not consider dangerous, from liver to Vegemite. Therefore, observing strict dietary restrictions is required before taking ayahuasca.
## "Ayahuasca tourism"
"Ayahuasca tourists" is a slighting term for those who quest for a transcendent experience through using ayahuasca and usually implies insincere Westerners who want a taste of an exotic ritual. Not all Westerners who have teamed up with Amazonian shamans are considered "ayahuasca tourists", or provide modified services directed specifically to Westerners. Genuine pilgrims from Colombia, Argentina, or Mexico also come for ayahuasca healing.
People such as these include many explorers of consciousness, writers, researchers, medical doctors, journalists, amateur anthropologists and ethno botanists, alongside vision quest seekers, and knowledge seekers who take part in ayahuasca retreats. The retreats offer the encounter with ayahuasca as an opportunity to re-balance and re-centre their lives, to clear emotional blocks, in a way that has to do with healing and personal evolution.
## Initiation
Usually a visitor who wishes to becomes a "dietero" or "dietera" that is, a male or female apprentice-shaman learning the way of the teacher plants undergoes a rigorous initiation. This can involve spending a year in the jungle. This initiation challenges and trains the initiate through extreme circumstances covering isolation, deprivation from utilities available in civilization and its conveniences, enduring radical weather of heavy rains, storms, intense heat, insects and solitude.[citation needed]
# Modern descriptions
Wade Davis (author of The Serpent and The Rainbow) describes the traditional mixture as tough in his book One River: "The smell and acrid taste was that of the entire jungle ground up and mixed with bile." [p.194]
Writer Kira Salak describes her personal experiences with ayahuasca in the March 2006 issue of [National Geographic Adventure] magazine. The article includes a candid description of how ayahuasca cured her depression, as well as provides detailed information about the brew. Here is an excerpt from the article about Dr. Charles Grob's landmark findings:
The taking of ayahuasca has been associated with a long list of documented cures: the disappearance of everything from metastasized colorectal cancer to cocaine addiction, even after just a ceremony or two. It has been medically proven to be nonaddictive and safe to ingest. Yet Western scientists have all but ignored it for decades, reluctant to risk their careers by researching a substance containing the outlawed DMT. Only in the past decade, and then only by a handful of researchers, has ayahuasca begun to be studied. At the vanguard of this research is Charles Grob, M.D., a professor of psychiatry and pediatrics at UCLA’s School of Medicine.
In 1993 Dr. Grob launched the Hoasca Project, the first in-depth study of the physical and psychological effects of ayahuasca on humans. His team went to Brazil, where the plant mixture can be taken legally, to study members of a church, the União do Vegetal (UDV), who use ayahuasca as a sacrament, and compared them to a control group that had never ingested the substance. The studies found that all the ayahuasca-using UDV members had experienced remission without recurrence of their addictions, depression, or anxiety disorders. Unlike most common anti-depressants, which Grob says can create such high levels of serotonin that cells may actually compensate by losing many of their serotonin receptors, the Hoasca Project showed that ayahuasca strongly enhances the body’s ability to absorb the serotonin that’s naturally there. 'Ayahuasca is perhaps a far more sophisticated and effective way to treat depression than SSRIs [antidepressant drugs],' Grob concludes, adding that the use of SSRIs is 'a rather crude way' of doing it. And ayahuasca, he insists, has great potential as a long-term solution.
# Plant constituents
## Traditional
Traditional Ayahuasca brews are always made with Banisteriopsis caapi as an MAOI, although DMT sources and other admixtures vary from region to region. There are several varieties of caapi, often known as different "colors", with varying effects, potencies, and uses.
DMT admixtures:
- Psychotria viridis (Chakruna) - leaves
- Diplopterys cabrerana (Chaliponga, Banisteriopsis rusbyana) - leaves
- Psychotria carthagensis (Amyruca) - leaves
Other common admixtures:
- Justicia pectoralis
- Brugmansia (Toé)
- Nicotiana rustica (Mapacho, variety of tobacco)
- Ilex guayusa, a relative of yerba mate
## Western Ayahuasca analogs
Although traditional plant materials are often used, sources with similar chemical constituents are often substituted for the traditional ingredients.
MAOI:
- Harmal (Peganum harmala, Syrian Rue) - seeds
- Passion flower
- medicinal MAOIs
DMT admixture sources:
- Acacia maidenii (Maiden's Wattle), Acacia phlebophylla, and other Acacias, most commonly employed in Australia - bark
- Anadenanthera peregrina, A. colubrina, A. excelsa, A. macrocarpa
- Mimosa hostilis (Jurema) - root bark - not traditionally employed with ayahuasca by any existing cultures, though likely it was in the past. Popular in Europe and North America.
# Legal status
Internationally, DMT is a Schedule I drug under the Convention on Psychotropic Substances. The Commentary on the Convention on Psychotropic Substances notes, however, that the plant itself is excluded from international control[1]:
A fax from the Secretary of the International Narcotics Control Board to the Netherlands Ministry of Public Health sent in 2001 goes on to state that "Consequently, preparations (e.g.decoctions) made of these plants, including ayahuasca, are not under international control and, therefore, not subject to any of the articles of the 1971 Convention." [2]
The legal status of these plants in the United States is somewhat questionable. Ayahuasca plants and preparations are legal as they contain no scheduled chemicals. However, brews made using DMT containing plants are illegal since DMT is a Schedule I drug. That said, some people are challenging this, using arguments similar to those used by peyotist religious sects, such as the Native American Church. A court case allowing União do Vegetal to use the tea for religious purposes in the United States, Gonzales v. O Centro Espirita Beneficente Uniao do Vegetal, was heard by the U.S. Supreme Court on November 1, 2005; the decision, released February 21, 2006, allows the UDV to use the tea in its ceremonies pursuant to the Religious Freedom Restoration Act.
Religious use in Brazil was legalized after two official inquiries into the tea in the mid-1980s, which concluded that ayahuasca is not a recreational drug and has valid spiritual uses. (More on the legal status of ayahuasca can be found in the Erowid vault on the legality of ayahuasca.)
In France, Santo Daime won a court case allowing them to use the tea in early 2005; however, they were not allowed an exception for religious purposes, but rather for the simple reason that they did not perform chemical extractions to end up with pure DMT and harmala and the plants used were not scheduled. Four months after the court victory, the common ingredients of Ayahuasca as well as harmala were declared stupéfiants, or narcotic schedule I substances, making the tea and its ingredients illegal to use or possess. See [3] and [4] Template:Fr icon for more information.
# External links
### Ayahuasca churches
- Ayahuasca Workshop Shamanic Cusco Perú
- Natureza DivinaTemplate:En icon
- Fatimiya Sufi Order
- PaDeva Church
- Friends of Santo Daime Australia
- Santo Daime Template:Nl icon
- Santo Daime Template:En icon
- Santo Daime (hinarios and text) Template:Pt icon
- Soga del Alma
- União do Vegetal Template:En icon
### Law
- Ayahuasca Church Permitted Usage
- Justices Take Issue With Ban Of Religious Tea
- Supreme Court Opinion in Gonzales v. UDV (2006) (PDF)
- Supreme Court Sides With Church in Ayahuasca Case
- Tea Case Could Cause Religious Liberty Tempest (backgrounder w/sources)
### Other
- M. Goldberg, E. Mosquera, R. Arawanza, and E. Rodriguez, Ethnobotany and Bioactivity of Ayahuasca
- General resource for ayahuasca and many other psychotropic substances (erowid.org)
- National Geographic Adventure article on ayahuasca
- Traditional Preparation Methods (Plot55.com)
- Growing Psychotria viridis (Plot55.com)
- Ayahuayra: How Ayahuasca is used to heal
- Ayahuasca and other "plant teachers"—educational potential?
- The Ayahuasca Forum
- Lila : Shamanism and Ayahuasca Library
- Biopark : An introduction to an extraordinary healing plant and her companions
- El Mundo Magico - Ayahuasca: The Magical Brew of Amazonian Shamans
# Books
- Adelaars, Arno. Ayahuasca. Rituale, Zaubertränke und visionäre Kunst aus Amazonien, ISBN 978-3-03800-270-3
- Burroughs, William S. & Ginsberg, Allen. The Yage Letters. San Francisco: City Lights Books, 1963. ISBN 0-87286-004-3
- De Rios, Marlene Dobkin. Visionary Vine: Hallucinogenic Healing in the Peruvian Amazon, (2nd ed.). Prospect Heights, IL: Waveland, 1984. ISBN 0-88133-093-0
- Hancock, Graham Supernatural: Meetings with the Ancient Teachers of Mankind. London: Century, 2005. ISBN-10: 1844136817 [5]
- Heaven, Ross. Charing, Howard G 'Plant Spirit Shamanism: Traditional Techniques for Healing the Soul'. Vermont: Destiny Books, 2006. ISBN 1-59477-118-9
- Lamb, F. Bruce. Rio Tigre and Beyond: The Amazon Jungle Medicine of Manuel Córdova. Berkeley: North Atlantic, 1985. ISBN 0-938190-59-8
- Luna, Luis Eduardo. Vegetalismo: Shamanism among the Mestizo Population of the Peruvian Amazon. Stockholm: Almqvist & Wiksell International, 1986. ISBN 91-22-00819-5
- Luna, Luis Eduardo & Amaringo, Pablo. Ayahuasca Visions: The Religious Iconography of A Peruvian Shaman. Berkeley: North Atlantic, 1999. ISBN 1-55643-311-5
- Luna, Luis Eduardo & White, Stephen F., eds. Ayahuasca Reader: Encounters with the Amazon's Sacred Vine. Santa Fe, NM: Synergetic, 2000. ISBN 0-907791-32-8
- Matteson Langdon, E. Jean & Baer, Gerhard, eds. Portals of Power: Shamanism in South America. Albuquerque: University of New Mexico Press, 1992. ISBN 0-8263-1345-0
- McKenna, Terence. Food of the Gods.
- Metzner, Ralph, ed. Ayahuasca: Hallucinogens, Consciousness, and the Spirit of Nature. New York: Thunder's Mouth, 1999. ISBN 1-56025-160-3
- Narby, Jeremy. The Cosmic Serpent: DNA and the Origins of Knowledge. New York: Jeremy P. Tarcher/Putnam, 1998. ISBN 0-87477-911-1
- O'Rourke, P.J. "All the Trouble in the World". New York: The Atlantic Monthly Press, 1994. ISBN 0-87113-611-2
- Ott, Jonathan. Ayahuasca Analogues: Pangæan Entheogens. Kennewick, Wash.: Natural Products, 1994. ISBN 0-9614234-5-5
- Perkins, John. The World Is As You Dream It: Shamanic Teachings from the Amazon and Andes. Rochester, Vt.: Park Street, 1994. ISBN 0-89281-459-4[6]
- Pinchbeck, Daniel. Breaking Open the Head: A Psychedelic Journey into the Heart of Contemporary Shamanism. New York: Broadway, 2002. ISBN 0-7679-0743-4[7]
- Polari de Alverga, Alex. Forest of Visions: Ayahuasca, Amazonian Spirituality, and the Santo Daime Tradition. Rochester, Vt.: Park Street, 1999. ISBN 0-89281-716-X
- Reichel-Dolmatoff, Gerardo. The Shaman and the Jaguar: A Study of Narcotic Drugs Among the Indians of Colombia. Philadelphia: Temple University Press, 1975. ISBN 0-87722-038-7
- Schultes, Richard Evans & Raffauf, Robert F. Vine of the Soul: Medicine Men, Their Plants and Rituals in the Colombian Amazonia. Oracle, AZ: Synergetic, 1992. ISBN 0-907791-24-7
- Shanon, Benny. The Antipodes of the Mind: Charting the Phenomenology of the Ayahuasca Experience. Oxford: Oxford University Press, 2002. ISBN 0-19-925293-9
- Stafford, Peter G. Heavenly Highs: Ayahuasca, Kava-Kava, Dmt, and Other Plants of the Gods. Berkeley: Ronin, 2004. ISBN 1-57951-069-8
- Strassman, Rick. DMT: The Spirit Molecule: A Doctor's Revolutionary Research into the Biology of Near-Death and Mystical Experiences. Rochester, Vt.: Park Street, 2001. ISBN 0-89281-927-8
- Taussig, Michael. Shamanism, Colonialism, and the Wild Man: A Study in Terror and Healing. Chicago: University of Chicago Press, 1986. ISBN 0-226-79012-6
- Wilcox, Joan Parisi (2003). Ayahuasca: The Visionary and Healing Powers of the Vine of the Soul. Rochester, Vt.: Park Street. ISBN 0-89281-131-5
# Filmography
- Dean Jefferys; Shamans of the Amazon doc 52 min. Australia 2001
- Jan Kounen, Blueberry l'expérience secrète film
- Jan Kounen, Autres mondes doc
- Glenn Switkes, Night of the Liana doc 45 min. Brazil 2002
# Fiction
- Balfour, Bruce. Prometheus Road. ISBN 0-441-01221-3 | https://www.wikidoc.org/index.php/Ayahuasca | |
bef1f2ebcca53c65fb764472f990fe4e89fdfd49 | wikidoc | Azaperone | Azaperone
# Overview
Azaperone (Stresnil, Fluoperidol) is a pyridinylpiperazine and butyrophenone neuroleptic drug with sedative and antiemetic effects, which is used mainly as a tranquilizer in veterinary medicine. It is used mainly in pigs and elephants. More rarely it may be used in humans as an antipsychotic drug, but this is uncommon. Use in horses is avoided as adverse reactions may occur.
Azaperone acts primarily as a dopamine antagonist but also has some antihistaminic and anticholinergic properties as seen with similar drugs such as haloperidol. Azaperone may cause hypotension and while it has minimal effects on respiration in pigs, high doses in humans can cause respiratory depression which may be why it is rarely used in humans.
The most common use for azaperone is in relatively small doses to reduce aggression in farmed pigs, either to stop them fighting or to encourage sows to accept piglets. Higher doses are used for anesthesia in combination with other drugs such as xylazine, tiletamine and zolazepam. Azaperone is also used in combination with strong narcotics such as etorphine or carfentanil for tranquilizing large animals such as elephants. | Azaperone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Azaperone (Stresnil, Fluoperidol) is a pyridinylpiperazine and butyrophenone neuroleptic drug with sedative and antiemetic effects, which is used mainly as a tranquilizer in veterinary medicine. It is used mainly in pigs and elephants. More rarely it may be used in humans as an antipsychotic drug, but this is uncommon. Use in horses is avoided as adverse reactions may occur.
Azaperone acts primarily as a dopamine antagonist but also has some antihistaminic and anticholinergic properties as seen with similar drugs such as haloperidol. Azaperone may cause hypotension and while it has minimal effects on respiration in pigs, high doses in humans can cause respiratory depression which may be why it is rarely used in humans.
The most common use for azaperone is in relatively small doses to reduce aggression in farmed pigs, either to stop them fighting or to encourage sows to accept piglets. Higher doses are used for anesthesia in combination with other drugs such as xylazine, tiletamine and zolazepam. Azaperone is also used in combination with strong narcotics such as etorphine or carfentanil for tranquilizing large animals such as elephants. | https://www.wikidoc.org/index.php/Azaperone | |
9581ffb78c77e8806204e4a2e6226abfc7c5a967 | wikidoc | Azficel-T | Azficel-T
# 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
Azficel-T is a autologous cellular product that is FDA approved for the treatment of improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults. Common adverse reactions include injection-site redness, bruising, swelling, pain, hemorrhage, edema, nodules, papules, irritation, dermatitis, and pruritus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- LAVIVTM is an autologous cellular product indicated for improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults.
- The safety and efficacy of LAVIV for areas other than the nasolabial folds have not been established.
- The efficacy of LAVIV beyond six months has not been established.
### Dosage
- For autologous intradermal injection only
- Only healthcare providers who have completed a Fibrocell-approved training program should administer LAVIV.
- LAVIV at 0.1 milliliter per linear centimeter into the nasolabial fold wrinkles. The recommended treatment regimen is three treatment sessions, administering up to 2 milliliters (2 vials) of LAVIV per session, at 3-6 week intervals.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Azficel-T in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Azficel-T in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Azficel-T in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Azficel-T in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Azficel-T in pediatric patients.
# Contraindications
- If LAVIV is administered to a patient who is not the individual whose skin was used to produce the LAVIV, serious immunological reactions can occur. Each vial of LAVIV has a unique patient identifier to assist in ensuring that there is no mismatch.
- Serious hypersensitivity reactions, including anaphylaxis, can occur in patients with known hypersensitivity to the ingredients in LAVIV. Do not use LAVIV in patients allergic to gentamicin, amphotericin, dimethyl sulfoxide (DMSO), or material of bovine origin.
- Injecting LAVIV into areas with skin infections can lead to local or systemic infection.
# Warnings
- Hypersensitivity reactions have occurred in patients treated with LAVIV.
- Injection-site bleeding and bruising can occur in patients treated with LAVIV. Patients taking aspirin, non-steroidal anti-inflammatory drugs (NSAIDS) or anticoagulants, as well as patients with coagulopathies, have a greater risk of severe bleeding or bruising.
- Leukocytoclastic vasculitis has occurred following treatment with LAVIV.
- Herpes labialis has occurred following treatment with LAVIV.
- Chemotherapeutic drugs may interfere with the function of LAVIV. Patients with malignancies requiring ongoing therapy should not use LAVIV. Furthermore, patients undergoing chemotherapy are often immunosuppressed, and therefore may be at increased risk of infection following the use of LAVIV.
- A case of basal cell carcinoma was reported near the injection site seven months following LAVIV treatment in clinical trials. While the etiology of the case is uncertain, LAVIV is not recommended for patients with a known history of skin cancer.
- The use of LAVIV requires three post-auricular skin biopsies and multiple injections in the nasolabial folds. These procedures traumatize the skin and may lead to keloid or hypertrophic scar formation in susceptible individuals. While excessive scarring or keloid formation was not observed in either the post-auricular biopsy or the injected areas during the clinical trials, the study population included only four African-American subjects, and Fitzpatrick skin types were not recorded. LAVIV is not recommended for patients with a known history of keloids or hypertrophic scarring.
- Disorders affecting dermal fibroblasts, formation of normal collagen matrices, or other skin components may cause an abnormal response to LAVIV. Thus, LAVIV is not recommended for patients with such genetic disorders as Ehlers-Danlos syndrome, achondroplasia, osteogenesis imperfecta, epidermolysis bullosa, Marfan syndrome, and ataxia-telangiectasia.
- Patients with active autoimmune disease or patients on immunosuppressant therapies may be more susceptible to infection and have difficulty healing following the use of LAVIV. LAVIV is an autologous cell product, and the safety and efficacy of LAVIV in patients with autoimmune disease are unknown.
- Patients undergoing the treatment procedures associated with LAVIV are not routinely tested for adventitious viruses. Therefore, healthcare providers should employ universal precautions when handling LAVIV or biopsy material.
- LAVIV is shipped following a passing sterility test result for cryopreserved bulk material (Drug Substance) and a negative Gram stain test result on the final LAVIV drug product. Full sterility test results are not available for the LAVIV drug product prior to treatment for up to 14 days. If microbial contamination is detected after the product has been shipped, Fibrocell will notify the health care providers and recommend appropriate actions.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions, occurring in ≥1% of subjects in clinical trials, were injection-site reactions, including redness, bruising, swelling, pain, hemorrhage, edema, nodules, papules, irritation, dermatitis, and pruritus.
- Adverse reactions occurring in less than 1% of trial subjects were acne, facial or eyelid edema, hypersensitivity or decreased skin sensation at the injection site, post-procedural discomfort (headache, toothache, and jaw pain), herpes labialis, hyperpigmentation at the injection site, injection-site ischemia, basal cell cancer, and leukocytoclastic vasculitis.
- Because clinical trials are conducted under widely varying conditions, adverse reactions observed in the clinical trials of a product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in practice.
- The overall clinical trial safety database for LAVIV includes 508 subjects who received at least one treatment of LAVIV and 354 subjects who received a vehicle-control in seven clinical trials for treatment of facial wrinkles (a skin biopsy study is described separately). This total safety population included patients aged 20 to 79 years, of whom 92% were female and 92% were White. The average duration of observation in the safety population was approximately 12 months.
- An integrated summary of the adverse reactions from the seven clinical trials is presented in TABLE 1. More than 80% of all adverse reactions were local and required no treatment. Eighty-six percent of all injection-site adverse reactions resolved within one week.
- The adverse reactions to the vehicle (TABLE 1) should not be viewed as adverse reactions to a placebo but rather as reactions to a non-cellular component of LAVIV, or to the injection procedure, or to both.
- Adverse reactions occurring in fewer than 1% of trial subjects were acne, facial or eyelid edema, hypersensitivity or decreased skin sensation at the injection site, post-procedural discomfort (headache, toothache, and jaw pain), herpes labialis, hyperpigmentation at the injection site, injection-site ischemia, basal cell cancer, and leukocytoclastic vasculitis. In the skin biopsy study (described below), one subject was hospitalized for leukocytoclastic vasculitis, with lesions on his legs and trunk appearing nine days after product administration in his upper arm. These lesions resolved within 35 days after onset.
- A skin biopsy study was conducted to observe tissue responses and adverse reactions to LAVIV at the histological level. Twenty-nine subjects who had participated in a prior clinical trial of LAVIV, and who had sufficient quantities of autologous fibroblasts remaining, received up to three treatments of LAVIV in their upper arms at five-week intervals. Seven subjects received three treatments; 21 received two treatments; and one received only one treatment. Saline injections and non-treated areas in the contralateral arm were used as controls. The dose of LAVIV used in the skin biopsy study was the same as in the clinical trials (0.1 milliliter per linear centimeter of skin). The subjects and the two independent histopathology evaluators were blinded to treatment at each skin area.
- Biopsies were taken from LAVIV- and saline-treated sites at 3 and 6 months after the last injection. Biopsies from untreated sites were taken only at 3 months. Histological evaluation was performed for all 29 subjects. At 3 months, histological examination showed inflammatory cell infiltration in 50% of LAVIV-treated sites as compared with 7% of placebo-treated or untreated sites. At 6 months, inflammatory cell infiltration was seen in 27% of the LAVIV-treated sites compared with 12% of placebo-treated sites. In all 29 subjects, there was no histological evidence of abnormal fibroblasts, significant scar formation, or abnormal organization of the extracellular matrix. There were no observed differences in epidermal/dermal thickness or cellularity between LAVIV-injected and placebo-injected skin samples.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Azficel-T in the drug label.
# Drug Interactions
- No drug interaction studies have been performed with LAVIV.
- Patients taking aspirin, NSAIDS or anticoagulants may experience increased bruising or bleeding at biopsy and/or injection sites. Concomitant use of aspirin, NSAIDs or anticoagulants is not recommended. Decisions regarding continued use or cessation of anticoagulants should be made in consultation with the health care provider.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with LAVIV. It is also unknown whether LAVIV can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. LAVIV should be used in a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Azficel-T in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Azficel-T during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Azficel-T with respect to nursing mothers.
### Pediatric Use
- Safety and efficacy of LAVIV in infants and children have not been established.
### Geriatic Use
- Clinical studies of LAVIV did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Azficel-T with respect to specific gender populations.
### Race
- Clinical studies of LAVIV did not include sufficient numbers of subjects in non-White populations to determine whether they respond differently from the population studied.
### Renal Impairment
There is no FDA guidance on the use of Azficel-T in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Azficel-T in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Azficel-T in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Azficel-T in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Confirm that the unique patient identifier on the LAVIV vial matches the identity of the patient who will receive the LAVIV injections.
- Allow the LAVIV vial(s) to reach room temperature before use.
- Examine vial(s) for leaks and for any evidence of damage or contamination.
- Gently invert each vial to re-suspend the product within the media. Tap the top of the vial to release any fluid retained in the top of the vial prior to opening the vial. DO NOT DILUTE THE PRODUCT.
- Before the injection, prepare a minimum of four sterile syringes and needles. Small unit syringes (e.g., 0.5 milliliter insulin syringes) are recommended for better injection control. A detachable larger bore needle (e.g., 21-gauge) should be used to withdraw product from the vials to minimize cell damage.
- Using aseptic technique, unscrew the vial cap and withdraw up to 0.5 milliliters from the vial into each syringe, noting the total volume. After a 21-gauge needle is used to withdraw LAVIV from the vial, the needle should be replaced with a 30-gauge needle prior to injection. Short, sharp needles (e.g., 30-gauge, half-inch needles) are recommended for better injection control and minimization of inflammation.
- Identify the areas to be injected and make sure the injection areas are free of cosmetics, hair or facial jewelry.
- Evaluate the need for topical anesthesia. If a topical anesthetic is administered, remove any topical anesthetic from the face prior to injection of LAVIV. DO NOT USE injectable local anesthetics.
- Clean the treatment area with an aseptic solution prior to injection.
- Place the patient in a comfortable position (e.g., recumbent) to facilitate proper injection angle.
- Inject LAVIV into the superficial papillary dermis at 0.1 milliliter per linear centimeter, using a 30-gauge needle. When the needle is inserted into the correct plane of the skin (i.e., along the line of each nasolabial fold wrinkle), the needle should be visible through the epidermis.
- Confirm intradermal injection by the appearance of blanching and a fluid bleb at the injection site. Avoid injecting LAVIV into the blood vessels, subcutaneously, or intramuscularly.
- Apply multiple injections as needed to cover the entire nasolabial fold wrinkle. Overlap injection areas slightly; otherwise, the last few millimeters of each injection site may receive no product. To prevent exudation of LAVIV from the injection site, make sure that the end of the needle is inserted slightly adjacent to the tract of the previous injection.
- After the injection, leave the treated area undisturbed. Do not rub, massage or compress the area. Apply a cold pack for 2-3 minutes. Do not place ice directly against the skin.
- Discard leftover LAVIV and injection materials as biohazardous waste.
- Counsel the patient on care of the injection site.
### Monitoring
There is limited information regarding Monitoring of Azficel-T in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Azficel-T in the drug label.
# Overdosage
There is limited information regarding Overdose of Azficel-T in the drug label.
# Pharmacology
There is limited information regarding Azficel-T Pharmacology in the drug label.
## Mechanism of Action
- The mechanism by which LAVIV improves the appearance of nasolabial fold wrinkles is unknown.
## Structure
- LAVIV is an autologous cellular product composed of fibroblasts suspended in Dulbecco's Modified Eagle's Medium (DMEM) without phenol red. Dermal fibroblasts from post-auricular skin biopsy tissue are aseptically expanded using standard tissue-culture procedures until sufficient cells for three doses are obtained. Cells are then cryopreserved in a protein-free solution containing DMSO. When the patient administration is scheduled, cells are thawed, washed, and shipped to the clinic. A final sterility test is initiated prior to shipping, but the result will not be available for up to 14 days. A passing sterility culture result from the test performed on the cryopreserved bulk material (Drug Substance) and a negative Gram stain test result on the final LAVIV drug product are required for release of a product for shipping.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Azficel-T in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Azficel-T in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Azficel-T in the drug label.
# Clinical Studies
- The effectiveness of LAVIV was demonstrated in two identically-designed, multi-center, randomized, double-blind, vehicle-controlled studies. The study population consisted of subjects with moderate to severe bilateral nasolabial fold wrinkles. A total of 421 subjects, aged 23 to 81 years, were randomized to receive LAVIV (n=210) or vehicle-control (n=211). In both studies, the major demographic features were similar between LAVIV and vehicle-control groups. Subjects in Study One (n=203) were predominantly female (90%), White (95%), and had an overall mean age of 56.7 years. Subjects in Study Two (n=218) were predominantly female (91%), White (89%), and had an overall mean age of 54.6 years.
- Each subject underwent three post-auricular skin punch biopsies to obtain skin tissue to generate LAVIV. Subjects whose biopsy samples met acceptance criteria were randomized in a 1:1 ratio to receive either LAVIV or vehicle-control (DMEM without phenol red). Biopsy samples for subjects assigned to receive LAVIV were provided to the manufacturer for culture and processing. The process for production of LAVIV takes approximately 11 to 22 weeks. Study agent (either LAVIV or vehicle-control) was then administered intradermally to nasolabial fold wrinkles on both sides of the face at a dose of 0.1 milliliter per linear centimeter, up to 2 milliliters (1-2 x107 cells/milliliter) per each treatment session. A total of three separate treatment sessions occurred at intervals of 5±1 weeks.
- Since LAVIV must be grown from subjects' own skin biopsies, the manufacturing process may not yield sufficient quantities of fibroblasts. Due to product manufacturing failure, 6.2% of subjects randomized to receive LAVIV in the two trials did not receive any LAVIV. In addition, 5.7% of subjects randomized to receive LAVIV had insufficient quantities of LAVIV to complete the planned three treatment sessions. A repeat biopsy was required in 1.5% of subjects as a result of shipping errors.
- For both clinical trials, the co-primary efficacy outcomes were the proportion of subjects with a two-point improvement from baseline in the appearance of the nasolabial fold wrinkles at six months after the third treatment session. The outcomes were assessed with live evaluations performed independently by subjects and by evaluating physicians. Both subjects and evaluators were blinded to treatment assignment. To maintain the blinding, the injector and evaluator for any given subject were different investigators. Subjects assessed their nasolabial fold wrinkles on a five-point Subject Wrinkle Assessment scale that ranged from -2 to +2. The evaluating physicians used a six-point Evaluator Wrinkle Severity Assessment scale that ranged from 0 to 5 (Lemperle scale). Evaluation with the Lemperle scale was aided by a photoguide, which correlated wrinkle appearance with a specific numerical score.
- TABLE 2 shows the efficacy results based on the intent-to-treat population, which included all randomized subjects. When subjects assessed themselves, 57% (Study One) and 45% (Study Two) of subjects receiving LAVIV achieved a 2-point improvement in the appearance of their nasolabial fold wrinkles compared with 30% (Study One) and 18% (Study Two) of subjects receiving vehicle-control. When assessed by evaluating physicians, 33% (Study One) and 19% (Study Two) of subjects receiving LAVIV achieved a 2-point improvement in their nasolabial fold wrinkles, compared with 7% of subjects receiving vehicle-control in both trials.
- Efficacy beyond six months after the third administration has not been established. No clinical studies have been conducted to evaluate the efficacy of repeating treatment(s) beyond six months.
- Geriatric
- Clinical studies did not include sufficient numbers of subjects aged 65 years and older to determine whether their responses to LAVIV treatment differ from those of younger subjects. Of the 421 subjects in the two efficacy trials, 71 (17%) were ≥ 65 years old. The overall responder rates in geriatric subjects were lower and less consistent than in subjects younger than 65 years of age.
- Race
- Non-White subjects accounted for 8% of the clinical study population. Therefore, there is insufficient information to assess the efficacy of LAVIV in non-Whites.
# How Supplied
- LAVIV is intended solely for autologous use.
- LAVIV is supplied in two vials, each containing approximately 18 million cells in 1.2 milliliters. The vials are packaged together in a tamper-evident biohazard bag and shipped at 2-8°C (36-46°F) inside a temperature-controlled shipping container.
- The manufacturing process for LAVIV takes approximately 11-22 weeks after receipt of the patient's biopsy samples by the manufacturer. Fibrocell will notify the clinic when each patient's treatment may be scheduled.
## Storage
- Employ universal precautions when handling LAVIV. Patients undergoing procedures associated with LAVIV are not routinely tested for adventitious viruses.
- DO NOT FREEZE, sterilize, or incubate LAVIV, as this may result in inactivation of the product.
- Protect LAVIV from exposure to sunlight.
- Inspect the packaging and vials for damage. LAVIV should not be used if the packaging, injection vial(s), or seal(s) are damaged.
- Store each vial on its side at 2-8°C (36-46°F) to minimize viscosity.
- Remove vials from the refrigerator 15-30 minutes before use to allow them to reach room temperature.
- Use product prior to the expiration date and time printed on the vial.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Prior to initiating treatment with LAVIV, the healthcare provider should
- Ask the patient about any history of skin cancer, keloids, scarring, or immune problems.
- Discuss the biopsy process and ask the patient to report any persistent symptoms related to the biopsy procedure.
- Manage expectations by telling the patient that
- The effects of LAVIV are not immediate, but may appear over the course of the three-treatment regimen.
- Sometimes the biopsies will not produce enough viable cells to manufacture enough LAVIV for injection. In such cases, the patient will be notified and may be offered the opportunity to repeat the procedure.
- Following treatment with LAVIV, provide post-injection instructions including the following
- Do not apply ice to the face. A cold compress may be applied for 2-3 minutes at a time, if needed to ease swelling or discomfort.
- Do not wash the site of injections for at least 24 hours.
- Do not scrub, rub or manipulate the treatment area for at least 72 hours.
- Do not apply any products (e.g., make-up, facial creams, sunscreen) to the treatment area for 72 hours.
- Expect mild to moderate redness, swelling, puffiness, or bruising following injections.
- Call the doctor or emergency department for any persistent or unexpected side effects.
### PATIENT PACKAGE INSERT
# Precautions with Alcohol
- Alcohol-Azficel-T interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Laviv®
# Look-Alike Drug Names
There is limited information regarding Azficel-T Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Azficel-T
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
Azficel-T is a autologous cellular product that is FDA approved for the treatment of improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults. Common adverse reactions include injection-site redness, bruising, swelling, pain, hemorrhage, edema, nodules, papules, irritation, dermatitis, and pruritus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- LAVIVTM is an autologous cellular product indicated for improvement of the appearance of moderate to severe nasolabial fold wrinkles in adults.
- The safety and efficacy of LAVIV for areas other than the nasolabial folds have not been established.
- The efficacy of LAVIV beyond six months has not been established.
### Dosage
- For autologous intradermal injection only
- Only healthcare providers who have completed a Fibrocell-approved training program should administer LAVIV.
- LAVIV at 0.1 milliliter per linear centimeter into the nasolabial fold wrinkles. The recommended treatment regimen is three treatment sessions, administering up to 2 milliliters (2 vials) of LAVIV per session, at 3-6 week intervals.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Azficel-T in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Azficel-T in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Azficel-T in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Azficel-T in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Azficel-T in pediatric patients.
# Contraindications
- If LAVIV is administered to a patient who is not the individual whose skin was used to produce the LAVIV, serious immunological reactions can occur. Each vial of LAVIV has a unique patient identifier to assist in ensuring that there is no mismatch.
- Serious hypersensitivity reactions, including anaphylaxis, can occur in patients with known hypersensitivity to the ingredients in LAVIV. Do not use LAVIV in patients allergic to gentamicin, amphotericin, dimethyl sulfoxide (DMSO), or material of bovine origin.
- Injecting LAVIV into areas with skin infections can lead to local or systemic infection.
# Warnings
- Hypersensitivity reactions have occurred in patients treated with LAVIV.
- Injection-site bleeding and bruising can occur in patients treated with LAVIV. Patients taking aspirin, non-steroidal anti-inflammatory drugs (NSAIDS) or anticoagulants, as well as patients with coagulopathies, have a greater risk of severe bleeding or bruising.
- Leukocytoclastic vasculitis has occurred following treatment with LAVIV.
- Herpes labialis has occurred following treatment with LAVIV.
- Chemotherapeutic drugs may interfere with the function of LAVIV. Patients with malignancies requiring ongoing therapy should not use LAVIV. Furthermore, patients undergoing chemotherapy are often immunosuppressed, and therefore may be at increased risk of infection following the use of LAVIV.
- A case of basal cell carcinoma was reported near the injection site seven months following LAVIV treatment in clinical trials. While the etiology of the case is uncertain, LAVIV is not recommended for patients with a known history of skin cancer.
- The use of LAVIV requires three post-auricular skin biopsies and multiple injections in the nasolabial folds. These procedures traumatize the skin and may lead to keloid or hypertrophic scar formation in susceptible individuals. While excessive scarring or keloid formation was not observed in either the post-auricular biopsy or the injected areas during the clinical trials, the study population included only four African-American subjects, and Fitzpatrick skin types were not recorded. LAVIV is not recommended for patients with a known history of keloids or hypertrophic scarring.
- Disorders affecting dermal fibroblasts, formation of normal collagen matrices, or other skin components may cause an abnormal response to LAVIV. Thus, LAVIV is not recommended for patients with such genetic disorders as Ehlers-Danlos syndrome, achondroplasia, osteogenesis imperfecta, epidermolysis bullosa, Marfan syndrome, and ataxia-telangiectasia.
- Patients with active autoimmune disease or patients on immunosuppressant therapies may be more susceptible to infection and have difficulty healing following the use of LAVIV. LAVIV is an autologous cell product, and the safety and efficacy of LAVIV in patients with autoimmune disease are unknown.
- Patients undergoing the treatment procedures associated with LAVIV are not routinely tested for adventitious viruses. Therefore, healthcare providers should employ universal precautions when handling LAVIV or biopsy material.
- LAVIV is shipped following a passing sterility test result for cryopreserved bulk material (Drug Substance) and a negative Gram stain test result on the final LAVIV drug product. Full sterility test results are not available for the LAVIV drug product prior to treatment for up to 14 days. If microbial contamination is detected after the product has been shipped, Fibrocell will notify the health care providers and recommend appropriate actions.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions, occurring in ≥1% of subjects in clinical trials, were injection-site reactions, including redness, bruising, swelling, pain, hemorrhage, edema, nodules, papules, irritation, dermatitis, and pruritus.
- Adverse reactions occurring in less than 1% of trial subjects were acne, facial or eyelid edema, hypersensitivity or decreased skin sensation at the injection site, post-procedural discomfort (headache, toothache, and jaw pain), herpes labialis, hyperpigmentation at the injection site, injection-site ischemia, basal cell cancer, and leukocytoclastic vasculitis.
- Because clinical trials are conducted under widely varying conditions, adverse reactions observed in the clinical trials of a product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in practice.
- The overall clinical trial safety database for LAVIV includes 508 subjects who received at least one treatment of LAVIV and 354 subjects who received a vehicle-control in seven clinical trials for treatment of facial wrinkles (a skin biopsy study is described separately). This total safety population included patients aged 20 to 79 years, of whom 92% were female and 92% were White. The average duration of observation in the safety population was approximately 12 months.
- An integrated summary of the adverse reactions from the seven clinical trials is presented in TABLE 1. More than 80% of all adverse reactions were local and required no treatment. Eighty-six percent of all injection-site adverse reactions resolved within one week.
- The adverse reactions to the vehicle (TABLE 1) should not be viewed as adverse reactions to a placebo but rather as reactions to a non-cellular component of LAVIV, or to the injection procedure, or to both.
- Adverse reactions occurring in fewer than 1% of trial subjects were acne, facial or eyelid edema, hypersensitivity or decreased skin sensation at the injection site, post-procedural discomfort (headache, toothache, and jaw pain), herpes labialis, hyperpigmentation at the injection site, injection-site ischemia, basal cell cancer, and leukocytoclastic vasculitis. In the skin biopsy study (described below), one subject was hospitalized for leukocytoclastic vasculitis, with lesions on his legs and trunk appearing nine days after product administration in his upper arm. These lesions resolved within 35 days after onset.
- A skin biopsy study was conducted to observe tissue responses and adverse reactions to LAVIV at the histological level. Twenty-nine subjects who had participated in a prior clinical trial of LAVIV, and who had sufficient quantities of autologous fibroblasts remaining, received up to three treatments of LAVIV in their upper arms at five-week intervals. Seven subjects received three treatments; 21 received two treatments; and one received only one treatment. Saline injections and non-treated areas in the contralateral arm were used as controls. The dose of LAVIV used in the skin biopsy study was the same as in the clinical trials (0.1 milliliter per linear centimeter of skin). The subjects and the two independent histopathology evaluators were blinded to treatment at each skin area.
- Biopsies were taken from LAVIV- and saline-treated sites at 3 and 6 months after the last injection. Biopsies from untreated sites were taken only at 3 months. Histological evaluation was performed for all 29 subjects. At 3 months, histological examination showed inflammatory cell infiltration in 50% of LAVIV-treated sites as compared with 7% of placebo-treated or untreated sites. At 6 months, inflammatory cell infiltration was seen in 27% of the LAVIV-treated sites compared with 12% of placebo-treated sites. In all 29 subjects, there was no histological evidence of abnormal fibroblasts, significant scar formation, or abnormal organization of the extracellular matrix. There were no observed differences in epidermal/dermal thickness or cellularity between LAVIV-injected and placebo-injected skin samples.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Azficel-T in the drug label.
# Drug Interactions
- No drug interaction studies have been performed with LAVIV.
- Patients taking aspirin, NSAIDS or anticoagulants may experience increased bruising or bleeding at biopsy and/or injection sites. Concomitant use of aspirin, NSAIDs or anticoagulants is not recommended. Decisions regarding continued use or cessation of anticoagulants should be made in consultation with the health care provider.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with LAVIV. It is also unknown whether LAVIV can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. LAVIV should be used in a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Azficel-T in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Azficel-T during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Azficel-T with respect to nursing mothers.
### Pediatric Use
- Safety and efficacy of LAVIV in infants and children have not been established.
### Geriatic Use
- Clinical studies of LAVIV did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Azficel-T with respect to specific gender populations.
### Race
- Clinical studies of LAVIV did not include sufficient numbers of subjects in non-White populations to determine whether they respond differently from the population studied.
### Renal Impairment
There is no FDA guidance on the use of Azficel-T in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Azficel-T in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Azficel-T in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Azficel-T in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Confirm that the unique patient identifier on the LAVIV vial matches the identity of the patient who will receive the LAVIV injections.
- Allow the LAVIV vial(s) to reach room temperature before use.
- Examine vial(s) for leaks and for any evidence of damage or contamination.
- Gently invert each vial to re-suspend the product within the media. Tap the top of the vial to release any fluid retained in the top of the vial prior to opening the vial. DO NOT DILUTE THE PRODUCT.
- Before the injection, prepare a minimum of four sterile syringes and needles. Small unit syringes (e.g., 0.5 milliliter insulin syringes) are recommended for better injection control. A detachable larger bore needle (e.g., 21-gauge) should be used to withdraw product from the vials to minimize cell damage.
- Using aseptic technique, unscrew the vial cap and withdraw up to 0.5 milliliters from the vial into each syringe, noting the total volume. After a 21-gauge needle is used to withdraw LAVIV from the vial, the needle should be replaced with a 30-gauge needle prior to injection. Short, sharp needles (e.g., 30-gauge, half-inch needles) are recommended for better injection control and minimization of inflammation.
- Identify the areas to be injected and make sure the injection areas are free of cosmetics, hair or facial jewelry.
- Evaluate the need for topical anesthesia. If a topical anesthetic is administered, remove any topical anesthetic from the face prior to injection of LAVIV. DO NOT USE injectable local anesthetics.
- Clean the treatment area with an aseptic solution prior to injection.
- Place the patient in a comfortable position (e.g., recumbent) to facilitate proper injection angle.
- Inject LAVIV into the superficial papillary dermis at 0.1 milliliter per linear centimeter, using a 30-gauge needle. When the needle is inserted into the correct plane of the skin (i.e., along the line of each nasolabial fold wrinkle), the needle should be visible through the epidermis.
- Confirm intradermal injection by the appearance of blanching and a fluid bleb at the injection site. Avoid injecting LAVIV into the blood vessels, subcutaneously, or intramuscularly.
- Apply multiple injections as needed to cover the entire nasolabial fold wrinkle. Overlap injection areas slightly; otherwise, the last few millimeters of each injection site may receive no product. To prevent exudation of LAVIV from the injection site, make sure that the end of the needle is inserted slightly adjacent to the tract of the previous injection.
- After the injection, leave the treated area undisturbed. Do not rub, massage or compress the area. Apply a cold pack for 2-3 minutes. Do not place ice directly against the skin.
- Discard leftover LAVIV and injection materials as biohazardous waste.
- Counsel the patient on care of the injection site.
### Monitoring
There is limited information regarding Monitoring of Azficel-T in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Azficel-T in the drug label.
# Overdosage
There is limited information regarding Overdose of Azficel-T in the drug label.
# Pharmacology
There is limited information regarding Azficel-T Pharmacology in the drug label.
## Mechanism of Action
- The mechanism by which LAVIV improves the appearance of nasolabial fold wrinkles is unknown.
## Structure
- LAVIV is an autologous cellular product composed of fibroblasts suspended in Dulbecco's Modified Eagle's Medium (DMEM) without phenol red. Dermal fibroblasts from post-auricular skin biopsy tissue are aseptically expanded using standard tissue-culture procedures until sufficient cells for three doses are obtained. Cells are then cryopreserved in a protein-free solution containing DMSO. When the patient administration is scheduled, cells are thawed, washed, and shipped to the clinic. A final sterility test is initiated prior to shipping, but the result will not be available for up to 14 days. A passing sterility culture result from the test performed on the cryopreserved bulk material (Drug Substance) and a negative Gram stain test result on the final LAVIV drug product are required for release of a product for shipping.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Azficel-T in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Azficel-T in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Azficel-T in the drug label.
# Clinical Studies
- The effectiveness of LAVIV was demonstrated in two identically-designed, multi-center, randomized, double-blind, vehicle-controlled studies. The study population consisted of subjects with moderate to severe bilateral nasolabial fold wrinkles. A total of 421 subjects, aged 23 to 81 years, were randomized to receive LAVIV (n=210) or vehicle-control (n=211). In both studies, the major demographic features were similar between LAVIV and vehicle-control groups. Subjects in Study One (n=203) were predominantly female (90%), White (95%), and had an overall mean age of 56.7 years. Subjects in Study Two (n=218) were predominantly female (91%), White (89%), and had an overall mean age of 54.6 years.
- Each subject underwent three post-auricular skin punch biopsies to obtain skin tissue to generate LAVIV. Subjects whose biopsy samples met acceptance criteria were randomized in a 1:1 ratio to receive either LAVIV or vehicle-control (DMEM without phenol red). Biopsy samples for subjects assigned to receive LAVIV were provided to the manufacturer for culture and processing. The process for production of LAVIV takes approximately 11 to 22 weeks. Study agent (either LAVIV or vehicle-control) was then administered intradermally to nasolabial fold wrinkles on both sides of the face at a dose of 0.1 milliliter per linear centimeter, up to 2 milliliters (1-2 x107 cells/milliliter) per each treatment session. A total of three separate treatment sessions occurred at intervals of 5±1 weeks.
- Since LAVIV must be grown from subjects' own skin biopsies, the manufacturing process may not yield sufficient quantities of fibroblasts. Due to product manufacturing failure, 6.2% of subjects randomized to receive LAVIV in the two trials did not receive any LAVIV. In addition, 5.7% of subjects randomized to receive LAVIV had insufficient quantities of LAVIV to complete the planned three treatment sessions. A repeat biopsy was required in 1.5% of subjects as a result of shipping errors.
- For both clinical trials, the co-primary efficacy outcomes were the proportion of subjects with a two-point improvement from baseline in the appearance of the nasolabial fold wrinkles at six months after the third treatment session. The outcomes were assessed with live evaluations performed independently by subjects and by evaluating physicians. Both subjects and evaluators were blinded to treatment assignment. To maintain the blinding, the injector and evaluator for any given subject were different investigators. Subjects assessed their nasolabial fold wrinkles on a five-point Subject Wrinkle Assessment scale that ranged from -2 to +2. The evaluating physicians used a six-point Evaluator Wrinkle Severity Assessment scale that ranged from 0 to 5 (Lemperle scale). Evaluation with the Lemperle scale was aided by a photoguide, which correlated wrinkle appearance with a specific numerical score.
- TABLE 2 shows the efficacy results based on the intent-to-treat population, which included all randomized subjects. When subjects assessed themselves, 57% (Study One) and 45% (Study Two) of subjects receiving LAVIV achieved a 2-point improvement in the appearance of their nasolabial fold wrinkles compared with 30% (Study One) and 18% (Study Two) of subjects receiving vehicle-control. When assessed by evaluating physicians, 33% (Study One) and 19% (Study Two) of subjects receiving LAVIV achieved a 2-point improvement in their nasolabial fold wrinkles, compared with 7% of subjects receiving vehicle-control in both trials.
- Efficacy beyond six months after the third administration has not been established. No clinical studies have been conducted to evaluate the efficacy of repeating treatment(s) beyond six months.
- Geriatric
- Clinical studies did not include sufficient numbers of subjects aged 65 years and older to determine whether their responses to LAVIV treatment differ from those of younger subjects. Of the 421 subjects in the two efficacy trials, 71 (17%) were ≥ 65 years old. The overall responder rates in geriatric subjects were lower and less consistent than in subjects younger than 65 years of age.
- Race
- Non-White subjects accounted for 8% of the clinical study population. Therefore, there is insufficient information to assess the efficacy of LAVIV in non-Whites.
# How Supplied
- LAVIV is intended solely for autologous use.
- LAVIV is supplied in two vials, each containing approximately 18 million cells in 1.2 milliliters. The vials are packaged together in a tamper-evident biohazard bag and shipped at 2-8°C (36-46°F) inside a temperature-controlled shipping container.
- The manufacturing process for LAVIV takes approximately 11-22 weeks after receipt of the patient's biopsy samples by the manufacturer. Fibrocell will notify the clinic when each patient's treatment may be scheduled.
## Storage
- Employ universal precautions when handling LAVIV. Patients undergoing procedures associated with LAVIV are not routinely tested for adventitious viruses.
- DO NOT FREEZE, sterilize, or incubate LAVIV, as this may result in inactivation of the product.
- Protect LAVIV from exposure to sunlight.
- Inspect the packaging and vials for damage. LAVIV should not be used if the packaging, injection vial(s), or seal(s) are damaged.
- Store each vial on its side at 2-8°C (36-46°F) to minimize viscosity.
- Remove vials from the refrigerator 15-30 minutes before use to allow them to reach room temperature.
- Use product prior to the expiration date and time printed on the vial.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Prior to initiating treatment with LAVIV, the healthcare provider should
- Ask the patient about any history of skin cancer, keloids, scarring, or immune problems.
- Discuss the biopsy process and ask the patient to report any persistent symptoms related to the biopsy procedure.
- Manage expectations by telling the patient that
- The effects of LAVIV are not immediate, but may appear over the course of the three-treatment regimen.
- Sometimes the biopsies will not produce enough viable cells to manufacture enough LAVIV for injection. In such cases, the patient will be notified and may be offered the opportunity to repeat the procedure.
- Following treatment with LAVIV, provide post-injection instructions including the following
- Do not apply ice to the face. A cold compress may be applied for 2-3 minutes at a time, if needed to ease swelling or discomfort.
- Do not wash the site of injections for at least 24 hours.
- Do not scrub, rub or manipulate the treatment area for at least 72 hours.
- Do not apply any products (e.g., make-up, facial creams, sunscreen) to the treatment area for 72 hours.
- Expect mild to moderate redness, swelling, puffiness, or bruising following injections.
- Call the doctor or emergency department for any persistent or unexpected side effects.
### PATIENT PACKAGE INSERT
# Precautions with Alcohol
- Alcohol-Azficel-T interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Laviv®[1]
# Look-Alike Drug Names
There is limited information regarding Azficel-T Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Azficel-T | |
db794ab74befb6813308ec26b162cbb0c12c6fc0 | wikidoc | Azurophil | Azurophil
Azurophil is the term used to refer to objects that are readily staining with an azure dye.
The term is used especially in reference to certain cytoplasmic granules in white blood cells, particularly hyperchromatin and reddish purple granules of certain blood cells.
As another example, neutrophils carry an arsenal of anti-microbial defensins within their azurophils, which eventually fuse with phagocytic vacuoles. | Azurophil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Azurophil is the term used to refer to objects that are readily staining with an azure dye.
The term is used especially in reference to certain cytoplasmic granules in white blood cells, particularly hyperchromatin and reddish purple granules of certain blood cells.
As another example, neutrophils carry an arsenal of anti-microbial defensins within their azurophils, which eventually fuse with phagocytic vacuoles. | https://www.wikidoc.org/index.php/Azurophil | |
5710bea99e78970d28d58f5f6e2cfd971e9a4579 | wikidoc | BC Powder | BC Powder
BC Powder is an over-the-counter analgesic pain reliever owned by GlaxoSmithKline Pharmaceuticals and manufactured in Memphis, TN. It was conceived in Durham, NC, in 1906, by Germain Bernard and C.T. Council, who took the initials of their last names to create the name of the nascent product. It contains 650 mg of aspirin, 33.3 mg of caffeine, and 195 mg of Salicylamide. BC readily promotes the fact that, due to its powder form, it dissolves faster than pain-relief tablets, and thus gets to work faster. It can be taken in a variety of ways, most commonly mixed into water or soda. BC is sold almost exclusively in the American South, where it is acknowledged to have a cult following. BC's marketers enjoy this honor, and sponsor many sporting events in the region. Indeed, the product's distinctive, oval-shaped blue logo is a familiar sight to attendees of Southern minor-league baseball parks and Southeastern Conference collegiate games.
BC Powder has historically been most commonly associated with relief of headaches. In fact, many non-users of the brand erroneously believe the name of the product to be "BC Headache Powder." However, recent advertising and marketing endeavors by the company suggest that it is eager to associate itself with relief of general bodily aches and pains as well.
For several years, BC's television and radio commercials have featured real-life users of the product, non-actors who are encouraged to submit their stories to BC Powder through contests announced on radio programs. Recently, most entries have been culled from listeners of the Charlotte, NC-based radio program "The Big Show with John Boy and Billy." In recent years, members of the "Tom Joyner Radio Show's" predominantly African-American audience have appeared in BC commercials after hearing of the promotion on that program, or from promotions held on Joyner's annual "Fantastic Voyage" fantasy cruise.
BC Powder also manufactures and markets BC Allergy Sinus Headache Powder and BC Arthritis Formula.
BC Powder is often confused with Goody's Powder, a similar product which contains Acetaminophen instead of Salicylamide. Coincidentally, Goody's is also owned by GlaxoSmithKline. | BC Powder
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
BC Powder is an over-the-counter analgesic pain reliever owned by GlaxoSmithKline Pharmaceuticals and manufactured in Memphis, TN. It was conceived in Durham, NC, in 1906, by Germain Bernard and C.T. Council, who took the initials of their last names to create the name of the nascent product. It contains 650 mg of aspirin, 33.3 mg of caffeine, and 195 mg of Salicylamide. BC readily promotes the fact that, due to its powder form, it dissolves faster than pain-relief tablets, and thus gets to work faster. It can be taken in a variety of ways, most commonly mixed into water or soda. BC is sold almost exclusively in the American South, where it is acknowledged to have a cult following. BC's marketers enjoy this honor, and sponsor many sporting events in the region. Indeed, the product's distinctive, oval-shaped blue logo is a familiar sight to attendees of Southern minor-league baseball parks and Southeastern Conference collegiate games.
BC Powder has historically been most commonly associated with relief of headaches. In fact, many non-users of the brand erroneously believe the name of the product to be "BC Headache Powder." However, recent advertising and marketing endeavors by the company suggest that it is eager to associate itself with relief of general bodily aches and pains as well.
For several years, BC's television and radio commercials have featured real-life users of the product, non-actors who are encouraged to submit their stories to BC Powder through contests announced on radio programs. Recently, most entries have been culled from listeners of the Charlotte, NC-based radio program "The Big Show with John Boy and Billy." In recent years, members of the "Tom Joyner Radio Show's" predominantly African-American audience have appeared in BC commercials after hearing of the promotion on that program, or from promotions held on Joyner's annual "Fantastic Voyage" fantasy cruise.
BC Powder also manufactures and markets BC Allergy Sinus Headache Powder and BC Arthritis Formula.
BC Powder is often confused with Goody's Powder, a similar product which contains Acetaminophen instead of Salicylamide. Coincidentally, Goody's is also owned by GlaxoSmithKline.
# External links
- Official BC Powder site
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/BC_Powder | |
d41fac0b0e78346fbf180f545ac5bbd90dca75b6 | wikidoc | BIP Trial | BIP Trial
## Objective
To determine the safety and efficacy of bezafibrate in raising HDL cholesterol and lowering triglycerides in patients with coronary artery disease.
## Methods
This is a double-blinded study where 3090 patients with a previous myocardial infarction or stable angina with a total cholesterol of 180 - 250 mg/dL, HDL-C≤45 mg/dL, triglycerides≤300 mg/dL, and low-density lipoprotein cholesterol≤180 mg/dL were randomized to receive either 400 mg of bezafibrate per day or a placebo; they were followed for a mean of 6.2 years. fatal or nonfatal myocardial infarction or sudden death were the primary outcomes considered.
# Results
- 18% increase in HDL-C and a 21% reduction observed in triglycerides.
- The reduction in the cumulative probability of the primary end point was 7.3% (P=0.24) after 6.2 years.
- Post hoc analysis in the group of patients with high baseline triglycerides (≥ 200 mg/dL) revealed a reduction by 39.5% (P=0.02) in the cumulative probability of the primary end point.
- Total and noncardiac mortality, adverse events and cancer were equally distributed between the two groups.
## Conclusion
Bezafibrate was safe and effective in elevating HDL-C levels and lowering triglycerides. A reduction of the incidence of primary end points was also observed. | BIP Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Click here to download slides for BIP Trial.
## Objective
To determine the safety and efficacy of bezafibrate in raising HDL cholesterol and lowering triglycerides in patients with coronary artery disease.
## Methods
This is a double-blinded study where 3090 patients with a previous myocardial infarction or stable angina with a total cholesterol of 180 - 250 mg/dL, HDL-C≤45 mg/dL, triglycerides≤300 mg/dL, and low-density lipoprotein cholesterol≤180 mg/dL were randomized to receive either 400 mg of bezafibrate per day or a placebo; they were followed for a mean of 6.2 years. fatal or nonfatal myocardial infarction or sudden death were the primary outcomes considered.
# Results
- 18% increase in HDL-C and a 21% reduction observed in triglycerides.
- The reduction in the cumulative probability of the primary end point was 7.3% (P=0.24) after 6.2 years.
- Post hoc analysis in the group of patients with high baseline triglycerides (≥ 200 mg/dL) revealed a reduction by 39.5% (P=0.02) in the cumulative probability of the primary end point.
- Total and noncardiac mortality, adverse events and cancer were equally distributed between the two groups.
## Conclusion
Bezafibrate was safe and effective in elevating HDL-C levels and lowering triglycerides. A reduction of the incidence of primary end points was also observed.[1] | https://www.wikidoc.org/index.php/BIP_Trial | |
8537a7c04f1c83bc41156afdc06c7aeeafdd29fd | wikidoc | Dasatinib | Dasatinib
# Disclaimer
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# Overview
Dasatinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia or acute lymphoblastic leukemia. Common adverse reactions include myelosuppression, fluid retention, diarrhea, headache, dyspnea, rash, fatigue, nausea, and hemorrhage.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dosage of Sprycel for chronic phase CML is 100 mg administered orally once daily. The recommended starting dosage of Sprycel for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily. Tablets should not be crushed or cut; they should be swallowed whole. Sprycel can be taken with or without a meal, either in the morning or in the evening.
- In clinical studies, treatment with Sprycel was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment after the achievement of a complete cytogenetic response (CCyR) has not been investigated.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dasatinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dasatinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and efficacy of Sprycel in patients less than 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dasatinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dasatinib in pediatric patients.
# Contraindications
- None
# Warnings
- Treatment with Sprycel is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In a dose-optimization trial in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens.
- Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Sprycel temporarily or dose reduction.
- In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving Sprycel. Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe thrombocytopenia.
- Patients were excluded from participation in initial Sprycel clinical studies if they took medications that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with Sprycel if the platelet count was >50,000–75,000 per microliter. Exercise caution if patients are required to take medications that inhibit platelet function or anticoagulants.
- Sprycel is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients. Severe ascites, pulmonary edema, and generalized edema were each reported in ≤1% of patients. Patients who develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by chest x-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens.
- In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Of the 2440 patients treated with Sprycel in clinical studies, 16 patients (1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms. In 865 patients with leukemia treated with Sprycel in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms.
- Administer Sprycel with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to Sprycel administration.
- Cardiac adverse reactions were reported in 7% of 258 patients taking Sprycel, including, 1.6% of patients with cardiomyopathy, congestive heart failure, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.
- Sprycel may increase the risk of developing pulmonary arterial hypertension (PAH) which may occur any time after initiation, including after more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of Sprycel. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating Sprycel and during treatment. If PAH is confirmed, Sprycel should be permanently discontinued.
- Sprycel can cause fetal harm when administered to a pregnant woman. Adverse fetal and infant outcomes have been reported from women who have taken Sprycel during pregnancy. In animal reproduction studies, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits at plasma concentrations below those in humans receiving therapeutic doses of dasatinib. If Sprycel is used during pregnancy, or if the patient becomes pregnant while taking Sprycel, the patient should be apprised of the potential hazard to the fetus.
- Advise females of reproductive potential to avoid pregnancy, which may include the use of contraception, during treatment with Sprycel.
# 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 Sprycel in clinical studies including 258 patients with newly diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL.
- In the newly diagnosed chronic phase CML trial with a minimum of 36 months follow up and median duration of therapy of 37 months, the median average daily dose was 99 mg.
- In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, 1520 patients had a minimum of 2 years follow up and 662 patients with chronic phase CML had a minimum of 60 months follow up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median duration of treatment with Sprycel 100 mg once daily was 37 months (range 1–65 months). The median duration of treatment with Sprycel 140 mg once daily was 15 months (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid blast CML.
- The majority of Sprycel-treated patients experienced adverse reactions at some time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of Sprycel-treated patients with a minimum of 12 months follow up. After a minimum of 36 months follow up, the cumulative discontinuation rate was 9%. Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reactions at 2 years were 15% in chronic phase CML for all dosages, 16% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization trial in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML with a minimum of 60 months follow up, the rate of discontinuation for adverse reactions was 18% in patients treated with 100 mg once daily.
- The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, rash, and nausea. Pleural effusions were reported in 50 patients (see Table 2).
- The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage.
- The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML included pleural effusion (4%), hemorrhage (2%), congestive heart failure (1%), pulmonary hypertension (1%), and pyrexia (1%). The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%).
### Chronic Myeloid Leukemia (CML)
- Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of patients are shown in Table 2 for newly diagnosed patients with chronic phase CML and Tables 3 and 4 for CML patients with resistance or intolerance to prior imatinib therapy.
- The cumulative rates of the majority of adverse reactions (all grades) in newly diagnosed patients with chronic phase CML were similar after 12 and 36 months minimum follow up including congestive heart failure/cardiac dysfunction (2% vs 2%), pericardial effusion (2% vs 3%), pulmonary edema (<1% vs 1%), gastrointestinal bleeding (2% vs 2%), diarrhea (18% vs 21%), and generalized edema (3% vs 3%). Cumulative adverse reaction rates (all grades) that increased between 12 months and 36 months minimum follow up included overall fluid retention (23% vs 31%), pleural effusion (12% vs 19%), and superficial edema (10% vs 13%). A total of 9 patients (3.5%) discontinued due to pleural effusion in the trial.
- At 36 months, there were 17 deaths in the dasatinib-treated patients (6.6%) and 20 deaths in the imatinib-treated patients (7.7%); 1 in each group was judged by the investigator as related to study therapy.
- With a minimum follow up of 60 months (see Table 3), the cumulative rates of the majority of adverse reactions (all grades) in patients with chronic phase CML treated with a starting dose of 100 mg once daily were identical with a minimum follow up of 24 and 60 months including congestive heart failure/cardiac dysfunction, pericardial effusion, pulmonary edema, and gastrointestinal bleeding or similar for diarrhea (27% vs 28%), and generalized edema (3% vs 4%). Cumulative adverse reaction rates (all grades) that increased between 24 months and 60 months minimum follow up included: overall fluid retention (34% vs 42%), pleural effusion (18% vs 24%), and superficial edema (18% vs 21%). The cumulative rate of Grade 3 or 4 pleural effusion was 2% versus 4%, respectively.
- Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 5 and 6). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.
- In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy.
- Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of Sprycel therapy often had recovery with oral calcium supplementation.
- Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 5. There were no discontinuations of Sprycel therapy in this patient population due to biochemical laboratory parameters.
- Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of Sprycel are shown by disease phase in Table 6.
- Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative Grade 3 or 4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%) and anemia (13% vs 13%).
### Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
- A total of 135 patients with Ph+ ALL were treated with Sprycel in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events, such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders, such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%).
### Additional Data From Clinical Trials
- The following adverse reactions were reported in patients in the Sprycel clinical studies at a frequency of ≥10%, 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance.
- 1%–<10% – asthenia, pain, chest pain, chills
- 0.1%–<1% – malaise, temperature intolerance.
- 1%–<10% – arrhythmia (including tachycardia), palpitations, flushing, hypertension
- 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia), hypotension, thrombophlebitis
- <0.1% – cor pulmonale, myocarditis, acute coronary syndrome, livedo reticularis
- 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder
- 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis
- <0.1% – protein losing gastroenteropathy, ileus
- 1%–<10% – pancytopenia
- <0.1% – pure red cell aplasia
- 1%–<10% – anorexia, appetite disturbances, hyperuricemia
- 0.1%–<1% – hypoalbuminemia
- 1%–<10% – muscular weakness, musculoskeletal stiffness, muscle spasm
- 0.1%–<1% – rhabdomyolysis, tendonitis, muscle inflammation
- 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence
- 0.1%–<1% – amnesia, tremor, syncope
- <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis, CN VII paralysis
- ≥10% ‒ cough
- 1%–<10% – lung infiltration, pneumonitis, pulmonary hypertension
- 0.1%–<1% – asthma, bronchospasm
- <0.1% – acute respiratory distress syndrome
- 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema)
- 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome
- 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including fatal outcomes)
- 1%–<10% – weight increased, weight decreased
- 0.1%–<1% – blood creatine phosphokinase increased
- 1%–<10% – insomnia, depression
- 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased
- 0.1%–<1% – gynecomastia, irregular menstruation
- 1%–<10% – contusion
- 1%–<10% – tinnitus
- 0.1%–<1% – vertigo
- 0.1%–<1% – cholestasis, cholecystitis, hepatitis
- 0.1%–<1% – urinary frequency, renal failure, proteinuria
- 0.1%–<1% – tumor lysis syndrome
- 0.1%–<1% – hypersensitivity (including erythema nodosum)
- 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye
- 0.1% –<1% – conjunctivitis
- <0.1% – visual impairment
## Postmarketing Experience
- The following additional adverse reactions have been identified during post approval use of Sprycel. 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.
- Atrial fibrillation/atrial flutter, thrombosis/embolism (including pulmonary embolism, deep vein thrombosis)
- Interstitial lung disease, pulmonary arterial hypertension
# Drug Interactions
Drugs That May Increase Dasatinib Plasma Concentrations
- CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a trial of 18 patients with solid tumors, 20-mg Sprycel once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Concomitant use of Sprycel and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. In patients receiving treatment with Sprycel, close monitoring for toxicity and a Sprycel dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided.
Drugs That May Decrease Dasatinib Plasma Concentrations
- CYP3A4 Inducers: When a single morning dose of Sprycel was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should be considered. If Sprycel must be administered with a CYP3A4 inducer, a dose increase in Sprycel should be considered.
- Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a trial of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of Sprycel was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of Sprycel, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of Sprycel with antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of Sprycel.
- H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a trial of 24 healthy subjects, administration of a single 50-mg dose of Sprycel 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. In a trial of 14 healthy subjects, administration of a single 100-mg dose of Sprycel 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with Sprycel is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of Sprycel) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving Sprycel therapy.
Drugs That May Have Their Plasma Concentration Altered By Dasatinib
- CYP3A4 Substrates: Single-dose data from a trial of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of Sprycel. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving Sprycel.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Risk Summary
- Sprycel can cause fetal harm when administered to a pregnant woman. There are no studies with Sprycel in pregnant women. However, in animal reproduction studies, embryo-fetal toxicities, including skeletal malformations, were observed at dasatinib doses producing plasma concentrations below those in humans receiving therapeutic doses of dasatinib. If Sprycel is used during pregnancy, or if the patient becomes pregnant while taking Sprycel, the patient should be apprised of the potential risk to the fetus.
- Data
- Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy.
- Clinical Considerations
- Transplacental transfer of dasatinib has been reported. Dasatinib has been measured in fetal plasma and amniotic fluid and concentrations were found to be comparable to those in maternal plasma. Hydrops fetalis and fetal bicytopenia have been reported with maternal exposure to dasatinib. There have been other reports of maternal dasatinib exposure with no adverse fetal outcomes noted.
- Animal Data
- In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day and rabbit: 0.5 mg/kg/day ) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 nghr/mL and 44 nghr/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. In a pre- and postnatal development study in rats, administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at maternal exposures that were below the exposures in patients treated with dasatinib at the recommended labeling dose.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dasatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dasatinib during labor and delivery.
### Nursing Mothers
- It is unknown whether Sprycel is present in human milk. However, dasatinib was present in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Sprycel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of Sprycel in patients less than 18 years of age have not been established.
### Geriatic Use
- In the newly diagnosed chronic phase CML trial, 25 patients (10%) were 65 years of age and over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of Sprycel with resistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over. No differences in efficacy were observed between older and younger patients. Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience toxicity.
### Gender
There is no FDA guidance on the use of Dasatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dasatinib with respect to specific racial populations.
### Renal Impairment
- There are currently no clinical studies with Sprycel in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney.
### Hepatic Impairment
- The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the dose-normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment.
- No dosage adjustment is necessary in patients with hepatic impairment. Caution is recommended when administering Sprycel to patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Sprycel can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to avoid pregnancy, which may include the use of contraception, during treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Sprycel.
### Immunocompromised Patients
There is no FDA guidance one the use of Dasatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Myelosuppression and Bleeding Events
- Severe thrombocytopenia, neutropenia, and anemia may occur. Use caution if used concomitantly with medications that inhibit platelet function or anticoagulants. Monitor complete blood counts regularly.
- Cardiac Dysfunction
- Monitor patients for signs or symptoms and treat appropriately.
# IV Compatibility
There is limited information regarding IV Compatibility of Dasatinib in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Experience with overdose of Sprycel in clinical studies is limited to isolated cases. The highest overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding.
- Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2).
### Management
- Since Sprycel is associated with severe myelosuppression, patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Dasatinib in the drug label.
# Pharmacology
## Mechanism of Action
- Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.
- In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.
## Structure
- Sprycel (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2--2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S - H2O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure:
- Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. Sprycel tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dasatinib in the drug label.
## Pharmacokinetics
Absorption
- Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean terminal half-life of dasatinib is 3 to 5 hours.
- Data from a trial of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically relevant.
Distribution
- In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100 to 500 ng/mL.
Metabolism
- Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites.
- The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% of the dasatinib AUC. This indicates that the active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also had several other inactive oxidative metabolites.
- Dasatinib is a weak time-dependent inhibitor of CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of human CYP enzymes.
Elimination
- Elimination is primarily via the feces. Following a single oral dose of -labeled dasatinib, approximately 4% and 85% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.
Effects of Age and Gender
- Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of dasatinib.
Hepatic Impairment
- Dasatinib doses of 50 mg and 20 mg were evaluated in eight patients with moderate (Child-Pugh class B) and seven patients with severe (Child-Pugh class C) hepatic impairment, respectively. Matched controls with normal hepatic function (n=15) were also evaluated and received a dasatinib dose of 70 mg. Compared to subjects with normal liver function, patients with moderate hepatic impairment had decreases in dose-normalized Cmax and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had dose-normalized Cmax decreased by 43% and AUC decreased by 28% compared to the normal controls.
- These differences in Cmax and AUC are not clinically relevant. Dose adjustment is not necessary in patients with hepatic impairment.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a two-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level approximately 60% of the human exposure at 100 mg once daily. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females and prostate adenoma in low-dose males.
- Dasatinib was clastogenic when tested in vitro in Chinese hamster ovary cells, with and without metabolic activation. Dasatinib was not mutagenic when tested in an in vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study.
- Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) similar to the human exposure at 100 mg daily; however, dasatinib induced embryo lethality. In repeat dose studies, administration of dasatinib resulted in reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents.
# Clinical Studies
Newly Diagnosed Chronic Phase CML
- An open-label, multicenter, international, randomized trial was conducted in adult patients with newly diagnosed chronic phase CML. A total of 519 patients were randomized to receive either Sprycel 100 mg once daily or imatinib 400 mg once daily. Patients with a history of cardiac disease were included in this trial except those which had a myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation. The primary endpoint was the rate of confirmed complete cytogenetic response (CCyR) within 12 months. Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least 28 days apart).
- Median age was 46 years in the Sprycel group and 49 years in the imatinib groups, with 10% and 11% of patients ≥65 years of age. There were slightly more male than female patients in both groups (59% vs 41%). Fifty-three percent of all patients were Caucasian and 39% were Asian. At baseline, the distribution of Hasford Scores was similar in the Sprycel and imatinib treatment groups (low risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively). With a minimum of 12 months follow up, 85% of patients randomized to Sprycel and 81% of patients randomized to imatinib were still on study.
- With a minimum of 24 months follow up, 77% of patients randomized to Sprycel and 75% of patients randomized to imatinib were still on study and with a minimum of 36 months follow up, 71% and 69% of patients, respectively, were still on study.
- Efficacy results are summarized in Table 7.
- After 36 months follow up, median time to confirmed CCyR was 3.1 months in 214 Sprycel responders and 5.8 months in 201 imatinib responders. Median time to MMR after 36 months follow up was 8.9 months in 179 Sprycel responders and 13.4 months in 146 imatinib responders.
- At 36 months, 8 patients (3%) on the dasatinib arm progressed to either accelerated phase or blast crisis while 13 patients (5%) on the imatinib arm progressed to either accelerated phase or blast crisis.
- The rate of MMR at any time in each risk group determined by Hasford score was higher in the Sprycel group compared with the imatinib group (low risk: 81% and 64%; intermediate risk: 64% and 56%; high risk: 61% and 42%, respectively).
- BCR-ABL sequencing was performed on blood samples from patients in the newly diagnosed trial who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L, and V299L.
- Dasatinib does not appear to be active against the T315I mutation, based on in vitro data.
- Imatinib-Resistant or Intolerant CML or Ph+ ALL
- The efficacy and safety of Sprycel were investigated in adult patients with CML or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL. In a clinical trial in chronic phase CML, resistance to imatinib was defined as failure to achieve a complete hematologic response (CHR; after 3 months), major cytogenetic response (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or loss of a previous molecular response (with concurrent ≥10% increase in Ph+ metaphases), cytogenetic response, or hematologic response. Imatinib intolerance was defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity.
- Results described below are based on a minimum of 2 years follow up after the start of Sprycel therapy in patients with a median time from initial diagnosis of approximately 5 years. Across all studies, 48% of patients were women, 81% were white, 15% were black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or older. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant. Overall, 80% of patients had imatinib-resistant disease and 20% of patients were intolerant to imatinib. The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients and >600 mg/day in 40% of the patients.
- The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary efficacy endpoint in accelerated phase, myeloid blast phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL).
Chronic Phase CML
- Dose-Optimization Trial: A randomized, open-label trial was conducted in patients with chronic phase CML to evaluate the efficacy and safety of Sprycel administered once daily compared with Sprycel administered twice daily. Patients with significant cardiac diseases, including myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation were excluded from the trial. The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML. A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized to the Sprycel 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. Median duration of treatment was 22 months.
- Efficacy was achieved across all Sprycel treatment groups with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI ).
- Efficacy results are presented in Table 8 for patients with chronic phase CML who received the recommended starting dose of 100 mg once daily. Additional efficacy results in this patient population are described after the table. Results for all patients with chronic phase CML, regardless of dosage (a starting dosage of 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily), were consistent with those for patients treated with 100 mg once daily.
- In the Sprycel 100 mg once daily group, median time to MCyR was 2.9 months (95% CI: ) with a minimum of 24 months follow up. Based on the Kaplan-Meier estimates, 93% (95% CI: ) of patients who had achieved an MCyR maintained that response for 18 months. In the 100 mg once daily group, MMR was achieved in 43% of all randomized patients within 5 years. The estimated rate of progression-free survival and overall survival at 2 years in all patients treated with 100 mg once daily was 80% (95% CI: ) and 91% (95% CI: ), respectively. Based on data six years after the last patient was enrolled in the trial, 64% were known to be alive at 5 years, 22% were known to have died prior to 5 years and 14% had an unknown 5-year survival status.
- By 5 years, transformation to either accelerated or blast phase occurred in eight patients on treatment.
Advanced Phase CML and Ph+ ALL
- Dose-Optimization Trial: One randomized open-label trial was conducted in patients with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of Sprycel administered once daily compared with Sprycel administered twice daily. The primary efficacy endpoint was MaHR. A total of 611 patients were randomized to either the Sprycel 140 mg once daily or 70 mg twice daily group. Median duration of treatment was approximately 6 months for both treatment groups. The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint.
- The efficacy and safety of Sprycel were also investigated in patients with Ph+ ALL in one randomized trial (starting dosage 140 mg once daily or 70 mg twice daily) and one single-arm trial (starting dosage 70 mg twice daily). The primary efficacy endpoint was MaHR. A total of 130 patients were enrolled in these studies. The median duration of therapy was 3 months.
- Response rates are presented in Table 9.
- In the Sprycel 140 mg once daily group, the median time to MaHR was 1.9 months for patients with accelerated phase CML, 1.9 months for patients with myeloid blast phase CML, and 1.8 months for patients with lymphoid blast phase CML.
- In patients with myeloid blast phase CML, the median duration of MaHR was 8 months and 9 months for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with lymphoid blast phase CML, the median duration of MaHR was 5 months and 8 months for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with Ph+ ALL who were treated with Sprycel 140 mg once daily, the median duration of MaHR was 4.6 months. The medians of progression-free survival for patients with Ph+ ALL treated with Sprycel 140 mg once daily and 70 mg twice daily were 4.0 months and 3.5 months, respectively.
# How Supplied
- Sprycel® (dasatinib) tablets are available as described in Table 10.
- Sprycel® tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).
- Sprycel is an antineoplastic product. Follow special handling and disposal procedures.
- Sprycel (dasatinib) tablets consist of a core tablet (containing the active drug substance), surrounded by a film coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. However, if tablets are inadvertently crushed or broken, pharmacy and clinical personnel should wear disposable chemotherapy gloves. Personnel who are pregnant should avoid exposure to crushed or broken tablets.
## Storage
There is limited information regarding Dasatinib Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Dasatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sprycel®
# Look-Alike Drug Names
There is limited information regarding Dasatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Dasatinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Overview
Dasatinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia or acute lymphoblastic leukemia. Common adverse reactions include myelosuppression, fluid retention, diarrhea, headache, dyspnea, rash, fatigue, nausea, and hemorrhage.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dosage of Sprycel for chronic phase CML is 100 mg administered orally once daily. The recommended starting dosage of Sprycel for accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily. Tablets should not be crushed or cut; they should be swallowed whole. Sprycel can be taken with or without a meal, either in the morning or in the evening.
- In clinical studies, treatment with Sprycel was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment after the achievement of a complete cytogenetic response (CCyR) has not been investigated.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dasatinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dasatinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and efficacy of Sprycel in patients less than 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dasatinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dasatinib in pediatric patients.
# Contraindications
- None
# Warnings
- Treatment with Sprycel is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In a dose-optimization trial in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens.
- Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Sprycel temporarily or dose reduction.
- In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving Sprycel. Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe thrombocytopenia.
- Patients were excluded from participation in initial Sprycel clinical studies if they took medications that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with Sprycel if the platelet count was >50,000–75,000 per microliter. Exercise caution if patients are required to take medications that inhibit platelet function or anticoagulants.
- Sprycel is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients. Severe ascites, pulmonary edema, and generalized edema were each reported in ≤1% of patients. Patients who develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by chest x-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens.
- In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Of the 2440 patients treated with Sprycel in clinical studies, 16 patients (1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms. In 865 patients with leukemia treated with Sprycel in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms.
- Administer Sprycel with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to Sprycel administration.
- Cardiac adverse reactions were reported in 7% of 258 patients taking Sprycel, including, 1.6% of patients with cardiomyopathy, congestive heart failure, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.
- Sprycel may increase the risk of developing pulmonary arterial hypertension (PAH) which may occur any time after initiation, including after more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of Sprycel. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating Sprycel and during treatment. If PAH is confirmed, Sprycel should be permanently discontinued.
- Sprycel can cause fetal harm when administered to a pregnant woman. Adverse fetal and infant outcomes have been reported from women who have taken Sprycel during pregnancy. In animal reproduction studies, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits at plasma concentrations below those in humans receiving therapeutic doses of dasatinib. If Sprycel is used during pregnancy, or if the patient becomes pregnant while taking Sprycel, the patient should be apprised of the potential hazard to the fetus.
- Advise females of reproductive potential to avoid pregnancy, which may include the use of contraception, during treatment with Sprycel.
# 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 Sprycel in clinical studies including 258 patients with newly diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL.
- In the newly diagnosed chronic phase CML trial with a minimum of 36 months follow up and median duration of therapy of 37 months, the median average daily dose was 99 mg.
- In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, 1520 patients had a minimum of 2 years follow up and 662 patients with chronic phase CML had a minimum of 60 months follow up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median duration of treatment with Sprycel 100 mg once daily was 37 months (range 1–65 months). The median duration of treatment with Sprycel 140 mg once daily was 15 months (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid blast CML.
- The majority of Sprycel-treated patients experienced adverse reactions at some time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of Sprycel-treated patients with a minimum of 12 months follow up. After a minimum of 36 months follow up, the cumulative discontinuation rate was 9%. Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reactions at 2 years were 15% in chronic phase CML for all dosages, 16% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization trial in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML with a minimum of 60 months follow up, the rate of discontinuation for adverse reactions was 18% in patients treated with 100 mg once daily.
- The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, rash, and nausea. Pleural effusions were reported in 50 patients (see Table 2).
- The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage.
- The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML included pleural effusion (4%), hemorrhage (2%), congestive heart failure (1%), pulmonary hypertension (1%), and pyrexia (1%). The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%).
### Chronic Myeloid Leukemia (CML)
- Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of patients are shown in Table 2 for newly diagnosed patients with chronic phase CML and Tables 3 and 4 for CML patients with resistance or intolerance to prior imatinib therapy.
- The cumulative rates of the majority of adverse reactions (all grades) in newly diagnosed patients with chronic phase CML were similar after 12 and 36 months minimum follow up including congestive heart failure/cardiac dysfunction (2% vs 2%), pericardial effusion (2% vs 3%), pulmonary edema (<1% vs 1%), gastrointestinal bleeding (2% vs 2%), diarrhea (18% vs 21%), and generalized edema (3% vs 3%). Cumulative adverse reaction rates (all grades) that increased between 12 months and 36 months minimum follow up included overall fluid retention (23% vs 31%), pleural effusion (12% vs 19%), and superficial edema (10% vs 13%). A total of 9 patients (3.5%) discontinued due to pleural effusion in the trial.
- At 36 months, there were 17 deaths in the dasatinib-treated patients (6.6%) and 20 deaths in the imatinib-treated patients (7.7%); 1 in each group was judged by the investigator as related to study therapy.
- With a minimum follow up of 60 months (see Table 3), the cumulative rates of the majority of adverse reactions (all grades) in patients with chronic phase CML treated with a starting dose of 100 mg once daily were identical with a minimum follow up of 24 and 60 months including congestive heart failure/cardiac dysfunction, pericardial effusion, pulmonary edema, and gastrointestinal bleeding or similar for diarrhea (27% vs 28%), and generalized edema (3% vs 4%). Cumulative adverse reaction rates (all grades) that increased between 24 months and 60 months minimum follow up included: overall fluid retention (34% vs 42%), pleural effusion (18% vs 24%), and superficial edema (18% vs 21%). The cumulative rate of Grade 3 or 4 pleural effusion was 2% versus 4%, respectively.
- Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 5 and 6). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.
- In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy.
- Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of Sprycel therapy often had recovery with oral calcium supplementation.
- Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 5. There were no discontinuations of Sprycel therapy in this patient population due to biochemical laboratory parameters.
- Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of Sprycel are shown by disease phase in Table 6.
- Among chronic phase CML patients with resistance or intolerance to prior imatinib therapy, cumulative Grade 3 or 4 cytopenias were similar at 2 and 5 years including: neutropenia (36% vs 36%), thrombocytopenia (23% vs 24%) and anemia (13% vs 13%).
### Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
- A total of 135 patients with Ph+ ALL were treated with Sprycel in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events, such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders, such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%).
### Additional Data From Clinical Trials
- The following adverse reactions were reported in patients in the Sprycel clinical studies at a frequency of ≥10%, 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance.
- 1%–<10% – asthenia, pain, chest pain, chills
- 0.1%–<1% – malaise, temperature intolerance.
- 1%–<10% – arrhythmia (including tachycardia), palpitations, flushing, hypertension
- 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia), hypotension, thrombophlebitis
- <0.1% – cor pulmonale, myocarditis, acute coronary syndrome, livedo reticularis
- 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder
- 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis
- <0.1% – protein losing gastroenteropathy, ileus
- 1%–<10% – pancytopenia
- <0.1% – pure red cell aplasia
- 1%–<10% – anorexia, appetite disturbances, hyperuricemia
- 0.1%–<1% – hypoalbuminemia
- 1%–<10% – muscular weakness, musculoskeletal stiffness, muscle spasm
- 0.1%–<1% – rhabdomyolysis, tendonitis, muscle inflammation
- 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence
- 0.1%–<1% – amnesia, tremor, syncope
- <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis, CN VII paralysis
- ≥10% ‒ cough
- 1%–<10% – lung infiltration, pneumonitis, pulmonary hypertension
- 0.1%–<1% – asthma, bronchospasm
- <0.1% – acute respiratory distress syndrome
- 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema)
- 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome
- 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including fatal outcomes)
- 1%–<10% – weight increased, weight decreased
- 0.1%–<1% – blood creatine phosphokinase increased
- 1%–<10% – insomnia, depression
- 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased
- 0.1%–<1% – gynecomastia, irregular menstruation
- 1%–<10% – contusion
- 1%–<10% – tinnitus
- 0.1%–<1% – vertigo
- 0.1%–<1% – cholestasis, cholecystitis, hepatitis
- 0.1%–<1% – urinary frequency, renal failure, proteinuria
- 0.1%–<1% – tumor lysis syndrome
- 0.1%–<1% – hypersensitivity (including erythema nodosum)
- 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye
- 0.1% –<1% – conjunctivitis
- <0.1% – visual impairment
## Postmarketing Experience
- The following additional adverse reactions have been identified during post approval use of Sprycel. 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.
- Atrial fibrillation/atrial flutter, thrombosis/embolism (including pulmonary embolism, deep vein thrombosis)
- Interstitial lung disease, pulmonary arterial hypertension
# Drug Interactions
Drugs That May Increase Dasatinib Plasma Concentrations
- CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a trial of 18 patients with solid tumors, 20-mg Sprycel once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Concomitant use of Sprycel and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. In patients receiving treatment with Sprycel, close monitoring for toxicity and a Sprycel dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided.
Drugs That May Decrease Dasatinib Plasma Concentrations
- CYP3A4 Inducers: When a single morning dose of Sprycel was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should be considered. If Sprycel must be administered with a CYP3A4 inducer, a dose increase in Sprycel should be considered.
- Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a trial of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of Sprycel was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of Sprycel, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of Sprycel with antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of Sprycel.
- H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a trial of 24 healthy subjects, administration of a single 50-mg dose of Sprycel 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. In a trial of 14 healthy subjects, administration of a single 100-mg dose of Sprycel 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with Sprycel is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of Sprycel) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving Sprycel therapy.
Drugs That May Have Their Plasma Concentration Altered By Dasatinib
- CYP3A4 Substrates: Single-dose data from a trial of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of Sprycel. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving Sprycel.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Risk Summary
- Sprycel can cause fetal harm when administered to a pregnant woman. There are no studies with Sprycel in pregnant women. However, in animal reproduction studies, embryo-fetal toxicities, including skeletal malformations, were observed at dasatinib doses producing plasma concentrations below those in humans receiving therapeutic doses of dasatinib. If Sprycel is used during pregnancy, or if the patient becomes pregnant while taking Sprycel, the patient should be apprised of the potential risk to the fetus.
- Data
- Based on human experience, dasatinib is suspected to cause congenital malformations, including neural tube defects, and harmful pharmacological effects on the fetus when administered during pregnancy.
- Clinical Considerations
- Transplacental transfer of dasatinib has been reported. Dasatinib has been measured in fetal plasma and amniotic fluid and concentrations were found to be comparable to those in maternal plasma. Hydrops fetalis and fetal bicytopenia have been reported with maternal exposure to dasatinib. There have been other reports of maternal dasatinib exposure with no adverse fetal outcomes noted.
- Animal Data
- In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m2/day] and rabbit: 0.5 mg/kg/day [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•hr/mL and 44 ng•hr/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, and clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. In a pre- and postnatal development study in rats, administration of dasatinib from gestation day (GD) 16 through lactation day (LD) 20, GD 21 through LD 20, or LD 4 through LD 20 resulted in extensive pup mortality at maternal exposures that were below the exposures in patients treated with dasatinib at the recommended labeling dose.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dasatinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dasatinib during labor and delivery.
### Nursing Mothers
- It is unknown whether Sprycel is present in human milk. However, dasatinib was present in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Sprycel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of Sprycel in patients less than 18 years of age have not been established.
### Geriatic Use
- In the newly diagnosed chronic phase CML trial, 25 patients (10%) were 65 years of age and over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of Sprycel with resistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over. No differences in efficacy were observed between older and younger patients. Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience toxicity.
### Gender
There is no FDA guidance on the use of Dasatinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dasatinib with respect to specific racial populations.
### Renal Impairment
- There are currently no clinical studies with Sprycel in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney.
### Hepatic Impairment
- The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the dose-normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment.
- No dosage adjustment is necessary in patients with hepatic impairment. Caution is recommended when administering Sprycel to patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Sprycel can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to avoid pregnancy, which may include the use of contraception, during treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Sprycel.
### Immunocompromised Patients
There is no FDA guidance one the use of Dasatinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Myelosuppression and Bleeding Events
- Severe thrombocytopenia, neutropenia, and anemia may occur. Use caution if used concomitantly with medications that inhibit platelet function or anticoagulants. Monitor complete blood counts regularly.
- Cardiac Dysfunction
- Monitor patients for signs or symptoms and treat appropriately.
# IV Compatibility
There is limited information regarding IV Compatibility of Dasatinib in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Experience with overdose of Sprycel in clinical studies is limited to isolated cases. The highest overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding.
- Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2).
### Management
- Since Sprycel is associated with severe myelosuppression, patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Dasatinib in the drug label.
# Pharmacology
## Mechanism of Action
- Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.
- In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.
## Structure
- Sprycel (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure:
- Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. Sprycel tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dasatinib in the drug label.
## Pharmacokinetics
Absorption
- Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean terminal half-life of dasatinib is 3 to 5 hours.
- Data from a trial of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically relevant.
Distribution
- In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100 to 500 ng/mL.
Metabolism
- Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites.
- The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% of the dasatinib AUC. This indicates that the active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also had several other inactive oxidative metabolites.
- Dasatinib is a weak time-dependent inhibitor of CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of human CYP enzymes.
Elimination
- Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled dasatinib, approximately 4% and 85% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.
Effects of Age and Gender
- Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of dasatinib.
Hepatic Impairment
- Dasatinib doses of 50 mg and 20 mg were evaluated in eight patients with moderate (Child-Pugh class B) and seven patients with severe (Child-Pugh class C) hepatic impairment, respectively. Matched controls with normal hepatic function (n=15) were also evaluated and received a dasatinib dose of 70 mg. Compared to subjects with normal liver function, patients with moderate hepatic impairment had decreases in dose-normalized Cmax and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had dose-normalized Cmax decreased by 43% and AUC decreased by 28% compared to the normal controls.
- These differences in Cmax and AUC are not clinically relevant. Dose adjustment is not necessary in patients with hepatic impairment.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a two-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level approximately 60% of the human exposure at 100 mg once daily. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females and prostate adenoma in low-dose males.
- Dasatinib was clastogenic when tested in vitro in Chinese hamster ovary cells, with and without metabolic activation. Dasatinib was not mutagenic when tested in an in vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study.
- Dasatinib did not affect mating or fertility in male and female rats at plasma drug exposure (AUC) similar to the human exposure at 100 mg daily; however, dasatinib induced embryo lethality. In repeat dose studies, administration of dasatinib resulted in reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents.
# Clinical Studies
Newly Diagnosed Chronic Phase CML
- An open-label, multicenter, international, randomized trial was conducted in adult patients with newly diagnosed chronic phase CML. A total of 519 patients were randomized to receive either Sprycel 100 mg once daily or imatinib 400 mg once daily. Patients with a history of cardiac disease were included in this trial except those which had a myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation. The primary endpoint was the rate of confirmed complete cytogenetic response (CCyR) within 12 months. Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least 28 days apart).
- Median age was 46 years in the Sprycel group and 49 years in the imatinib groups, with 10% and 11% of patients ≥65 years of age. There were slightly more male than female patients in both groups (59% vs 41%). Fifty-three percent of all patients were Caucasian and 39% were Asian. At baseline, the distribution of Hasford Scores was similar in the Sprycel and imatinib treatment groups (low risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively). With a minimum of 12 months follow up, 85% of patients randomized to Sprycel and 81% of patients randomized to imatinib were still on study.
- With a minimum of 24 months follow up, 77% of patients randomized to Sprycel and 75% of patients randomized to imatinib were still on study and with a minimum of 36 months follow up, 71% and 69% of patients, respectively, were still on study.
- Efficacy results are summarized in Table 7.
- After 36 months follow up, median time to confirmed CCyR was 3.1 months in 214 Sprycel responders and 5.8 months in 201 imatinib responders. Median time to MMR after 36 months follow up was 8.9 months in 179 Sprycel responders and 13.4 months in 146 imatinib responders.
- At 36 months, 8 patients (3%) on the dasatinib arm progressed to either accelerated phase or blast crisis while 13 patients (5%) on the imatinib arm progressed to either accelerated phase or blast crisis.
- The rate of MMR at any time in each risk group determined by Hasford score was higher in the Sprycel group compared with the imatinib group (low risk: 81% and 64%; intermediate risk: 64% and 56%; high risk: 61% and 42%, respectively).
- BCR-ABL sequencing was performed on blood samples from patients in the newly diagnosed trial who discontinued dasatinib or imatinib therapy. Among dasatinib-treated patients the mutations detected were T315I, F317I/L, and V299L.
- Dasatinib does not appear to be active against the T315I mutation, based on in vitro data.
- Imatinib-Resistant or Intolerant CML or Ph+ ALL
- The efficacy and safety of Sprycel were investigated in adult patients with CML or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL. In a clinical trial in chronic phase CML, resistance to imatinib was defined as failure to achieve a complete hematologic response (CHR; after 3 months), major cytogenetic response (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or loss of a previous molecular response (with concurrent ≥10% increase in Ph+ metaphases), cytogenetic response, or hematologic response. Imatinib intolerance was defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity.
- Results described below are based on a minimum of 2 years follow up after the start of Sprycel therapy in patients with a median time from initial diagnosis of approximately 5 years. Across all studies, 48% of patients were women, 81% were white, 15% were black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or older. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant. Overall, 80% of patients had imatinib-resistant disease and 20% of patients were intolerant to imatinib. The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients and >600 mg/day in 40% of the patients.
- The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary efficacy endpoint in accelerated phase, myeloid blast phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL).
Chronic Phase CML
- Dose-Optimization Trial: A randomized, open-label trial was conducted in patients with chronic phase CML to evaluate the efficacy and safety of Sprycel administered once daily compared with Sprycel administered twice daily. Patients with significant cardiac diseases, including myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation were excluded from the trial. The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML. A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized to the Sprycel 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. Median duration of treatment was 22 months.
- Efficacy was achieved across all Sprycel treatment groups with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [−6.8%–10.6%]).
- Efficacy results are presented in Table 8 for patients with chronic phase CML who received the recommended starting dose of 100 mg once daily. Additional efficacy results in this patient population are described after the table. Results for all patients with chronic phase CML, regardless of dosage (a starting dosage of 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily), were consistent with those for patients treated with 100 mg once daily.
- In the Sprycel 100 mg once daily group, median time to MCyR was 2.9 months (95% CI: [2.8%–3.0%]) with a minimum of 24 months follow up. Based on the Kaplan-Meier estimates, 93% (95% CI: [88%–98%]) of patients who had achieved an MCyR maintained that response for 18 months. In the 100 mg once daily group, MMR was achieved in 43% of all randomized patients within 5 years. The estimated rate of progression-free survival and overall survival at 2 years in all patients treated with 100 mg once daily was 80% (95% CI: [73%–87%]) and 91% (95% CI: [86%–96%]), respectively. Based on data six years after the last patient was enrolled in the trial, 64% were known to be alive at 5 years, 22% were known to have died prior to 5 years and 14% had an unknown 5-year survival status.
- By 5 years, transformation to either accelerated or blast phase occurred in eight patients on treatment.
Advanced Phase CML and Ph+ ALL
- Dose-Optimization Trial: One randomized open-label trial was conducted in patients with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of Sprycel administered once daily compared with Sprycel administered twice daily. The primary efficacy endpoint was MaHR. A total of 611 patients were randomized to either the Sprycel 140 mg once daily or 70 mg twice daily group. Median duration of treatment was approximately 6 months for both treatment groups. The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint.
- The efficacy and safety of Sprycel were also investigated in patients with Ph+ ALL in one randomized trial (starting dosage 140 mg once daily or 70 mg twice daily) and one single-arm trial (starting dosage 70 mg twice daily). The primary efficacy endpoint was MaHR. A total of 130 patients were enrolled in these studies. The median duration of therapy was 3 months.
- Response rates are presented in Table 9.
- In the Sprycel 140 mg once daily group, the median time to MaHR was 1.9 months for patients with accelerated phase CML, 1.9 months for patients with myeloid blast phase CML, and 1.8 months for patients with lymphoid blast phase CML.
- In patients with myeloid blast phase CML, the median duration of MaHR was 8 months and 9 months for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with lymphoid blast phase CML, the median duration of MaHR was 5 months and 8 months for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with Ph+ ALL who were treated with Sprycel 140 mg once daily, the median duration of MaHR was 4.6 months. The medians of progression-free survival for patients with Ph+ ALL treated with Sprycel 140 mg once daily and 70 mg twice daily were 4.0 months and 3.5 months, respectively.
# How Supplied
- Sprycel® (dasatinib) tablets are available as described in Table 10.
- Sprycel® tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).
- Sprycel is an antineoplastic product. Follow special handling and disposal procedures.
- Sprycel (dasatinib) tablets consist of a core tablet (containing the active drug substance), surrounded by a film coating to prevent exposure of pharmacy and clinical personnel to the active drug substance. However, if tablets are inadvertently crushed or broken, pharmacy and clinical personnel should wear disposable chemotherapy gloves. Personnel who are pregnant should avoid exposure to crushed or broken tablets.
## Storage
There is limited information regarding Dasatinib Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Dasatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sprycel®[1]
# Look-Alike Drug Names
There is limited information regarding Dasatinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/BMS-354825 | |
1bab48baa0fb8194fc091873a4b225adb7033e25 | wikidoc | Baby acne | Baby acne
Baby acne, also known as acne neonatorum, is a condition that affects roughly 20% of newborn babies. Lesions appear at around 2 weeks postpartum and commonly disappear after 3 months. Lesions include small, red, papules, which mainly affect the cheeks, as well as the nasal bridge of infants. Infants usually develop neonatal acne because of stimulation of the baby's sebaceous glands by lingering maternal hormones after delivery. These hormones cross the placenta into the baby and after delivery they cause the oil glands on the skin to form bumps that look like pimples.
Baby acne usually clears up within a few weeks, but it can linger for months.
Tiny bumps on a baby's face after birth that disappear within a few weeks are called milia and are unrelated to baby acne.
Baby acne has recently been described to be caused by saprophytic yeast of the Malassezia species, which cause a primary skin infection leading to the appearance of acne-like pustules. Initially it was believed to be the common yeast species, Malassezia furfur, which also causes 'cradle-cap' in infants. However, new publications have pointed to another species, Malassezia sympolais. Treatment options are still the same for both species, which includes low dose topical antifungals. | Baby acne
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Baby acne, also known as acne neonatorum, is a condition that affects roughly 20% of newborn babies. Lesions appear at around 2 weeks postpartum and commonly disappear after 3 months. Lesions include small, red, papules, which mainly affect the cheeks, as well as the nasal bridge of infants. Infants usually develop neonatal acne because of stimulation of the baby's sebaceous glands by lingering maternal hormones after delivery. These hormones cross the placenta into the baby and after delivery they cause the oil glands on the skin to form bumps that look like pimples.[2]
Baby acne usually clears up within a few weeks, but it can linger for months.
Tiny bumps on a baby's face after birth that disappear within a few weeks are called milia and are unrelated to baby acne.
Baby acne has recently been described to be caused by saprophytic yeast of the Malassezia species, which cause a primary skin infection leading to the appearance of acne-like pustules. Initially it was believed to be the common yeast species, Malassezia furfur, which also causes 'cradle-cap' in infants. However, new publications have pointed to another species, Malassezia sympolais. Treatment options are still the same for both species, which includes low dose topical antifungals. | https://www.wikidoc.org/index.php/Baby_acne | |
a5932f0f65589e3892d1b367edcd1ff3c03cb348 | wikidoc | Mupirocin | Mupirocin
# Disclaimer
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# Overview
Mupirocin is an anti-bacterial, anti-infective agent that is FDA approved for the treatment of impetigo. Common adverse reactions include application site pain, sensation of burning of skin, stinging of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- BACTROBAN Ointment is indicated for the topical treatment of impetigo due to: S. aureus and S. pyogenes.
- Dosing Information
- A small amount of BACTROBAN Ointment should be applied to the affected area 3 times daily. The area treated may be covered with a gauze dressing if desired. Patients not showing a clinical response within 3 to 5 days should be re-evaluated.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Mupirocin in adult patients.
### Non–Guideline-Supported Use
- Complication of catheter - Infectious disease, Exit site; Prophylaxis
- Superficial bacterial infection of skin
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- A small amount of BACTROBAN Ointment should be applied to the affected area 3 times daily. The area treated may be covered with a gauze dressing if desired. Patients not showing a clinical response within 3 to 5 days should be re-evaluated.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Mupirocin in pediatric patients.
### Non–Guideline-Supported Use
- Superficial bacterial infection of skin
# Contraindications
- This drug is contraindicated in patients with known hypersensitivity to any of the constituents of the product.
# Warnings
- Avoid contact with the eyes. In case of accidental contact, rinse well with water.
- In the event of sensitization or severe local irritation from BACTROBAN Ointment, usage should be discontinued.
- Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BACTROBAN, 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 isolates 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 antibacterial drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
### PRECAUTIONS
- As with other antibacterial products, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi.
- BACTROBAN Ointment is not formulated for use on mucosal surfaces. Intranasal use has been associated with isolated reports of stinging and drying. A paraffin-based formulation — BACTROBAN® Nasal (mupirocin calcium ointment) — is available for intranasal use.
- Polyethylene glycol can be absorbed from open wounds and damaged skin and is excreted by the kidneys. In common with other polyethylene glycol-based ointments, BACTROBAN Ointment should not be used in conditions where absorption of large quantities of polyethylene glycol is possible, especially if there is evidence of moderate or severe renal impairment.
- BACTROBAN Ointment should not be used with intravenous cannulae or at central intravenous sites because of the potential to promote fungal infections and antimicrobial resistance.
Information for Patients
- Use this medication only as directed by the healthcare provider. It is for external use only. Avoid contact with the eyes. If BACTROBAN Ointment gets in or near the eyes, rinse thoroughly with water. The medication should be stopped and the healthcare provider contacted if irritation, severe itching, or rash occurs.
- If impetigo has not improved in 3 to 5 days, contact the healthcare provider.
Drug Interactions
- The effect of the concurrent application of BACTROBAN Ointment and other drug products has not been studied.
# Adverse Reactions
## Clinical Trials Experience
- The following local adverse reactions have been reported in connection with the use of BACTROBAN Ointment: burning, stinging, or pain in 1.5% of subjects; itching in 1% of subjects; rash, nausea, erythema, dry skin, tenderness, swelling, contact dermatitis, and increased exudate in less than 1% of subjects.
- Systemic allergic reactions, including anaphylaxis, urticaria, angioedema, and generalized rash have been reported in patients treated with formulations of BACTROBAN.
## Postmarketing Experience
There is limited information regarding Mupirocin Postmarketing Experience in the drug label.
# Drug Interactions
- The effect of the concurrent application of BACTROBAN Ointment and other drug products has not been studied.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Teratogenic Effects:Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits with mupirocin administered subcutaneously at doses up to 22 and 43 times, respectively, the human topical dose (approximately 60 mg mupirocin per day) on a mg/m2 basis and revealed no evidence of harm to the fetus due to mupirocin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal 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 Mupirocin in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Mupirocin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BACTROBAN Ointment is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of BACTROBAN Ointment have been established in the age range of 2 months to 16 years. Use of BACTROBAN Ointment in these age groups is supported by evidence from adequate and well-controlled trials of BACTROBAN Ointment in impetigo in pediatric subjects studied as a part of the pivotal clinical trials (see CLINICAL STUDIES).
### Geriatic Use
- There is no FDA guidance on the use of Mupirocin with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Mupirocin with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Mupirocin with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Mupirocin in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Mupirocin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Mupirocin in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Mupirocin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- A small amount of BACTROBAN Ointment should be applied to the affected area 3 times daily. The area treated may be covered with a gauze dressing if desired. Patients not showing a clinical response within 3 to 5 days should be re-evaluated.
### Monitoring
- There is limited information regarding Monitoring of Mupirocin in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Mupirocin in the drug label.
# Overdosage
There is limited information regarding Mupirocin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Mupirocin Mechanism of Action in the drug label.
## Structure
- Each gram of BACTROBAN Ointment (mupirocin ointment, 2%) contains 20 mg mupirocin in a bland water miscible ointment base (polyethylene glycol ointment, N.F.) consisting of polyethylene glycol 400 and polyethylene glycol 3350. Mupirocin is a naturally occurring antibiotic. The chemical name is (E)-(2S,3R,4R,5S)-5-tetrahydro-3,4-dihydroxy-β-methyl-2H-pyran-2-crotonic acid, ester with 9-hydroxynonanoic acid. The molecular formula of mupirocin is C26H44O9, and the molecular weight is 500.63. The chemical structure is:
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Mupirocin in the drug label.
## Pharmacokinetics
- Application of 14C-labeled mupirocin ointment to the lower arm of normal male subjects followed by occlusion for 24 hours showed no measurable systemic absorption (<1.1 nanogram mupirocin per milliliter of whole blood). Measurable radioactivity was present in the stratum corneum of these subjects 72 hours after application.
- Following intravenous or oral administration, mupirocin is rapidly metabolized. The principal metabolite, monic acid, is eliminated by renal excretion, and demonstrates no antibacterial activity. In a trial conducted in 7 healthy adult male subjects, the elimination half-life after intravenous administration of mupirocin was 20 to 40 minutes for mupirocin and 30 to 80 minutes for monic acid. The pharmacokinetics of mupirocin has not been studied in individuals with renal insufficiency.
Microbiology
- Mupirocin is an antibacterial agent produced by fermentation using the organism Pseudomonas fluorescens. It is active against a wide range of gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). It is also active against certain gram-negative bacteria. Mupirocin inhibits bacterial protein synthesis by reversibly and specifically binding to bacterial isoleucyl transfer-RNA synthetase. Due to this unique mode of action, mupirocin demonstrates no in vitro cross-resistance with other classes of antimicrobial agents.
- Resistance occurs rarely. However, when mupirocin resistance does occur, it appears to result from the production of a modified isoleucyl-tRNA synthetase. High-level plasmid-mediated resistance (MIC >1,024 mcg/mL) has been reported in some strains of S. aureus and coagulase-negative staphylococci.
- Mupirocin is bactericidal at concentrations achieved by topical administration. However, the minimum bactericidal concentration (MBC) against relevant pathogens is generally 8-fold to 30-fold higher than the minimum inhibitory concentration (MIC). In addition, mupirocin is highly protein-bound (>97%), and the effect of wound secretions on the MICs of mupirocin has not been determined.
- Mupirocin has been shown to be active against most strains of S. aureus and Streptococcus pyogenes, both in vitro and in clinical trials. The following in vitro data are available, BUT THEIR CLINICAL SIGNIFICANCE IS UNKNOWN. Mupirocin is active against most strains of Staphylococcus epidermidis and Staphylococcus saprophyticus.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies in animals to evaluate carcinogenic potential of mupirocin have not been conducted.
- Results of the following studies performed with mupirocin calcium or mupirocin sodium in vitro and in vivo did not indicate a potential for genotoxicity: Rat primary hepatocyte unscheduled DNA synthesis, sediment analysis for DNA strand breaks, Salmonella reversion test (Ames), Escherichia coli mutation assay, metaphase analysis of human lymphocytes, mouse lymphoma assay, and bone marrow micronuclei assay in mice.
- Reproduction studies were performed in male and female rats with mupirocin administered subcutaneously at doses up to 14 times a human topical dose (approximately 60 mg mupirocin per day) on a mg/m2 basis and revealed no evidence of impaired fertility and reproductive performance from mupirocin.
# Clinical Studies
- The efficacy of topical BACTROBAN Ointment in impetigo was tested in 2 trials. In the first, subjects with impetigo were randomized to receive either BACTROBAN Ointment or vehicle placebo 3 times daily for 8 to 12 days. Clinical efficacy rates at end of therapy in the evaluable populations (adults and pediatric subjects included) were 71% for BACTROBAN Ointment (n = 49) and 35% for vehicle placebo (n = 51). Pathogen eradication rates in the evaluable populations were 94% for BACTROBAN Ointment and 62% for vehicle placebo. There were no side effects reported in the group receiving BACTROBAN Ointment.
- In the second trial, subjects with impetigo were randomized to receive either BACTROBAN Ointment 3 times daily or 30 to 40 mg/kg oral erythromycin ethylsuccinate per day (this was an unblinded trial) for 8 days. There was a follow-up visit 1 week after treatment ended. Clinical efficacy rates at the follow-up visit in the evaluable populations (adults and pediatric subjects included) were 93% for BACTROBAN Ointment (n = 29) and 78.5% for erythromycin (n = 28). Pathogen eradication rates in the evaluable populations were 100% for both test groups. There were no side effects reported in the group receiving BACTROBAN Ointment.
Pediatrics
- There were 91 pediatric subjects aged 2 months to 15 years in the first trial described above. Clinical efficacy rates at end of therapy in the evaluable populations were 78% for BACTROBAN Ointment (n = 42) and 36% for vehicle placebo (n = 49). In the second trial described above, all subjects were pediatric except 2 adults in the group receiving BACTROBAN Ointment. The age range of the pediatric subjects was 7 months to 13 years. The clinical efficacy rate for BACTROBAN Ointment (n = 27) was 96%, and for erythromycin it was unchanged (78.5%).
# How Supplied
- BACTROBAN Ointment is supplied in 22-gram tubes.
- NDC 0029-1525-44 (22-gram tube)
## Storage
- Store at controlled room temperature 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Use this medication only as directed by the healthcare provider. It is for external use only. Avoid contact with the eyes. If BACTROBAN Ointment gets in or near the eyes, rinse thoroughly with water. The medication should be stopped and the healthcare provider contacted if irritation, severe itching, or rash occurs.
- If impetigo has not improved in 3 to 5 days, contact the healthcare provider.
# Precautions with Alcohol
- Alcohol-Mupirocin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Bactroban,
Centany,
Centany AT.
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Mupirocin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Mupirocin is an anti-bacterial, anti-infective agent that is FDA approved for the treatment of impetigo. Common adverse reactions include application site pain, sensation of burning of skin, stinging of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- BACTROBAN Ointment is indicated for the topical treatment of impetigo due to: S. aureus and S. pyogenes.
- Dosing Information
- A small amount of BACTROBAN Ointment should be applied to the affected area 3 times daily. The area treated may be covered with a gauze dressing if desired. Patients not showing a clinical response within 3 to 5 days should be re-evaluated.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Mupirocin in adult patients.
### Non–Guideline-Supported Use
- Complication of catheter - Infectious disease, Exit site; Prophylaxis
- Superficial bacterial infection of skin
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- A small amount of BACTROBAN Ointment should be applied to the affected area 3 times daily. The area treated may be covered with a gauze dressing if desired. Patients not showing a clinical response within 3 to 5 days should be re-evaluated.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Mupirocin in pediatric patients.
### Non–Guideline-Supported Use
- Superficial bacterial infection of skin
# Contraindications
- This drug is contraindicated in patients with known hypersensitivity to any of the constituents of the product.
# Warnings
- Avoid contact with the eyes. In case of accidental contact, rinse well with water.
- In the event of sensitization or severe local irritation from BACTROBAN Ointment, usage should be discontinued.
- Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BACTROBAN, 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 isolates 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 antibacterial drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
### PRECAUTIONS
- As with other antibacterial products, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi.
- BACTROBAN Ointment is not formulated for use on mucosal surfaces. Intranasal use has been associated with isolated reports of stinging and drying. A paraffin-based formulation — BACTROBAN® Nasal (mupirocin calcium ointment) — is available for intranasal use.
- Polyethylene glycol can be absorbed from open wounds and damaged skin and is excreted by the kidneys. In common with other polyethylene glycol-based ointments, BACTROBAN Ointment should not be used in conditions where absorption of large quantities of polyethylene glycol is possible, especially if there is evidence of moderate or severe renal impairment.
- BACTROBAN Ointment should not be used with intravenous cannulae or at central intravenous sites because of the potential to promote fungal infections and antimicrobial resistance.
Information for Patients
- Use this medication only as directed by the healthcare provider. It is for external use only. Avoid contact with the eyes. If BACTROBAN Ointment gets in or near the eyes, rinse thoroughly with water. The medication should be stopped and the healthcare provider contacted if irritation, severe itching, or rash occurs.
- If impetigo has not improved in 3 to 5 days, contact the healthcare provider.
Drug Interactions
- The effect of the concurrent application of BACTROBAN Ointment and other drug products has not been studied.
# Adverse Reactions
## Clinical Trials Experience
- The following local adverse reactions have been reported in connection with the use of BACTROBAN Ointment: burning, stinging, or pain in 1.5% of subjects; itching in 1% of subjects; rash, nausea, erythema, dry skin, tenderness, swelling, contact dermatitis, and increased exudate in less than 1% of subjects.
- Systemic allergic reactions, including anaphylaxis, urticaria, angioedema, and generalized rash have been reported in patients treated with formulations of BACTROBAN.
## Postmarketing Experience
There is limited information regarding Mupirocin Postmarketing Experience in the drug label.
# Drug Interactions
- The effect of the concurrent application of BACTROBAN Ointment and other drug products has not been studied.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Teratogenic Effects:Pregnancy Category B
- Reproduction studies have been performed in rats and rabbits with mupirocin administered subcutaneously at doses up to 22 and 43 times, respectively, the human topical dose (approximately 60 mg mupirocin per day) on a mg/m2 basis and revealed no evidence of harm to the fetus due to mupirocin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal 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 Mupirocin in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Mupirocin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BACTROBAN Ointment is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of BACTROBAN Ointment have been established in the age range of 2 months to 16 years. Use of BACTROBAN Ointment in these age groups is supported by evidence from adequate and well-controlled trials of BACTROBAN Ointment in impetigo in pediatric subjects studied as a part of the pivotal clinical trials (see CLINICAL STUDIES).
### Geriatic Use
- There is no FDA guidance on the use of Mupirocin with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Mupirocin with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Mupirocin with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Mupirocin in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Mupirocin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Mupirocin in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Mupirocin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- A small amount of BACTROBAN Ointment should be applied to the affected area 3 times daily. The area treated may be covered with a gauze dressing if desired. Patients not showing a clinical response within 3 to 5 days should be re-evaluated.
### Monitoring
- There is limited information regarding Monitoring of Mupirocin in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Mupirocin in the drug label.
# Overdosage
There is limited information regarding Mupirocin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Mupirocin Mechanism of Action in the drug label.
## Structure
- Each gram of BACTROBAN Ointment (mupirocin ointment, 2%) contains 20 mg mupirocin in a bland water miscible ointment base (polyethylene glycol ointment, N.F.) consisting of polyethylene glycol 400 and polyethylene glycol 3350. Mupirocin is a naturally occurring antibiotic. The chemical name is (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-Epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-β-methyl-2H-pyran-2-crotonic acid, ester with 9-hydroxynonanoic acid. The molecular formula of mupirocin is C26H44O9, and the molecular weight is 500.63. The chemical structure is:
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Mupirocin in the drug label.
## Pharmacokinetics
- Application of 14C-labeled mupirocin ointment to the lower arm of normal male subjects followed by occlusion for 24 hours showed no measurable systemic absorption (<1.1 nanogram mupirocin per milliliter of whole blood). Measurable radioactivity was present in the stratum corneum of these subjects 72 hours after application.
- Following intravenous or oral administration, mupirocin is rapidly metabolized. The principal metabolite, monic acid, is eliminated by renal excretion, and demonstrates no antibacterial activity. In a trial conducted in 7 healthy adult male subjects, the elimination half-life after intravenous administration of mupirocin was 20 to 40 minutes for mupirocin and 30 to 80 minutes for monic acid. The pharmacokinetics of mupirocin has not been studied in individuals with renal insufficiency.
Microbiology
- Mupirocin is an antibacterial agent produced by fermentation using the organism Pseudomonas fluorescens. It is active against a wide range of gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). It is also active against certain gram-negative bacteria. Mupirocin inhibits bacterial protein synthesis by reversibly and specifically binding to bacterial isoleucyl transfer-RNA synthetase. Due to this unique mode of action, mupirocin demonstrates no in vitro cross-resistance with other classes of antimicrobial agents.
- Resistance occurs rarely. However, when mupirocin resistance does occur, it appears to result from the production of a modified isoleucyl-tRNA synthetase. High-level plasmid-mediated resistance (MIC >1,024 mcg/mL) has been reported in some strains of S. aureus and coagulase-negative staphylococci.
- Mupirocin is bactericidal at concentrations achieved by topical administration. However, the minimum bactericidal concentration (MBC) against relevant pathogens is generally 8-fold to 30-fold higher than the minimum inhibitory concentration (MIC). In addition, mupirocin is highly protein-bound (>97%), and the effect of wound secretions on the MICs of mupirocin has not been determined.
- Mupirocin has been shown to be active against most strains of S. aureus and Streptococcus pyogenes, both in vitro and in clinical trials. The following in vitro data are available, BUT THEIR CLINICAL SIGNIFICANCE IS UNKNOWN. Mupirocin is active against most strains of Staphylococcus epidermidis and Staphylococcus saprophyticus.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies in animals to evaluate carcinogenic potential of mupirocin have not been conducted.
- Results of the following studies performed with mupirocin calcium or mupirocin sodium in vitro and in vivo did not indicate a potential for genotoxicity: Rat primary hepatocyte unscheduled DNA synthesis, sediment analysis for DNA strand breaks, Salmonella reversion test (Ames), Escherichia coli mutation assay, metaphase analysis of human lymphocytes, mouse lymphoma assay, and bone marrow micronuclei assay in mice.
- Reproduction studies were performed in male and female rats with mupirocin administered subcutaneously at doses up to 14 times a human topical dose (approximately 60 mg mupirocin per day) on a mg/m2 basis and revealed no evidence of impaired fertility and reproductive performance from mupirocin.
# Clinical Studies
- The efficacy of topical BACTROBAN Ointment in impetigo was tested in 2 trials. In the first, subjects with impetigo were randomized to receive either BACTROBAN Ointment or vehicle placebo 3 times daily for 8 to 12 days. Clinical efficacy rates at end of therapy in the evaluable populations (adults and pediatric subjects included) were 71% for BACTROBAN Ointment (n = 49) and 35% for vehicle placebo (n = 51). Pathogen eradication rates in the evaluable populations were 94% for BACTROBAN Ointment and 62% for vehicle placebo. There were no side effects reported in the group receiving BACTROBAN Ointment.
- In the second trial, subjects with impetigo were randomized to receive either BACTROBAN Ointment 3 times daily or 30 to 40 mg/kg oral erythromycin ethylsuccinate per day (this was an unblinded trial) for 8 days. There was a follow-up visit 1 week after treatment ended. Clinical efficacy rates at the follow-up visit in the evaluable populations (adults and pediatric subjects included) were 93% for BACTROBAN Ointment (n = 29) and 78.5% for erythromycin (n = 28). Pathogen eradication rates in the evaluable populations were 100% for both test groups. There were no side effects reported in the group receiving BACTROBAN Ointment.
Pediatrics
- There were 91 pediatric subjects aged 2 months to 15 years in the first trial described above. Clinical efficacy rates at end of therapy in the evaluable populations were 78% for BACTROBAN Ointment (n = 42) and 36% for vehicle placebo (n = 49). In the second trial described above, all subjects were pediatric except 2 adults in the group receiving BACTROBAN Ointment. The age range of the pediatric subjects was 7 months to 13 years. The clinical efficacy rate for BACTROBAN Ointment (n = 27) was 96%, and for erythromycin it was unchanged (78.5%).
# How Supplied
- BACTROBAN Ointment is supplied in 22-gram tubes.
- NDC 0029-1525-44 (22-gram tube)
## Storage
- Store at controlled room temperature 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Use this medication only as directed by the healthcare provider. It is for external use only. Avoid contact with the eyes. If BACTROBAN Ointment gets in or near the eyes, rinse thoroughly with water. The medication should be stopped and the healthcare provider contacted if irritation, severe itching, or rash occurs.
- If impetigo has not improved in 3 to 5 days, contact the healthcare provider.
# Precautions with Alcohol
- Alcohol-Mupirocin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Bactroban,
Centany,
Centany AT.
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Bactroban | |
41c6a2a77a89200f9b4ffe2e4da1acef9c7ccb11 | wikidoc | Halitosis | Halitosis
Synonyms and keywords: oral malodor; breath odor; foul breath; fetor oris; fetor ex ore; bad breath
# Overview
The word halitosis is derived from the Latin word ‘halitus’, meaning more than a socially acceptable degree of bad breath from the mouth. The majority of the time, it is due to poor dental, tongue hygiene, and gum infections. It can be physiological due to decreased saliva flow or an underlying disease. The patient can perceive the bad breath, or others might complain about it. It adversely affects the patient’s social and professional life.
# Classification
- Halitosis can be classified into physiologic, pathologic, or subjective:
Physiologic halitosis occurs due to decreased saliva production. It occurs in the morning when the mouth is dry, and there is an overgrowth of oral bacteria. Tobacco smoking and certain food items like garlic and onion also cause bad breath due to aromatic compounds. Physiological halitosis improves significantly by flossing, tooth brushing, rinsing with mouthwash, and drinking water.
Pathological halitosis occurs due to an underlying disease. The common causes include postnasal drip, sinusitis, gingivitis, and caries. The tonsillar inflammation and peri-tonsillar abscesses can also result in bad breath.
Subjective halitosis is also called psychogenic halitosis. The patient thinks that they have bad breath, while the diagnostic tests are negative for halitosis.
- Physiologic halitosis occurs due to decreased saliva production. It occurs in the morning when the mouth is dry, and there is an overgrowth of oral bacteria. Tobacco smoking and certain food items like garlic and onion also cause bad breath due to aromatic compounds. Physiological halitosis improves significantly by flossing, tooth brushing, rinsing with mouthwash, and drinking water.
- Pathological halitosis occurs due to an underlying disease. The common causes include postnasal drip, sinusitis, gingivitis, and caries. The tonsillar inflammation and peri-tonsillar abscesses can also result in bad breath.
- Subjective halitosis is also called psychogenic halitosis. The patient thinks that they have bad breath, while the diagnostic tests are negative for halitosis.
# Pathophysiology
- It is thought that halitosis is produced by bacterial overgrowth in the oral cavity.
- Poor oral hygiene, dental caries, or gum infection results in the growth of gram-negative anaerobes in the mouth.
- These bacteria thrive on debris material entrapped between teeth and gums. Lysosomal enzymes secreted by the bacteria break down the glycoproteins in the food particles. It results in volatile compounds like hydrogen sulfide, dimethyl sulfide, and methyl mercaptan, resulting in halitosis.
- The Bacteroides, Prevotella, and Fusobacterium species are mainly responsible for halitosis.
# Causes
Common causes of halitosis include:
- Gingivitis
- Plaques on the tongue
- Inflammation of the gum around the impacted wisdom tooth
- Ucerative gingival infection
- Herepes stomatitis
- Chronic sinusitis
- Allergies
- Post-nasal drip
- Foreign objects in the nasal cavity
- Tonsillitis and peri-tonsillar abcsess
- Chronic bronchitis
- Bronchial carcinoma
- Gastroesophageal reflux disease
- Food containing onion, garlic and spices
- Caffeine intake
- Smoking
- Psycogenic halitosis
# Differntiating Halitosis from other Diseases
Halitosis must be differentiated whether it has a physiological cause, some underlying disease, or psychogenic cause.
# Epidemiology and Demographics
- The prevalence of halitosis is approximately 32,000 per 100,000 individuals worldwide.
- Halitosis affects men and women equally.
- It is more common in middle and lower socioeconomic classes.
- The prevalence of halitosis is increasing with time.
# Risk Factors
Common risk factors in the development of halitosis include:
- Hepatic cirrhosis and hepatic failure
- Chronic kidney disease
- Diabetic ketoacidosis
- Xerostomia
- Gastritis due to Helicobacter pylori infection
# Screening
There is insufficient evidence to recommend routine screening for halitosis.
# Natual History, Complications, and Prognosis
Common complications of untreated halitosis include mood disorders like depression, anxiety, paranoia, phobia, and obsessive-compulsive disorder.
# Diagnosis
## Diagnostic Study of Choice
Organoleptic measurement is the gold standard test for the diagnosis of halitosis.
### Organoleptic Measurement
- It is one of the oldest techniques to detect a bad smell.
- The air expelled from both nose and mouth is smelled to detect a foul odor.
- The patient inspires from the nose with mouth close and then expires from the mouth, while the examiner detects it from a distance of 20 cm through a pipette.
- This diagnostic test is highly subjective, and the examiner grades the smell from a grade of 0 to 5, with zero being no smell and five being severe pungent smell.
## History and Symptoms
- The hallmark of halitosis is a bad odor from the mouth.
- A detailed history should be taken from the patient to rule out physiological and pseudo-halitosis. The frequency, onset, time, duration, exacerbating and relieving factors should be asked. A detailed medication history, Alchohol consumption and smoking should also be inquired .
## Physical Examination
- Physical examination of patients with halitosis is usually remarkable for dental caries, gingivitis, post-nasal drip and sinusitis.
- A detailed oral examination should be carried out to rule out any dental or gum disease.
- Upper Respiratory tract examination should be done to rule out nasal polyps, adenoids, post-nasal drip, and tonsillar hypertrophy. A detailed chest examination should be done to rule out chest infection.
## Laboratory Findings
- An elevated level of the volatile sulfur compound in exhaled air from the mouth is diagnostic of halitosis.
- Volatile Sulfur compound monitors can measure the levels of volatile sulfur compounds content in exhaled air from the mouth.
- Patients are asked to close their mouths and hold their breath for two to three minutes.
- Air is then collected from the mouth through a particular instrument, and the level of volatile sulfur compound is measured in parts per billion (ppb).
- Patients with halitosis have greater than 100 ppb levels of volatile sulfur compounds.
- BANA is a test by which chemicals that cause halitosis are detected by strip.
- The main substrate on the test strip is benzoyl-DL-arginine-a-naphthylamide. Obligate anaerobes in the mouth hydrolyze BANA and release volatile compounds that cause halitosis.
- In addition, it also detects bacteria responsible for dental and gingival diseases.
## Electrocardiogram
There are no ECG findings associated with halitosis.
## X ray
There are no x-ray findings associated with halitosis.
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with halitosis.
## CT scan
There are no CT scan findings associated with halitosis.
## MRI
There are no MRI findings associated with halitosis.
## Other Diagnostic Studies
Other diagnostic studies for halitosis include gas chromatography, which demonstrates elevated levels of volatile sulfur compounds, including hydrogen sulfide, and methyl mercaptan. The pros of gas chromatography are that it has higher sensitivity than organoleptic measurements and can even detect low levels of volatile sulfur compounds. The drawbacks are this test is expensive and requires a skilled person to perform it.
# Treatment
## Medical Therapy
Supportive therapy for halitosis includes:
- Adequate hydration to keep the oral cavity moist.
- Regular brushing and flossing with proper technique to avoid the buildup of food residue, dental plaques, and carries.
- Proper cleaning of the tongue to remove plaque and coating.
- Dietary modification with decreased intake of food products releases aromatic compounds, i.e., onion, garlic, alcohol, and caffeine.
- Quit smoking
- During the daytime, patients should chew sugar-free gums, as gums stimulate saliva production and keep the oral cavity moist.
- Rinse and gargle with mouthwash at least once a day, preferably at bedtime.
- Underlying dental and gum diseases should be appropriately treated as this will significantly reduce the oral bacterial flora.
- If an underlying medical disease is the cause of the halitosis, the patient needs to be referred to a particular specialty consultant.
- In patients with psychogenic halitosis, the physician should give the patients an appropriate assurance. The patients might need to be referred for psychiatric consultation for proper treatment.
## Surgery
Surgical intervention is not recommended for the management of halitosis.
## Primary Prevention
There are no established measures for the primary prevention of halitosis.
## Secondary Prevention
There are no established measures for the secondary prevention of halitosis. | Halitosis
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Mydah Sajid, M.B.B.S.
Synonyms and keywords: oral malodor; breath odor; foul breath; fetor oris; fetor ex ore; bad breath
# Overview
The word halitosis is derived from the Latin word ‘halitus’, meaning more than a socially acceptable degree of bad breath from the mouth. The majority of the time, it is due to poor dental, tongue hygiene, and gum infections. It can be physiological due to decreased saliva flow or an underlying disease. The patient can perceive the bad breath, or others might complain about it. It adversely affects the patient’s social and professional life.[1]
# Classification
- Halitosis can be classified into physiologic, pathologic, or subjective:
Physiologic halitosis occurs due to decreased saliva production. It occurs in the morning when the mouth is dry, and there is an overgrowth of oral bacteria. Tobacco smoking and certain food items like garlic and onion also cause bad breath due to aromatic compounds. Physiological halitosis improves significantly by flossing, tooth brushing, rinsing with mouthwash, and drinking water.[2]
Pathological halitosis occurs due to an underlying disease. The common causes include postnasal drip, sinusitis, gingivitis, and caries. The tonsillar inflammation and peri-tonsillar abscesses can also result in bad breath.[2]
Subjective halitosis is also called psychogenic halitosis. The patient thinks that they have bad breath, while the diagnostic tests are negative for halitosis.[3]
- Physiologic halitosis occurs due to decreased saliva production. It occurs in the morning when the mouth is dry, and there is an overgrowth of oral bacteria. Tobacco smoking and certain food items like garlic and onion also cause bad breath due to aromatic compounds. Physiological halitosis improves significantly by flossing, tooth brushing, rinsing with mouthwash, and drinking water.[2]
- Pathological halitosis occurs due to an underlying disease. The common causes include postnasal drip, sinusitis, gingivitis, and caries. The tonsillar inflammation and peri-tonsillar abscesses can also result in bad breath.[2]
- Subjective halitosis is also called psychogenic halitosis. The patient thinks that they have bad breath, while the diagnostic tests are negative for halitosis.[3]
# Pathophysiology
- It is thought that halitosis is produced by bacterial overgrowth in the oral cavity.
- Poor oral hygiene, dental caries, or gum infection results in the growth of gram-negative anaerobes in the mouth.[4]
- These bacteria thrive on debris material entrapped between teeth and gums. Lysosomal enzymes secreted by the bacteria break down the glycoproteins in the food particles. It results in volatile compounds like hydrogen sulfide, dimethyl sulfide, and methyl mercaptan, resulting in halitosis.[5]
- The Bacteroides, Prevotella, and Fusobacterium species are mainly responsible for halitosis.[6]
# Causes
Common causes of halitosis include:[1]
- Gingivitis
- Plaques on the tongue
- Inflammation of the gum around the impacted wisdom tooth
- Ucerative gingival infection
- Herepes stomatitis
- Chronic sinusitis
- Allergies
- Post-nasal drip
- Foreign objects in the nasal cavity
- Tonsillitis and peri-tonsillar abcsess
- Chronic bronchitis
- Bronchial carcinoma
- Gastroesophageal reflux disease
- Food containing onion, garlic and spices
- Caffeine intake
- Smoking
- Psycogenic halitosis
# Differntiating Halitosis from other Diseases
Halitosis must be differentiated whether it has a physiological cause, some underlying disease, or psychogenic cause.
# Epidemiology and Demographics
- The prevalence of halitosis is approximately 32,000 per 100,000 individuals worldwide.[7]
- Halitosis affects men and women equally.[8]
- It is more common in middle and lower socioeconomic classes.[7]
- The prevalence of halitosis is increasing with time.
# Risk Factors
Common risk factors in the development of halitosis include:[9]
- Hepatic cirrhosis and hepatic failure
- Chronic kidney disease
- Diabetic ketoacidosis
- Xerostomia
- Gastritis due to Helicobacter pylori infection
# Screening
There is insufficient evidence to recommend routine screening for halitosis.
# Natual History, Complications, and Prognosis
Common complications of untreated halitosis include mood disorders like depression, anxiety, paranoia, phobia, and obsessive-compulsive disorder.[10]
# Diagnosis
## Diagnostic Study of Choice
Organoleptic measurement is the gold standard test for the diagnosis of halitosis.[11]
### Organoleptic Measurement
- It is one of the oldest techniques to detect a bad smell.
- The air expelled from both nose and mouth is smelled to detect a foul odor.
- The patient inspires from the nose with mouth close and then expires from the mouth, while the examiner detects it from a distance of 20 cm through a pipette.[3]
- This diagnostic test is highly subjective, and the examiner grades the smell from a grade of 0 to 5, with zero being no smell and five being severe pungent smell.[12]
## History and Symptoms
- The hallmark of halitosis is a bad odor from the mouth.
- A detailed history should be taken from the patient to rule out physiological and pseudo-halitosis. The frequency, onset, time, duration, exacerbating and relieving factors should be asked. A detailed medication history, Alchohol consumption and smoking should also be inquired .[12]
## Physical Examination
- Physical examination of patients with halitosis is usually remarkable for dental caries, gingivitis, post-nasal drip and sinusitis.[13]
- A detailed oral examination should be carried out to rule out any dental or gum disease.
- Upper Respiratory tract examination should be done to rule out nasal polyps, adenoids, post-nasal drip, and tonsillar hypertrophy. A detailed chest examination should be done to rule out chest infection.
## Laboratory Findings
- An elevated level of the volatile sulfur compound in exhaled air from the mouth is diagnostic of halitosis.
- Volatile Sulfur compound monitors can measure the levels of volatile sulfur compounds content in exhaled air from the mouth.
- Patients are asked to close their mouths and hold their breath for two to three minutes.
- Air is then collected from the mouth through a particular instrument, and the level of volatile sulfur compound is measured in parts per billion (ppb).
- Patients with halitosis have greater than 100 ppb levels of volatile sulfur compounds.[14][15]
- BANA is a test by which chemicals that cause halitosis are detected by strip.
- The main substrate on the test strip is benzoyl-DL-arginine-a-naphthylamide. Obligate anaerobes in the mouth hydrolyze BANA and release volatile compounds that cause halitosis.
- In addition, it also detects bacteria responsible for dental and gingival diseases.[16][3]
## Electrocardiogram
There are no ECG findings associated with halitosis.
## X ray
There are no x-ray findings associated with halitosis.
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with halitosis.
## CT scan
There are no CT scan findings associated with halitosis.
## MRI
There are no MRI findings associated with halitosis.
## Other Diagnostic Studies
Other diagnostic studies for halitosis include gas chromatography, which demonstrates elevated levels of volatile sulfur compounds, including hydrogen sulfide, and methyl mercaptan. The pros of gas chromatography are that it has higher sensitivity than organoleptic measurements and can even detect low levels of volatile sulfur compounds. The drawbacks are this test is expensive and requires a skilled person to perform it.[17][18][19]
# Treatment
## Medical Therapy
Supportive therapy for halitosis includes:[20]
- Adequate hydration to keep the oral cavity moist.
- Regular brushing and flossing with proper technique to avoid the buildup of food residue, dental plaques, and carries.
- Proper cleaning of the tongue to remove plaque and coating.
- Dietary modification with decreased intake of food products releases aromatic compounds, i.e., onion, garlic, alcohol, and caffeine.
- Quit smoking
- During the daytime, patients should chew sugar-free gums, as gums stimulate saliva production and keep the oral cavity moist.
- Rinse and gargle with mouthwash at least once a day, preferably at bedtime.
- Underlying dental and gum diseases should be appropriately treated as this will significantly reduce the oral bacterial flora.[21]
- If an underlying medical disease is the cause of the halitosis, the patient needs to be referred to a particular specialty consultant.[3]
- In patients with psychogenic halitosis, the physician should give the patients an appropriate assurance. The patients might need to be referred for psychiatric consultation for proper treatment.[3]
## Surgery
Surgical intervention is not recommended for the management of halitosis.
## Primary Prevention
There are no established measures for the primary prevention of halitosis.
## Secondary Prevention
There are no established measures for the secondary prevention of halitosis. | https://www.wikidoc.org/index.php/Bad_breath | |
c989b2090f9983f89443e69f17d3a50e7b0e9ae9 | wikidoc | Baker Act | Baker Act
# Overview
Enacted in 1971, the Baker Act is a statute of the state of Florida aimed at protecting the rights of persons with mental illness along with maintaining public safety. The act was named for then-Representative, Maxine Baker, who was known for having an interest in mental health issues, and serving as chair for the Florida House of Representatives on mental health. Its intent was to promote the use of community-based mental health care instead of institutionalizing persons with mental illness.
The Baker Act allows for involuntary examination (what some call emergency commitment). It can be initiated by judges, law enforcement officials, or mental health professionals. There must be evidence that the person a) has a mental illness (as defined in the Baker Act) and b) is a harm to self, harm to others, or self neglectful (as defined in the Baker Act). Examinations may last up to 72 hours and occur in 100+ Florida Department of Children and Families designated receiving facilities statewide.
Many things may occur after the examination. This includes the release of the individual to the community (or other community placement), a petition for involuntary inpatient placement (what some call civil commitment), involuntary outpatient placement (what some call outpatient commitment or assisted treatment orders), or voluntary treatment (if the person is competent to consent to voluntary treatment and consents to voluntary treatment). The involuntary outpatient placement language in the Baker Act took effect in 2005. | Baker Act
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Enacted in 1971, the Baker Act is a statute of the state of Florida aimed at protecting the rights of persons with mental illness along with maintaining public safety. The act was named for then-Representative, Maxine Baker, who was known for having an interest in mental health issues, and serving as chair for the Florida House of Representatives on mental health. Its intent was to promote the use of community-based mental health care instead of institutionalizing persons with mental illness.
The Baker Act allows for involuntary examination (what some call emergency commitment). It can be initiated by judges, law enforcement officials, or mental health professionals. There must be evidence that the person a) has a mental illness (as defined in the Baker Act) and b) is a harm to self, harm to others, or self neglectful (as defined in the Baker Act). Examinations may last up to 72 hours and occur in 100+ Florida Department of Children and Families designated receiving facilities statewide.
Many things may occur after the examination. This includes the release of the individual to the community (or other community placement), a petition for involuntary inpatient placement (what some call civil commitment), involuntary outpatient placement (what some call outpatient commitment or assisted treatment orders), or voluntary treatment (if the person is competent to consent to voluntary treatment and consents to voluntary treatment). The involuntary outpatient placement language in the Baker Act took effect in 2005. | https://www.wikidoc.org/index.php/Baker_Act | |
33ba83a8053fb27baf22a77d66f1feb86b2f42ab | wikidoc | Bandicoot | Bandicoot
A bandicoot is any of about 20 species of small to medium-sized, terrestrial marsupial omnivores in the order Peramelemorphia. The word bandicoot is an anglicised form of the Telugu word pandi-kokku, (loosely, pig-rat) which originally referred to the unrelated Indian Bandicoot Rat. The other two species of peramelemorphs are the bilbies.
Classification within the Peramelemorphia used to be simple: there were thought to be two families in the order — the short-legged and mostly herbivorous bandicoots, and the longer-legged, more nearly carnivorous bilbies. In recent years, however, it has become clear that the situation is more complex. First, the bandicoots of the New Guinean and far-northern Australian rainforests were deemed distinct from all other bandicoots, and these were grouped together in the separate family Peroryctidae. More recently, the bandicoot families were reunited in Peramelidae, with the New Guinean species split into four genera in two subfamilies, Peroryctinae and Echymiperinae, while the "true bandicoots" occupy the subfamily Peramelinae. The only exception is the extinct Pig-footed Bandicoot, which has been given its own family, Chaeropodidae.
The embryos of bandicoots, unlike other marsupials, form a placenta-like organ that connects it to the uterine wall. The function of this organ is probably to transfer nutrients from the mother; however the structure is small compared to those of the placentalia.
- ORDER PERAMELEMORPHIA
Family Thylacomyidae: bilbies, 2 species
Family †Chaeropodidae: Pig-footed Bandicoot
Family Peramelidae
Subfamily Peramelinae
Genus Isoodon: short-nosed bandicoots
Genus Perameles: long-nosed bandicoots
Subfamily Peroryctinae
Genus Peroryctes: New Guinean long-nosed bandicoots
Subfamily Echymiperinae
Genus Echymipera: New Guinean spiny bandicoots
Genus Microperoryctes: New Guinean mouse bandicoots
Genus Rhynchomeles: Ceram Bandicoot
Superfamily †Yaraloidea
Family †Yaralidae: fossil bandicoots, 2 species
- Family Thylacomyidae: bilbies, 2 species
- Family †Chaeropodidae: Pig-footed Bandicoot
- Family Peramelidae
Subfamily Peramelinae
Genus Isoodon: short-nosed bandicoots
Genus Perameles: long-nosed bandicoots
Subfamily Peroryctinae
Genus Peroryctes: New Guinean long-nosed bandicoots
Subfamily Echymiperinae
Genus Echymipera: New Guinean spiny bandicoots
Genus Microperoryctes: New Guinean mouse bandicoots
Genus Rhynchomeles: Ceram Bandicoot
- Subfamily Peramelinae
Genus Isoodon: short-nosed bandicoots
Genus Perameles: long-nosed bandicoots
- Genus Isoodon: short-nosed bandicoots
- Genus Perameles: long-nosed bandicoots
- Subfamily Peroryctinae
Genus Peroryctes: New Guinean long-nosed bandicoots
- Genus Peroryctes: New Guinean long-nosed bandicoots
- Subfamily Echymiperinae
Genus Echymipera: New Guinean spiny bandicoots
Genus Microperoryctes: New Guinean mouse bandicoots
Genus Rhynchomeles: Ceram Bandicoot
- Genus Echymipera: New Guinean spiny bandicoots
- Genus Microperoryctes: New Guinean mouse bandicoots
- Genus Rhynchomeles: Ceram Bandicoot
- Superfamily †Yaraloidea
Family †Yaralidae: fossil bandicoots, 2 species
- Family †Yaralidae: fossil bandicoots, 2 species | Bandicoot
A bandicoot is any of about 20 species of small to medium-sized, terrestrial marsupial omnivores in the order Peramelemorphia. The word bandicoot is an anglicised form of the Telugu word pandi-kokku, (loosely, pig-rat) which originally referred to the unrelated Indian Bandicoot Rat. The other two species of peramelemorphs are the bilbies.
Classification within the Peramelemorphia used to be simple: there were thought to be two families in the order — the short-legged and mostly herbivorous bandicoots, and the longer-legged, more nearly carnivorous bilbies. In recent years, however, it has become clear that the situation is more complex. First, the bandicoots of the New Guinean and far-northern Australian rainforests were deemed distinct from all other bandicoots, and these were grouped together in the separate family Peroryctidae. More recently, the bandicoot families were reunited in Peramelidae, with the New Guinean species split into four genera in two subfamilies, Peroryctinae and Echymiperinae, while the "true bandicoots" occupy the subfamily Peramelinae. The only exception is the extinct Pig-footed Bandicoot, which has been given its own family, Chaeropodidae.
The embryos of bandicoots, unlike other marsupials, form a placenta-like organ that connects it to the uterine wall. The function of this organ is probably to transfer nutrients from the mother; however the structure is small compared to those of the placentalia.
- ORDER PERAMELEMORPHIA
Family Thylacomyidae: bilbies, 2 species
Family †Chaeropodidae: Pig-footed Bandicoot
Family Peramelidae
Subfamily Peramelinae
Genus Isoodon: short-nosed bandicoots
Genus Perameles: long-nosed bandicoots
Subfamily Peroryctinae
Genus Peroryctes: New Guinean long-nosed bandicoots
Subfamily Echymiperinae
Genus Echymipera: New Guinean spiny bandicoots
Genus Microperoryctes: New Guinean mouse bandicoots
Genus Rhynchomeles: Ceram Bandicoot
Superfamily †Yaraloidea
Family †Yaralidae: fossil bandicoots, 2 species
- Family Thylacomyidae: bilbies, 2 species
- Family †Chaeropodidae: Pig-footed Bandicoot
- Family Peramelidae
Subfamily Peramelinae
Genus Isoodon: short-nosed bandicoots
Genus Perameles: long-nosed bandicoots
Subfamily Peroryctinae
Genus Peroryctes: New Guinean long-nosed bandicoots
Subfamily Echymiperinae
Genus Echymipera: New Guinean spiny bandicoots
Genus Microperoryctes: New Guinean mouse bandicoots
Genus Rhynchomeles: Ceram Bandicoot
- Subfamily Peramelinae
Genus Isoodon: short-nosed bandicoots
Genus Perameles: long-nosed bandicoots
- Genus Isoodon: short-nosed bandicoots
- Genus Perameles: long-nosed bandicoots
- Subfamily Peroryctinae
Genus Peroryctes: New Guinean long-nosed bandicoots
- Genus Peroryctes: New Guinean long-nosed bandicoots
- Subfamily Echymiperinae
Genus Echymipera: New Guinean spiny bandicoots
Genus Microperoryctes: New Guinean mouse bandicoots
Genus Rhynchomeles: Ceram Bandicoot
- Genus Echymipera: New Guinean spiny bandicoots
- Genus Microperoryctes: New Guinean mouse bandicoots
- Genus Rhynchomeles: Ceram Bandicoot
- Superfamily †Yaraloidea
Family †Yaralidae: fossil bandicoots, 2 species
- Family †Yaralidae: fossil bandicoots, 2 species | https://www.wikidoc.org/index.php/Bandicoot | |
7e8957cac6fa1fe95644c67361f6cdfa9c0fcb4d | wikidoc | Bangungot | Bangungot
Sudden Unexpected Death Syndrome (called bangungot in the Philippines, lai tai in Thailand, and hukuri in Japan) is sudden unexpected death of adolescents and adults during sleep. Bangungot is rarely observed in the Western world, and appears to occur more commonly among young men in East and Southeast Asian countries. The term originated from the Tagalog word meaning "bad dream." The root of this term is the fact that survivors of bangungot often describe dreaming about falling into a bottomless pit. While experiencing this, the person is aware that he is dreaming but feels like there is something that stops him from moving and awaking.
SUDS has been cloaked in superstition. In Thailand it is particularly believed to be linked to eating rice cakes. Filipinos believe ingesting high levels of carbohydrates just before sleeping causes bangungot.
It has only been recently that the scientific world has begun to understand this syndrome. Victims of bangungot have not been found to have any organic heart diseases or structural heart problems.
However, cardiac activity during SUDS episodes indicates irregular heart rhythms and ventricular fibrillation. The victim survives this episode if the heart's rhythm goes back to normal. Older folks in the Philippines recommend trying wiggling the big toe while experiencing this to snap back.
Ongoing genetic studies by Spanish electrophysiologist Dr. Josep Brugada Terradellas show that SUDS results from mutations in the cardiac sodium channel gene. This means that it is a chromosomal problem, which is why it runs in families. Thus, doctors say that families who have kin that have suffered from or died of SUDS must see a heart specialist.
In the Philippines, most cases of bangungot have been linked with Acute Hemorrhagic Pancreatitis, whereas in Thailand and Laos, bangungot (or in their term, Sudden Adult Death Syndrome) is caused by the Brugada syndrome.
Bangungot is also depicted in the Philippines as a mythological creature called batibat. This hag-like creature sits on the victim's face so as to immobilize and suffocate him. | Bangungot
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Sudden Unexpected Death Syndrome (called bangungot in the Philippines, lai tai in Thailand, and hukuri in Japan) is sudden unexpected death of adolescents and adults during sleep. Bangungot is rarely observed in the Western world, and appears to occur more commonly among young men in East and Southeast Asian countries. The term originated from the Tagalog word meaning "bad dream." The root of this term is the fact that survivors of bangungot often describe dreaming about falling into a bottomless pit. While experiencing this, the person is aware that he is dreaming but feels like there is something that stops him from moving and awaking.
SUDS has been cloaked in superstition. In Thailand it is particularly believed to be linked to eating rice cakes. Filipinos believe ingesting high levels of carbohydrates just before sleeping causes bangungot.
It has only been recently that the scientific world has begun to understand this syndrome. Victims of bangungot have not been found to have any organic heart diseases or structural heart problems.
However, cardiac activity during SUDS episodes indicates irregular heart rhythms and ventricular fibrillation. The victim survives this episode if the heart's rhythm goes back to normal. Older folks in the Philippines recommend trying wiggling the big toe while experiencing this to snap back.
Ongoing genetic studies by Spanish electrophysiologist Dr. Josep Brugada Terradellas show that SUDS results from mutations in the cardiac sodium channel gene. This means that it is a chromosomal problem, which is why it runs in families. Thus, doctors say that families who have kin that have suffered from or died of SUDS must see a heart specialist.
In the Philippines, most cases of bangungot have been linked with Acute Hemorrhagic Pancreatitis, whereas in Thailand and Laos, bangungot (or in their term, Sudden Adult Death Syndrome) is caused by the Brugada syndrome.[1]
Bangungot is also depicted in the Philippines as a mythological creature called batibat. This hag-like creature sits on the victim's face so as to immobilize and suffocate him. | https://www.wikidoc.org/index.php/Bangungot | |
8fc57e3aa3546ee02bd76e814a54f90537d36475 | wikidoc | Bar chart | Bar chart
# Overview
A bar chart, also known as a bar graph, is a chart with rectangular bars of lengths usually proportional to the magnitudes or frequencies of what they represent. Bar charts are used for comparing two or more values. The bars can be horizontally or vertically oriented. Sometimes a stretched graphic is used instead of a solid bar.
# Example
The example chart is based on the results of the election for the European Parliament in 2004 and in 1999. The following table lists the number of seats allocated to each party group. The results of 1999 have been multiplied by 1.16933, to compensate for the change in number of seats between those years.
A bar chart visualizing the above results of the 2004 election can look like this:
(If all the values were arranged in descending order this type of bar graph would be called a pareto chart.)
ImageSize = width:400 height:240
PlotArea = width:300 height:150 left:50 bottom:40
AlignBars = late
DateFormat = yyyy
Period = from:0 till:300
TimeAxis = orientation:vertical
ScaleMajor = unit:year increment:50 start:0
BarData=
Colors =
TextData =
PlotData=
This bar chart shows both the results of 2004, and those of 1999:
ImageSize = width:480 height:240
PlotArea = width:360 height:150 left:50 bottom:40
AlignBars = late
DateFormat = yyyy
Period = from:0 till:300
TimeAxis = orientation:vertical
ScaleMajor = unit:year increment:50 start:0
BarData=
Colors =
TextData =
PlotData=
# History
The bar chart is possibly the invention of the Scots engineer and economist William Playfair (1759-1823). A bar chart was used in his work The Commercial and Political Atlas (London, 1786). | Bar chart
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A bar chart, also known as a bar graph, is a chart with rectangular bars of lengths usually proportional to the magnitudes or frequencies of what they represent. Bar charts are used for comparing two or more values. The bars can be horizontally or vertically oriented. Sometimes a stretched graphic is used instead of a solid bar.
# Example
The example chart is based on the results of the election for the European Parliament in 2004 and in 1999. The following table lists the number of seats allocated to each party group. The results of 1999 have been multiplied by 1.16933, to compensate for the change in number of seats between those years.
A bar chart visualizing the above results of the 2004 election can look like this:
(If all the values were arranged in descending order this type of bar graph would be called a pareto chart.)
<timeline>
ImageSize = width:400 height:240
PlotArea = width:300 height:150 left:50 bottom:40
AlignBars = late
DateFormat = yyyy
Period = from:0 till:300
TimeAxis = orientation:vertical
ScaleMajor = unit:year increment:50 start:0
BarData=
Colors =
TextData =
PlotData=
</timeline>
This bar chart shows both the results of 2004, and those of 1999:
<timeline>
ImageSize = width:480 height:240
PlotArea = width:360 height:150 left:50 bottom:40
AlignBars = late
DateFormat = yyyy
Period = from:0 till:300
TimeAxis = orientation:vertical
ScaleMajor = unit:year increment:50 start:0
BarData=
Colors =
TextData =
PlotData=
</timeline>
# History
The bar chart is possibly the invention of the Scots engineer and economist William Playfair (1759-1823). A bar chart was used in his work The Commercial and Political Atlas (London, 1786). | https://www.wikidoc.org/index.php/Bar_chart | |
938a3ba9be0c90b46c573285043c7b505197156b | wikidoc | Entecavir | Entecavir
# 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
Entecavir is a reverse transcriptase inhibitor that is FDA approved for the {{{indicationType}}} of chronic hepatitis B virus infection in adults and children at least 2 years of age. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, fatigue, dizziness, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Compensated Liver Disease
The recommended dose of BARACLUDE for chronic hepatitis B virus infection in nucleoside-inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily.
The recommended dose of BARACLUDE in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.
- The recommended dose of BARACLUDE for chronic hepatitis B virus infection in nucleoside-inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily.
- The recommended dose of BARACLUDE in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.
- Decompensated Liver Disease
The recommended dose of BARACLUDE for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.
- The recommended dose of BARACLUDE for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.
- Renal Impairment
In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 2. The once-daily dosing regimens are preferred.
- In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 2. The once-daily dosing regimens are preferred.
- Duration of Therapy
The optimal duration of treatment with BARACLUDE for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.
- The optimal duration of treatment with BARACLUDE for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Entecavir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Entecavir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Table 1 describes the recommended dose of BARACLUDE for pediatric patients 2 years of age or older and weighing at least 10 kg. The oral solution should be used for patients with body weight up to 30 kg.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Entecavir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Entecavir in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Severe Acute Exacerbations of Hepatitis B
- Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
- Patients Co-infected with HIV and HBV
- BARACLUDE has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if BARACLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therefore, therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.
- Lactic Acidosis and Severe Hepatomegaly with Steatosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors, including BARACLUDE, alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside inhibitor exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogue inhibitors to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
- Lactic acidosis with BARACLUDE use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. Treatment with BARACLUDE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
# 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.
- Compensated Liver Disease
- Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection and compensated liver disease received double-blind treatment with BARACLUDE 0.5 mg/day (n=679), BARACLUDE 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for BARACLUDE-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for BARACLUDE-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of BARACLUDE and lamivudine were comparable in these studies.
- The most common adverse reactions of any severity (≥3%) with at least a possible relation to study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and dizziness. One percent of BARACLUDE-treated subjects in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results.
- Clinical adverse reactions of moderate-severe intensity and considered at least possibly related to treatment occurring during therapy in four clinical studies in which BARACLUDE was compared with lamivudine are presented in Table 3.
- Laboratory Abnormalities
- Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of BARACLUDE compared with lamivudine are listed in Table 4.
- Among BARACLUDE-treated subjects in these studies, on-treatment ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with continued treatment. A majority of these exacerbations were associated with a ≥2 log10/mL reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.
- Exacerbations of Hepatitis after Discontinuation of Treatment
- An exacerbation of hepatitis or ALT flare was defined as ALT greater than 10 times ULN and greater than 2 times the subject’s reference level (minimum of the baseline or last measurement at end of dosing). For all subjects who discontinued treatment (regardless of reason), Table 5 presents the proportion of subjects in each study who experienced post-treatment ALT flares. In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If BARACLUDE is discontinued without regard to treatment response, the rate of post-treatment flares could be higher.
- Decompensated Liver Disease
- Study AI463048 was a randomized, open-label study of BARACLUDE 1 mg once daily versus adefovir dipivoxil 10 mg once daily given for up to 48 weeks in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher. Among the 102 subjects receiving BARACLUDE, the most common treatment-emergent adverse events of any severity, regardless of causality, occurring through Week 48 were peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). Clinical adverse reactions not listed in Table 3 that were observed through Week 48 include blood bicarbonate decreased (2%) and renal failure (<1%).
- Eighteen of 102 (18%) subjects treated with BARACLUDE and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the BARACLUDE group and 16 in the adefovir dipivoxil group) were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. The rate of hepatocellular carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with BARACLUDE and 8% (7/89) for subjects treated with adefovir dipivoxil. Five percent of subjects in either treatment arm discontinued therapy due to an adverse event through Week 48.
- No subject in either treatment arm experienced an on-treatment hepatic flare (ALT >2 × baseline and >10 × ULN) through Week 48. Eleven of 102 (11%) subjects treated with BARACLUDE and 11/89 (13%) subjects treated with adefovir dipivoxil had a confirmed increase in serum creatinine of 0.5 mg/dL through Week 48.
- HIV/HBV Co-infected
- The safety profile of BARACLUDE 1 mg (n=51) in HIV/HBV co-infected subjects enrolled in Study AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and similar to that seen in non-HIV infected subjects.
- Liver Transplant Recipients
- Among 65 subjects receiving BARACLUDE in an open-label, post-liver transplant trial, the frequency and nature of adverse events were consistent with those expected in patients who have received a liver transplant and the known safety profile of BARACLUDE.
- Clinical Trial Experience in Pediatric Subjects
- 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 safety of BARACLUDE in pediatric subjects 2 to less than 18 years of age is based on two ongoing clinical trials in subjects with chronic HBV infection (one Phase 2 pharmacokinetic trial and one Phase 3 trial ). These trials provide experience in 168 HBeAg-positive subjects treated with BARACLUDE for a median duration of 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with BARACLUDE were consistent with those observed in clinical trials of BARACLUDE in adults. Adverse drug reactions reported in greater than 1% of pediatric subjects included abdominal pain, rash events, poor palatability (“product taste abnormal”), nausea, diarrhea, and vomiting.
## Postmarketing Experience
- The following adverse reactions have been reported during postmarketing use of BARACLUDE. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to BARACLUDE exposure.
- Immune system disorders: Anaphylactoid reaction.
- Metabolism and nutrition disorders: Lactic acidosis.
- Hepatobiliary disorders: Increased transaminases.
- Skin and subcutaneous tissue disorders: Alopecia, rash.
# Drug Interactions
- Since entecavir is primarily eliminated by the kidneys, coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. Coadministration of entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions. The effects of coadministration of BARACLUDE with other drugs that are renally eliminated or are known to affect renal function have not been evaluated, and patients should be monitored closely for adverse events when BARACLUDE is coadministered with such drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of BARACLUDE in pregnant women. Because animal reproduction studies are not always predictive of human response, BARACLUDE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to BARACLUDE, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
- Animal Data
- Animal reproduction studies with entecavir in rats and rabbits revealed no evidence of teratogenicity. Developmental toxicity studies were performed in rats and rabbits. There were no signs of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately 28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose of 1 mg/day. In rats, maternal toxicity, embryofetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryofetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring occurred when rats received oral entecavir at exposures greater than 94 times those in humans.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Entecavir in women who are pregnant.
### Labor and Delivery
- There are no studies in pregnant women and no data on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
### Nursing Mothers
- It is not known whether BARACLUDE is excreted into human milk; however, entecavir is excreted into the milk of rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from BARACLUDE, a decision should be made to discontinue nursing or to discontinue BARACLUDE taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.
### Pediatric Use
- BARACLUDE was evaluated in two clinical trials of pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease. The exposure of BARACLUDE in nucleoside-inhibitor-treatment-naïve and lamivudine-experienced pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease receiving 0.015 mg/kg (up to 0.5 mg once daily) or 0.03 mg/kg (up to 1 mg once daily), respectively, was evaluated in Study AI463028. Safety and efficacy of the selected dose in treatment-naïve pediatric subjects were confirmed in Study AI463189, a randomized, placebo-controlled treatment trial.
- There are limited data available on the use of BARACLUDE in lamivudine-experienced pediatric patients; BARACLUDE should be used in these patients only if the potential benefit justifies the potential risk to the child. Since some pediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of BARACLUDE on future treatment options.
- The efficacy and safety of BARACLUDE have not been established in patients less than 2 years of age. Use of BARACLUDE in this age group has not been evaluated because treatment of HBV in this age group is rarely required.
### Geriatic Use
- Clinical studies of BARACLUDE did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Entecavir is 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 Entecavir with respect to specific gender populations.
### Race
- There are no significant racial differences in entecavir pharmacokinetics. The safety and efficacy of BARACLUDE 0.5 mg once daily were assessed in a single-arm, open-label trial of HBeAg-positive or -negative, nucleoside-inhibitor-naïve, Black/African American (n=40) and Hispanic (n=6) subjects with chronic HBV infection. In this trial, 76% of subjects were male, the mean age was 42 years, 57% were HBeAg-positive, the mean baseline HBV DNA was 7.0 log10 IU/mL, and the mean baseline ALT was 162 U/L. At Week 48 of treatment, 32 of 46 (70%) subjects had HBV DNA <50 IU/mL (approximately 300 copies/mL), 31 of 46 (67%) subjects had ALT normalization (≤1 × ULN), and 12 of 26 (46%) HBeAg-positive subjects had HBe seroconversion. Safety data were similar to those observed in the larger controlled clinical trials.
### Renal Impairment
- Dosage adjustment of BARACLUDE is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or CAPD.
### Hepatic Impairment
There is no FDA guidance on the use of Entecavir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Entecavir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Entecavir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Entecavir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Entecavir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is limited experience of entecavir overdosage reported in patients. Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events.
### Management
- If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
- Following a single 1 mg dose of entecavir, a 4-hour hemodialysis session removed approximately 13% of the entecavir dose.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Entecavir in the drug label.
# Pharmacology
## Mechanism of Action
- Entecavir, a guanosine nucleoside analogue with activity against HBV reverse transcriptase (rt), is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV reverse transcriptase: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ with Ki values ranging from 18 to >160 μM.
## Structure
- BARACLUDE® is the tradename for entecavir, a guanosine nucleoside analogue with selective activity against HBV. The chemical name for entecavir is 2-amino-1,9-dihydro-9--6H-purin-6-one, monohydrate. Its molecular formula is C12H15N5O3∙H2O, which corresponds to a molecular weight of 295.3. Entecavir has the following structural formula:
- Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25° C ± 0.5° C.
- BARACLUDE film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir. BARACLUDE 0.5 mg and 1 mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5 mg tablet only), and iron oxide red (1 mg tablet only). BARACLUDE Oral Solution is available for oral administration as a ready-to-use solution containing 0.05 mg of entecavir per milliliter. BARACLUDE Oral Solution contains the following inactive ingredients: maltitol, sodium citrate, citric acid, methylparaben, propylparaben, and orange flavor.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Entecavir in the drug label.
## Pharmacokinetics
- The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects and subjects with chronic hepatitis B virus infection.
- Absorption
- Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1 mg, Cmax and area under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after 6 to 10 days of once-daily administration with approximately 2-fold accumulation. For a 0.5 mg oral dose, Cmax at steady state was 4.2 ng/mL and trough plasma concentration (Ctrough) was 0.3 ng/mL. For a 1 mg oral dose, Cmax was 8.2 ng/mL and Ctrough was 0.5 ng/mL.
- In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solution. The oral solution and tablet may be used interchangeably.
- Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1.0–1.5 hours fed vs. 0.75 hours fasted), a decrease in Cmax of 44%–46%, and a decrease in AUC of 18%–20%.
- Distribution
- Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues.
- Binding of entecavir to human serum proteins in vitro was approximately 13%.
- Metabolism and Elimination
- Following administration of 14C-entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system.
- After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128–149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours.
- Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion.
- Special Populations
- Gender: There are no significant gender differences in entecavir pharmacokinetics.
- Race: There are no significant racial differences in entecavir pharmacokinetics.
- Elderly: The effect of age on the pharmacokinetics of entecavir was evaluated following administration of a single 1 mg oral dose in healthy young and elderly volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects. The disparity in exposure between elderly and young subjects was most likely attributable to differences in renal function. Dosage adjustment of BARACLUDE should be based on the renal function of the patient, rather than age.
- Pediatrics: The steady-state pharmacokinetics of entecavir were evaluated in nucleoside-inhibitor-naïve and lamivudine-experienced HBeAg-positive pediatric subjects 2 to less than 18 years of age with compensated liver disease. Results are shown in Table 6. Entecavir exposure among nucleoside-inhibitor-naïve subjects was similar to the exposure achieved in adults receiving once-daily doses of 0.5 mg. Entecavir exposure among lamivudine-experienced subjects was similar to the exposure achieved in adults receiving once-daily doses of 1 mg.
- Renal impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in subjects (without chronic hepatitis B virus infection) with selected degrees of renal impairment, including subjects whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Results are shown in Table 7.
- Following a single 1 mg dose of entecavir administered 2 hours before the hemodialysis session, hemodialysis removed approximately 13% of the entecavir dose over 4 hours. CAPD removed approximately 0.3% of the dose over 7 days.
- Hepatic impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in adult subjects (without chronic hepatitis B virus infection) with moderate or severe hepatic impairment (Child-Turcotte-Pugh Class B or C). The pharmacokinetics of entecavir were similar between hepatically impaired and healthy control subjects; therefore, no dosage adjustment of BARACLUDE is recommended for patients with hepatic impairment. The pharmacokinetics of entecavir have not been studied in pediatric subjects with hepatic impairment.
- Post-liver transplant: Limited data are available on the safety and efficacy of BARACLUDE in liver transplant recipients. In a small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of cyclosporine A (n=5) or tacrolimus (n=4), entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these subjects. The potential for pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus was not formally evaluated.
- Drug Interactions
- The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations up to approximately 340-fold higher than those observed in humans, entecavir did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. The pharmacokinetics of entecavir are unlikely to be affected by coadministration with agents that are either metabolized by, inhibit, or induce the CYP450 system. Likewise, the pharmacokinetics of known CYP substrates are unlikely to be affected by coadministration of entecavir.
- The steady-state pharmacokinetics of entecavir and coadministered drug were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate.
## Nonclinical Toxicology
- Carcinogenesis
- Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures up to approximately 42 times (mice) and 35 times (rats) those observed in humans at the highest recommended dose of 1 mg/day. In mouse and rat studies, entecavir was positive for carcinogenic findings.
- In mice, lung adenomas were increased in males and females at exposures 3 and 40 times those in humans. Lung carcinomas in both male and female mice were increased at exposures 40 times those in humans. Combined lung adenomas and carcinomas were increased in male mice at exposures 3 times and in female mice at exposures 40 times those in humans. Tumor development was preceded by pneumocyte proliferation in the lung, which was not observed in rats, dogs, or monkeys administered entecavir, supporting the conclusion that lung tumors in mice may be a species-specific event. Hepatocellular carcinomas were increased in males and combined liver adenomas and carcinomas were also increased at exposures 42 times those in humans. Vascular tumors in female mice (hemangiomas of ovaries and uterus and hemangiosarcomas of spleen) were increased at exposures 40 times those in humans. In rats, hepatocellular adenomas were increased in females at exposures 24 times those in humans; combined adenomas and carcinomas were also increased in females at exposures 24 times those in humans. Brain gliomas were induced in both males and females at exposures 35 and 24 times those in humans. Skin fibromas were induced in females at exposures 4 times those in humans.
- It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
- Mutagenesis
- Entecavir was clastogenic to human lymphocyte cultures. Entecavir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Entecavir was also negative in an oral micronucleus study and an oral DNA repair study in rats.
- Impairment of Fertility
- In reproductive toxicology studies, in which animals were administered entecavir at up to 30 mg/kg for up to 4 weeks, no evidence of impaired fertility was seen in male or female rats at systemic exposures greater than 90 times those achieved in humans at the highest recommended dose of 1 mg/day. In rodent and dog toxicology studies, seminiferous tubular degeneration was observed at exposures 35 times or greater than those achieved in humans. No testicular changes were evident in monkeys.
# Clinical Studies
- At 48 Weeks
- The safety and efficacy of BARACLUDE in adults were evaluated in three Phase 3 active-controlled trials. These studies included 1633 subjects 16 years of age or older with chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Subjects had persistently elevated ALT levels at least 1.3 times ULN and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The safety and efficacy of BARACLUDE were also evaluated in a study of 191 HBV-infected subjects with decompensated liver disease and in a study of 68 subjects co-infected with HBV and HIV.
- Nucleoside-inhibitor-naïve Subjects with Compensated Liver Disease
- HBeAg-positive: Study AI463022 was a multinational, randomized, double-blind study of BARACLUDE 0.5 mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 709 (of 715 randomized) nucleoside-inhibitor-naïve subjects with chronic hepatitis B virus infection, compensated liver disease, and detectable HBeAg. The mean age of subjects was 35 years, 75% were male, 57% were Asian, 40% were Caucasian, and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 9.66 log10 copies/mL, and mean serum ALT level was 143 U/L. Paired, adequate liver biopsy samples were available for 89% of subjects.
- HBeAg-negative (anti-HBe-positive/HBV DNA-positive): Study AI463027 was a multinational, randomized, double-blind study of BARACLUDE 0.5 mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 638 (of 648 randomized) nucleoside-inhibitor-naïve subjects with HBeAg-negative (HBeAb-positive) chronic hepatitis B virus infection and compensated liver disease. The mean age of subjects was 44 years, 76% were male, 39% were Asian, 58% were Caucasian, and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 7.58 log10 copies/mL, and mean serum ALT level was 142 U/L. Paired, adequate liver biopsy samples were available for 88% of subjects.
- In Studies AI463022 and AI463027, BARACLUDE was superior to lamivudine on the primary efficacy endpoint of Histologic Improvement, defined as a 2-point or greater reduction in Knodell Necroinflammatory Score with no worsening in Knodell Fibrosis Score at Week 48, and on the secondary efficacy measures of reduction in viral load and ALT normalization. Histologic Improvement and change in Ishak Fibrosis Score are shown in Table 8. Selected virologic, biochemical, and serologic outcome measures are shown in Table 9.
- Histologic Improvement was independent of baseline levels of HBV DNA or ALT.
- Lamivudine-refractory Subjects with Compensated Liver Disease
- Study AI463026 was a multinational, randomized, double-blind study of BARACLUDE in 286 (of 293 randomized) subjects with lamivudine-refractory chronic hepatitis B virus infection and compensated liver disease. Subjects receiving lamivudine at study entry either switched to BARACLUDE 1 mg once daily (with neither a washout nor an overlap period) or continued on lamivudine 100 mg for a minimum of 52 weeks. The mean age of subjects was 39 years, 76% were male, 37% were Asian, 62% were Caucasian, and 52% had previously received interferon-α. The mean duration of prior lamivudine therapy was 2.7 years, and 85% had lamivudine resistance substitutions at baseline by an investigational line probe assay. At baseline, subjects had a mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.36 log10 copies/mL, and mean serum ALT level was 128 U/L. Paired, adequate liver biopsy samples were available for 87% of subjects.
- BARACLUDE was superior to lamivudine on a primary endpoint of Histologic Improvement (using the Knodell Score at Week 48). These results and change in Ishak Fibrosis Score are shown in Table 10. Table 11 shows selected virologic, biochemical, and serologic endpoints.
- Histologic Improvement was independent of baseline levels of HBV DNA or ALT.
- Subjects with Decompensated Liver Disease
- Study AI463048 was a randomized, open-label study of BARACLUDE 1 mg once daily versus adefovir dipivoxil 10 mg once daily in 191 (of 195 randomized) adult subjects with HBeAg-positive or -negative chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher. Subjects were either HBV-treatment-naïve or previously treated, predominantly with lamivudine or interferon-α.
- In Study AI463048, 100 subjects were randomized to treatment with BARACLUDE and 91 subjects to treatment with adefovir dipivoxil. Two subjects randomized to treatment with adefovir dipivoxil actually received treatment with BARACLUDE for the duration of the study. The mean age of subjects was 52 years, 74% were male, 54% were Asian, 33% were Caucasian, and 5% were Black/African American. At baseline, subjects had a mean serum HBV DNA by PCR of 7.83 log10 copies/mL and mean ALT level of 100 U/L; 54% of subjects were HBeAg-positive; 35% had genotypic evidence of lamivudine resistance. The baseline mean CTP score was 8.6. Results for selected study endpoints at Week 48 are shown in Table 12.
- Subjects Co-infected with HIV and HBV
- Study AI463038 was a randomized, double-blind, placebo-controlled study of BARACLUDE versus placebo in 68 subjects co-infected with HIV and HBV who experienced recurrence of HBV viremia while receiving a lamivudine-containing highly active antiretroviral (HAART) regimen. Subjects continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day) and were assigned to add either BARACLUDE 1 mg once daily (51 subjects) or placebo (17 subjects) for 24 weeks followed by an open-label phase for an additional 24 weeks where all subjects received BARACLUDE. At baseline, subjects had a mean serum HBV DNA level by PCR of 9.13 log10 copies/mL. Ninety-nine percent of subjects were HBeAg-positive at baseline, with a mean baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2 log10 copies/mL through 24 weeks of blinded therapy. Virologic and biochemical endpoints at Week 24 are shown in Table 13. There are no data in patients with HIV/HBV co-infection who have not received prior lamivudine therapy. BARACLUDE has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment.
- For subjects originally assigned to BARACLUDE, at the end of the open-label phase (Week 48), 8% of subjects had HBV DNA <300 copies/mL by PCR, the mean change from baseline HBV DNA by PCR was −4.20 log10 copies/mL, and 37% of subjects with abnormal ALT at baseline had ALT normalization (≤1 × ULN).
- Beyond 48 Weeks
- The optimal duration of therapy with BARACLUDE is unknown. According to protocol-mandated criteria in the Phase 3 clinical trials, subjects discontinued BARACLUDE or lamivudine treatment after 52 weeks according to a definition of response based on HBV virologic suppression (<0.7 MEq/mL by bDNA assay) and loss of HBeAg (in HBeAg-positive subjects) or ALT <1.25 × ULN (in HBeAg-negative subjects) at Week 48. Subjects who achieved virologic suppression but did not have serologic response (HBeAg-positive) or did not achieve ALT <1.25 × ULN (HBeAg-negative) continued blinded dosing through 96 weeks or until the response criteria were met. These protocol-specified subject management guidelines are not intended as guidance for clinical practice.
- Nucleoside-inhibitor-naïve Subjects
- Among nucleoside-inhibitor-naïve, HBeAg-positive subjects (Study AI463022), 243 (69%) BARACLUDE-treated subjects and 164 (46%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. Of those continuing blinded treatment in Year 2, 180 (74%) BARACLUDE subjects and 60 (37%) lamivudine subjects achieved HBV DNA <300 copies/mL by PCR at the end of dosing (up to 96 weeks). 193 (79%) BARACLUDE subjects achieved ALT ≤1 × ULN compared to 112 (68%) lamivudine subjects, and HBeAg seroconversion occurred in 26 (11%) BARACLUDE subjects and 20 (12%) lamivudine subjects.
- Among nucleoside-inhibitor-naïve, HBeAg-positive subjects, 74 (21%) BARACLUDE subjects and 67 (19%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. Among BARACLUDE responders, 26 (35%) subjects had HBV DNA <300 copies/mL, 55 (74%) subjects had ALT ≤1 × ULN, and 56 (76%) subjects sustained HBeAg seroconversion at the end of follow-up. Among lamivudine responders, 20 (30%) subjects had HBV DNA <300 copies/mL, 41 (61%) subjects had ALT ≤1 × ULN, and 47 (70%) subjects sustained HBeAg seroconversion at the end of follow-up.
- Among nucleoside-inhibitor-naïve, HBeAg-negative subjects (Study AI463027), 26 (8%) BARACLUDE-treated subjects and 28 (9%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. In this small cohort continuing treatment in Year 2, 22 BARACLUDE and 16 lamivudine subjects had HBV DNA <300 copies/mL by PCR, and 7 and 6 subjects, respectively, had ALT ≤1 × ULN at the end of dosing (up to 96 weeks).
- Among nucleoside-inhibitor-naïve, HBeAg-negative subjects, 275 (85%) BARACLUDE subjects and 245 (78%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. In this cohort, very few subjects in each treatment arm had HBV DNA <300 copies/mL by PCR at the end of follow-up. At the end of follow-up, 126 (46%) BARACLUDE subjects and 84 (34%) lamivudine subjects had ALT ≤1 × ULN.
- Lamivudine-refractory Subjects
- Among lamivudine-refractory subjects (Study AI463026), 77 (55%) BARACLUDE-treated subjects and 3 (2%) lamivudine subjects continued blinded treatment for up to 96 weeks. In this cohort of BARACLUDE subjects, 31 (40%) subjects achieved HBV DNA <300 copies/mL, 62 (81%) subjects had ALT ≤1 × ULN, and 8 (10%) subjects demonstrated HBeAg seroconversion at the end of dosing.
- The pharmacokinetics, safety and antiviral activity of BARACLUDE in pediatric subjects were initially assessed in Study AI463028. Twenty-four treatment-naïve and 19 lamivudine-experienced HBeAg-positive pediatric subjects 2 to less than 18 years of age with compensated CHB and elevated ALT were treated with BARACLUDE 0.015 mg/kg (up to 0.5 mg) or 0.03 mg/kg (up to 1 mg) once daily. Fifty-eight percent (14/24) of treatment-naïve subjects and 47% (9/19) of lamivudine-experienced subjects achieved HBV DNA <50 IU/mL at Week 48 and ALT normalized in 83% (20/24) of treatment-naïve and 95% (18/19) of lamivudine-experienced subjects.
- Safety and antiviral efficacy were confirmed in Study AI463189, an ongoing study of BARACLUDE among 180 nucleoside-inhibitor-treatment-naïve pediatric subjects 2 to less than 18 years of age with HBeAg-positive chronic hepatitis B infection, compensated liver disease, and elevated ALT. Subjects were randomized 2:1 to receive blinded treatment with BARACLUDE 0.015 mg/kg up to 0.5 mg/day (N=120) or placebo (N=60). The randomization was stratified by age group (2 to 6 years; >6 to 12 years; and >12 to <18 years). Baseline demographics and HBV disease characteristics were comparable between the 2 treatment arms and across age cohorts. At study entry, the mean HBV DNA was 8.1 log10 IU/mL and mean ALT was 103 U/L. The primary efficacy endpoint was a composite of HBeAg seroconversion and serum HBV DNA <50 IU/mL at Week 48 assessed in the first 123 subjects reaching 48 weeks of blinded treatment. Twenty-four percent (20/82) of subjects in the BARACLUDE-treated group and 2% (1/41) of subjects in the placebo-treated group met the primary endpoint. Forty-six percent (38/82) of BARACLUDE-treated subjects and 2% (1/41) of placebo-treated subjects achieved HBV DNA <50 IU/mL at Week 48. ALT normalization occurred in 67% (55/82) of BARACLUDE-treated subjects and 22% (9/41) of placebo-treated subjects; 24% (20/82) of BARACLUDE-treated subjects and 12% (5/41) of placebo-treated subjects had HBeAg seroconversion.
# How Supplied
- BARACLUDE® (entecavir) Tablets and Oral Solution are available in the following strengths and configurations of plastic bottles with child-resistant closures:
- BARACLUDE Oral Solution is a ready-to-use product; dilution or mixing with water or any other solvent or liquid product is not recommended. Each bottle of the oral solution is accompanied by a dosing spoon that is calibrated in 0.5 mL increments up to 10 mL.
- Storage
- BARACLUDE Tablets should be stored in a tightly closed container at 25°C (77°F); excursions permitted between 15°C and 30°C (59° and 86°F). Store in the outer carton to protect from light.
## Storage
There is limited information regarding Entecavir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Physicians should inform their patients of the following important points when initiating BARACLUDE treatment:
- Patients should remain under the care of a physician while taking BARACLUDE. They should discuss any new symptoms or concurrent medications with their physician.
- Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
- Patients should be advised to take BARACLUDE on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).
- Patients using the oral solution should be instructed to hold the dosing spoon in a vertical position and fill it gradually to the mark corresponding to the prescribed dose. Rinsing of the dosing spoon with water is recommended after each daily dose. Some patients may find it difficult to accurately measure the prescribed dose using the provided dosing spoon; therefore, patients/caregivers should refer to the steps in the Patient Information section that demonstrate the correct technique of using the provided dosing spoon to measure the prescribed BARACLUDE dose.
- Patients should be advised to take a missed dose as soon as remembered unless it is almost time for the next dose. Patients should not take two doses at the same time.
- Patients should be advised that treatment with BARACLUDE will not cure HBV.
- Patients should be informed that BARACLUDE may lower the amount of HBV in the body, may lower the ability of HBV to multiply and infect new liver cells, and may improve the condition of the liver.
- Patients should be informed that it is not known whether BARACLUDE will reduce their chances of getting liver cancer or cirrhosis.
- Post-treatment Exacerbation of Hepatitis
- Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician.
- HIV/HBV Co-infection
- Patients should be offered HIV antibody testing before starting BARACLUDE therapy. They should be informed that if they have HIV infection and are not receiving effective HIV treatment, BARACLUDE may increase the chance of HIV resistance to HIV medication.
# Precautions with Alcohol
- Alcohol-Entecavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Baraclude®
# Look-Alike Drug Names
There is limited information regarding Entecavir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Entecavir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [3]
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# Black Box Warning
# Overview
Entecavir is a reverse transcriptase inhibitor that is FDA approved for the {{{indicationType}}} of chronic hepatitis B virus infection in adults and children at least 2 years of age. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, fatigue, dizziness, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Compensated Liver Disease
The recommended dose of BARACLUDE for chronic hepatitis B virus infection in nucleoside-inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily.
The recommended dose of BARACLUDE in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.
- The recommended dose of BARACLUDE for chronic hepatitis B virus infection in nucleoside-inhibitor-treatment-naïve adults and adolescents 16 years of age and older is 0.5 mg once daily.
- The recommended dose of BARACLUDE in adults and adolescents (at least 16 years of age) with a history of hepatitis B viremia while receiving lamivudine or known lamivudine or telbivudine resistance substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L is 1 mg once daily.
- Decompensated Liver Disease
The recommended dose of BARACLUDE for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.
- The recommended dose of BARACLUDE for chronic hepatitis B virus infection in adults with decompensated liver disease is 1 mg once daily.
- Renal Impairment
In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 2. The once-daily dosing regimens are preferred.
- In adult subjects with renal impairment, the apparent oral clearance of entecavir decreased as creatinine clearance decreased. Dosage adjustment is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), as shown in Table 2. The once-daily dosing regimens are preferred.
- Duration of Therapy
The optimal duration of treatment with BARACLUDE for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.
- The optimal duration of treatment with BARACLUDE for patients with chronic hepatitis B virus infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Entecavir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Entecavir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Table 1 describes the recommended dose of BARACLUDE for pediatric patients 2 years of age or older and weighing at least 10 kg. The oral solution should be used for patients with body weight up to 30 kg.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Entecavir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Entecavir in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Severe Acute Exacerbations of Hepatitis B
- Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
- Patients Co-infected with HIV and HBV
- BARACLUDE has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development of resistance to HIV nucleoside reverse transcriptase inhibitors if BARACLUDE is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therefore, therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving HAART. Before initiating BARACLUDE therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.
- Lactic Acidosis and Severe Hepatomegaly with Steatosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors, including BARACLUDE, alone or in combination with antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside inhibitor exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogue inhibitors to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors.
- Lactic acidosis with BARACLUDE use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. Treatment with BARACLUDE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
# 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.
- Compensated Liver Disease
- Assessment of adverse reactions is based on four studies (AI463014, AI463022, AI463026, and AI463027) in which 1720 subjects with chronic hepatitis B virus infection and compensated liver disease received double-blind treatment with BARACLUDE 0.5 mg/day (n=679), BARACLUDE 1 mg/day (n=183), or lamivudine (n=858) for up to 2 years. Median duration of therapy was 69 weeks for BARACLUDE-treated subjects and 63 weeks for lamivudine-treated subjects in Studies AI463022 and AI463027 and 73 weeks for BARACLUDE-treated subjects and 51 weeks for lamivudine-treated subjects in Studies AI463026 and AI463014. The safety profiles of BARACLUDE and lamivudine were comparable in these studies.
- The most common adverse reactions of any severity (≥3%) with at least a possible relation to study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. The most common adverse reactions among lamivudine-treated subjects were headache, fatigue, and dizziness. One percent of BARACLUDE-treated subjects in these four studies compared with 4% of lamivudine-treated subjects discontinued for adverse events or abnormal laboratory test results.
- Clinical adverse reactions of moderate-severe intensity and considered at least possibly related to treatment occurring during therapy in four clinical studies in which BARACLUDE was compared with lamivudine are presented in Table 3.
- Laboratory Abnormalities
- Frequencies of selected treatment-emergent laboratory abnormalities reported during therapy in four clinical trials of BARACLUDE compared with lamivudine are listed in Table 4.
- Among BARACLUDE-treated subjects in these studies, on-treatment ALT elevations greater than 10 times the upper limit of normal (ULN) and greater than 2 times baseline generally resolved with continued treatment. A majority of these exacerbations were associated with a ≥2 log10/mL reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.
- Exacerbations of Hepatitis after Discontinuation of Treatment
- An exacerbation of hepatitis or ALT flare was defined as ALT greater than 10 times ULN and greater than 2 times the subject’s reference level (minimum of the baseline or last measurement at end of dosing). For all subjects who discontinued treatment (regardless of reason), Table 5 presents the proportion of subjects in each study who experienced post-treatment ALT flares. In these studies, a subset of subjects was allowed to discontinue treatment at or after 52 weeks if they achieved a protocol-defined response to therapy. If BARACLUDE is discontinued without regard to treatment response, the rate of post-treatment flares could be higher.
- Decompensated Liver Disease
- Study AI463048 was a randomized, open-label study of BARACLUDE 1 mg once daily versus adefovir dipivoxil 10 mg once daily given for up to 48 weeks in adult subjects with chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher. Among the 102 subjects receiving BARACLUDE, the most common treatment-emergent adverse events of any severity, regardless of causality, occurring through Week 48 were peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). Clinical adverse reactions not listed in Table 3 that were observed through Week 48 include blood bicarbonate decreased (2%) and renal failure (<1%).
- Eighteen of 102 (18%) subjects treated with BARACLUDE and 18/89 (20%) subjects treated with adefovir dipivoxil died during the first 48 weeks of therapy. The majority of deaths (11 in the BARACLUDE group and 16 in the adefovir dipivoxil group) were due to liver-related causes such as hepatic failure, hepatic encephalopathy, hepatorenal syndrome, and upper gastrointestinal hemorrhage. The rate of hepatocellular carcinoma (HCC) through Week 48 was 6% (6/102) for subjects treated with BARACLUDE and 8% (7/89) for subjects treated with adefovir dipivoxil. Five percent of subjects in either treatment arm discontinued therapy due to an adverse event through Week 48.
- No subject in either treatment arm experienced an on-treatment hepatic flare (ALT >2 × baseline and >10 × ULN) through Week 48. Eleven of 102 (11%) subjects treated with BARACLUDE and 11/89 (13%) subjects treated with adefovir dipivoxil had a confirmed increase in serum creatinine of 0.5 mg/dL through Week 48.
- HIV/HBV Co-infected
- The safety profile of BARACLUDE 1 mg (n=51) in HIV/HBV co-infected subjects enrolled in Study AI463038 was similar to that of placebo (n=17) through 24 weeks of blinded treatment and similar to that seen in non-HIV infected subjects.
- Liver Transplant Recipients
- Among 65 subjects receiving BARACLUDE in an open-label, post-liver transplant trial, the frequency and nature of adverse events were consistent with those expected in patients who have received a liver transplant and the known safety profile of BARACLUDE.
- Clinical Trial Experience in Pediatric Subjects
- 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 safety of BARACLUDE in pediatric subjects 2 to less than 18 years of age is based on two ongoing clinical trials in subjects with chronic HBV infection (one Phase 2 pharmacokinetic trial [AI463028] and one Phase 3 trial [AI463189]). These trials provide experience in 168 HBeAg-positive subjects treated with BARACLUDE for a median duration of 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with BARACLUDE were consistent with those observed in clinical trials of BARACLUDE in adults. Adverse drug reactions reported in greater than 1% of pediatric subjects included abdominal pain, rash events, poor palatability (“product taste abnormal”), nausea, diarrhea, and vomiting.
## Postmarketing Experience
- The following adverse reactions have been reported during postmarketing use of BARACLUDE. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to BARACLUDE exposure.
- Immune system disorders: Anaphylactoid reaction.
- Metabolism and nutrition disorders: Lactic acidosis.
- Hepatobiliary disorders: Increased transaminases.
- Skin and subcutaneous tissue disorders: Alopecia, rash.
# Drug Interactions
- Since entecavir is primarily eliminated by the kidneys, coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. Coadministration of entecavir with lamivudine, adefovir dipivoxil, or tenofovir disoproxil fumarate did not result in significant drug interactions. The effects of coadministration of BARACLUDE with other drugs that are renally eliminated or are known to affect renal function have not been evaluated, and patients should be monitored closely for adverse events when BARACLUDE is coadministered with such drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of BARACLUDE in pregnant women. Because animal reproduction studies are not always predictive of human response, BARACLUDE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to BARACLUDE, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
- Animal Data
- Animal reproduction studies with entecavir in rats and rabbits revealed no evidence of teratogenicity. Developmental toxicity studies were performed in rats and rabbits. There were no signs of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately 28 (rat) and 212 (rabbit) times the human exposure achieved at the highest recommended human dose of 1 mg/day. In rats, maternal toxicity, embryofetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossification (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs were observed at exposures 3100 times those in humans. In rabbits, embryofetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib were observed at exposures 883 times those in humans. In a peri-postnatal study, no adverse effects on offspring occurred when rats received oral entecavir at exposures greater than 94 times those in humans.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Entecavir in women who are pregnant.
### Labor and Delivery
- There are no studies in pregnant women and no data on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
### Nursing Mothers
- It is not known whether BARACLUDE is excreted into human milk; however, entecavir is excreted into the milk of rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from BARACLUDE, a decision should be made to discontinue nursing or to discontinue BARACLUDE taking into consideration the importance of continued hepatitis B therapy to the mother and the known benefits of breastfeeding.
### Pediatric Use
- BARACLUDE was evaluated in two clinical trials of pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease. The exposure of BARACLUDE in nucleoside-inhibitor-treatment-naïve and lamivudine-experienced pediatric subjects 2 years of age and older with HBeAg-positive chronic HBV infection and compensated liver disease receiving 0.015 mg/kg (up to 0.5 mg once daily) or 0.03 mg/kg (up to 1 mg once daily), respectively, was evaluated in Study AI463028. Safety and efficacy of the selected dose in treatment-naïve pediatric subjects were confirmed in Study AI463189, a randomized, placebo-controlled treatment trial.
- There are limited data available on the use of BARACLUDE in lamivudine-experienced pediatric patients; BARACLUDE should be used in these patients only if the potential benefit justifies the potential risk to the child. Since some pediatric patients may require long-term or even lifetime management of chronic active hepatitis B, consideration should be given to the impact of BARACLUDE on future treatment options.
- The efficacy and safety of BARACLUDE have not been established in patients less than 2 years of age. Use of BARACLUDE in this age group has not been evaluated because treatment of HBV in this age group is rarely required.
### Geriatic Use
- Clinical studies of BARACLUDE did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Entecavir is 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 Entecavir with respect to specific gender populations.
### Race
- There are no significant racial differences in entecavir pharmacokinetics. The safety and efficacy of BARACLUDE 0.5 mg once daily were assessed in a single-arm, open-label trial of HBeAg-positive or -negative, nucleoside-inhibitor-naïve, Black/African American (n=40) and Hispanic (n=6) subjects with chronic HBV infection. In this trial, 76% of subjects were male, the mean age was 42 years, 57% were HBeAg-positive, the mean baseline HBV DNA was 7.0 log10 IU/mL, and the mean baseline ALT was 162 U/L. At Week 48 of treatment, 32 of 46 (70%) subjects had HBV DNA <50 IU/mL (approximately 300 copies/mL), 31 of 46 (67%) subjects had ALT normalization (≤1 × ULN), and 12 of 26 (46%) HBeAg-positive subjects had HBe seroconversion. Safety data were similar to those observed in the larger controlled clinical trials.
### Renal Impairment
- Dosage adjustment of BARACLUDE is recommended for patients with creatinine clearance less than 50 mL/min, including patients on hemodialysis or CAPD.
### Hepatic Impairment
There is no FDA guidance on the use of Entecavir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Entecavir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Entecavir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Entecavir in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Entecavir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is limited experience of entecavir overdosage reported in patients. Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days had no increase in or unexpected adverse events.
### Management
- If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
- Following a single 1 mg dose of entecavir, a 4-hour hemodialysis session removed approximately 13% of the entecavir dose.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Entecavir in the drug label.
# Pharmacology
## Mechanism of Action
- Entecavir, a guanosine nucleoside analogue with activity against HBV reverse transcriptase (rt), is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV reverse transcriptase: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ with Ki values ranging from 18 to >160 μM.
## Structure
- BARACLUDE® is the tradename for entecavir, a guanosine nucleoside analogue with selective activity against HBV. The chemical name for entecavir is 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate. Its molecular formula is C12H15N5O3∙H2O, which corresponds to a molecular weight of 295.3. Entecavir has the following structural formula:
- Entecavir is a white to off-white powder. It is slightly soluble in water (2.4 mg/mL), and the pH of the saturated solution in water is 7.9 at 25° C ± 0.5° C.
- BARACLUDE film-coated tablets are available for oral administration in strengths of 0.5 mg and 1 mg of entecavir. BARACLUDE 0.5 mg and 1 mg film-coated tablets contain the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet coating contains titanium dioxide, hypromellose, polyethylene glycol 400, polysorbate 80 (0.5 mg tablet only), and iron oxide red (1 mg tablet only). BARACLUDE Oral Solution is available for oral administration as a ready-to-use solution containing 0.05 mg of entecavir per milliliter. BARACLUDE Oral Solution contains the following inactive ingredients: maltitol, sodium citrate, citric acid, methylparaben, propylparaben, and orange flavor.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Entecavir in the drug label.
## Pharmacokinetics
- The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects and subjects with chronic hepatitis B virus infection.
- Absorption
- Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1 mg, Cmax and area under the concentration-time curve (AUC) at steady state increased in proportion to dose. Steady state was achieved after 6 to 10 days of once-daily administration with approximately 2-fold accumulation. For a 0.5 mg oral dose, Cmax at steady state was 4.2 ng/mL and trough plasma concentration (Ctrough) was 0.3 ng/mL. For a 1 mg oral dose, Cmax was 8.2 ng/mL and Ctrough was 0.5 ng/mL.
- In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solution. The oral solution and tablet may be used interchangeably.
- Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1.0–1.5 hours fed vs. 0.75 hours fasted), a decrease in Cmax of 44%–46%, and a decrease in AUC of 18%–20%.
- Distribution
- Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues.
- Binding of entecavir to human serum proteins in vitro was approximately 13%.
- Metabolism and Elimination
- Following administration of 14C-entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system.
- After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128–149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours.
- Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion.
- Special Populations
- Gender: There are no significant gender differences in entecavir pharmacokinetics.
- Race: There are no significant racial differences in entecavir pharmacokinetics.
- Elderly: The effect of age on the pharmacokinetics of entecavir was evaluated following administration of a single 1 mg oral dose in healthy young and elderly volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects. The disparity in exposure between elderly and young subjects was most likely attributable to differences in renal function. Dosage adjustment of BARACLUDE should be based on the renal function of the patient, rather than age.
- Pediatrics: The steady-state pharmacokinetics of entecavir were evaluated in nucleoside-inhibitor-naïve and lamivudine-experienced HBeAg-positive pediatric subjects 2 to less than 18 years of age with compensated liver disease. Results are shown in Table 6. Entecavir exposure among nucleoside-inhibitor-naïve subjects was similar to the exposure achieved in adults receiving once-daily doses of 0.5 mg. Entecavir exposure among lamivudine-experienced subjects was similar to the exposure achieved in adults receiving once-daily doses of 1 mg.
- Renal impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in subjects (without chronic hepatitis B virus infection) with selected degrees of renal impairment, including subjects whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Results are shown in Table 7.
- Following a single 1 mg dose of entecavir administered 2 hours before the hemodialysis session, hemodialysis removed approximately 13% of the entecavir dose over 4 hours. CAPD removed approximately 0.3% of the dose over 7 days.
- Hepatic impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in adult subjects (without chronic hepatitis B virus infection) with moderate or severe hepatic impairment (Child-Turcotte-Pugh Class B or C). The pharmacokinetics of entecavir were similar between hepatically impaired and healthy control subjects; therefore, no dosage adjustment of BARACLUDE is recommended for patients with hepatic impairment. The pharmacokinetics of entecavir have not been studied in pediatric subjects with hepatic impairment.
- Post-liver transplant: Limited data are available on the safety and efficacy of BARACLUDE in liver transplant recipients. In a small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of cyclosporine A (n=5) or tacrolimus (n=4), entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these subjects. The potential for pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus was not formally evaluated.
- Drug Interactions
- The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations up to approximately 340-fold higher than those observed in humans, entecavir did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. The pharmacokinetics of entecavir are unlikely to be affected by coadministration with agents that are either metabolized by, inhibit, or induce the CYP450 system. Likewise, the pharmacokinetics of known CYP substrates are unlikely to be affected by coadministration of entecavir.
- The steady-state pharmacokinetics of entecavir and coadministered drug were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate.
## Nonclinical Toxicology
- Carcinogenesis
- Long-term oral carcinogenicity studies of entecavir in mice and rats were carried out at exposures up to approximately 42 times (mice) and 35 times (rats) those observed in humans at the highest recommended dose of 1 mg/day. In mouse and rat studies, entecavir was positive for carcinogenic findings.
- In mice, lung adenomas were increased in males and females at exposures 3 and 40 times those in humans. Lung carcinomas in both male and female mice were increased at exposures 40 times those in humans. Combined lung adenomas and carcinomas were increased in male mice at exposures 3 times and in female mice at exposures 40 times those in humans. Tumor development was preceded by pneumocyte proliferation in the lung, which was not observed in rats, dogs, or monkeys administered entecavir, supporting the conclusion that lung tumors in mice may be a species-specific event. Hepatocellular carcinomas were increased in males and combined liver adenomas and carcinomas were also increased at exposures 42 times those in humans. Vascular tumors in female mice (hemangiomas of ovaries and uterus and hemangiosarcomas of spleen) were increased at exposures 40 times those in humans. In rats, hepatocellular adenomas were increased in females at exposures 24 times those in humans; combined adenomas and carcinomas were also increased in females at exposures 24 times those in humans. Brain gliomas were induced in both males and females at exposures 35 and 24 times those in humans. Skin fibromas were induced in females at exposures 4 times those in humans.
- It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
- Mutagenesis
- Entecavir was clastogenic to human lymphocyte cultures. Entecavir was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains in the presence or absence of metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells. Entecavir was also negative in an oral micronucleus study and an oral DNA repair study in rats.
- Impairment of Fertility
- In reproductive toxicology studies, in which animals were administered entecavir at up to 30 mg/kg for up to 4 weeks, no evidence of impaired fertility was seen in male or female rats at systemic exposures greater than 90 times those achieved in humans at the highest recommended dose of 1 mg/day. In rodent and dog toxicology studies, seminiferous tubular degeneration was observed at exposures 35 times or greater than those achieved in humans. No testicular changes were evident in monkeys.
# Clinical Studies
- At 48 Weeks
- The safety and efficacy of BARACLUDE in adults were evaluated in three Phase 3 active-controlled trials. These studies included 1633 subjects 16 years of age or older with chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Subjects had persistently elevated ALT levels at least 1.3 times ULN and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The safety and efficacy of BARACLUDE were also evaluated in a study of 191 HBV-infected subjects with decompensated liver disease and in a study of 68 subjects co-infected with HBV and HIV.
- Nucleoside-inhibitor-naïve Subjects with Compensated Liver Disease
- HBeAg-positive: Study AI463022 was a multinational, randomized, double-blind study of BARACLUDE 0.5 mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 709 (of 715 randomized) nucleoside-inhibitor-naïve subjects with chronic hepatitis B virus infection, compensated liver disease, and detectable HBeAg. The mean age of subjects was 35 years, 75% were male, 57% were Asian, 40% were Caucasian, and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 9.66 log10 copies/mL, and mean serum ALT level was 143 U/L. Paired, adequate liver biopsy samples were available for 89% of subjects.
- HBeAg-negative (anti-HBe-positive/HBV DNA-positive): Study AI463027 was a multinational, randomized, double-blind study of BARACLUDE 0.5 mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 638 (of 648 randomized) nucleoside-inhibitor-naïve subjects with HBeAg-negative (HBeAb-positive) chronic hepatitis B virus infection and compensated liver disease. The mean age of subjects was 44 years, 76% were male, 39% were Asian, 58% were Caucasian, and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 7.58 log10 copies/mL, and mean serum ALT level was 142 U/L. Paired, adequate liver biopsy samples were available for 88% of subjects.
- In Studies AI463022 and AI463027, BARACLUDE was superior to lamivudine on the primary efficacy endpoint of Histologic Improvement, defined as a 2-point or greater reduction in Knodell Necroinflammatory Score with no worsening in Knodell Fibrosis Score at Week 48, and on the secondary efficacy measures of reduction in viral load and ALT normalization. Histologic Improvement and change in Ishak Fibrosis Score are shown in Table 8. Selected virologic, biochemical, and serologic outcome measures are shown in Table 9.
- Histologic Improvement was independent of baseline levels of HBV DNA or ALT.
- Lamivudine-refractory Subjects with Compensated Liver Disease
- Study AI463026 was a multinational, randomized, double-blind study of BARACLUDE in 286 (of 293 randomized) subjects with lamivudine-refractory chronic hepatitis B virus infection and compensated liver disease. Subjects receiving lamivudine at study entry either switched to BARACLUDE 1 mg once daily (with neither a washout nor an overlap period) or continued on lamivudine 100 mg for a minimum of 52 weeks. The mean age of subjects was 39 years, 76% were male, 37% were Asian, 62% were Caucasian, and 52% had previously received interferon-α. The mean duration of prior lamivudine therapy was 2.7 years, and 85% had lamivudine resistance substitutions at baseline by an investigational line probe assay. At baseline, subjects had a mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.36 log10 copies/mL, and mean serum ALT level was 128 U/L. Paired, adequate liver biopsy samples were available for 87% of subjects.
- BARACLUDE was superior to lamivudine on a primary endpoint of Histologic Improvement (using the Knodell Score at Week 48). These results and change in Ishak Fibrosis Score are shown in Table 10. Table 11 shows selected virologic, biochemical, and serologic endpoints.
- Histologic Improvement was independent of baseline levels of HBV DNA or ALT.
- Subjects with Decompensated Liver Disease
- Study AI463048 was a randomized, open-label study of BARACLUDE 1 mg once daily versus adefovir dipivoxil 10 mg once daily in 191 (of 195 randomized) adult subjects with HBeAg-positive or -negative chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher. Subjects were either HBV-treatment-naïve or previously treated, predominantly with lamivudine or interferon-α.
- In Study AI463048, 100 subjects were randomized to treatment with BARACLUDE and 91 subjects to treatment with adefovir dipivoxil. Two subjects randomized to treatment with adefovir dipivoxil actually received treatment with BARACLUDE for the duration of the study. The mean age of subjects was 52 years, 74% were male, 54% were Asian, 33% were Caucasian, and 5% were Black/African American. At baseline, subjects had a mean serum HBV DNA by PCR of 7.83 log10 copies/mL and mean ALT level of 100 U/L; 54% of subjects were HBeAg-positive; 35% had genotypic evidence of lamivudine resistance. The baseline mean CTP score was 8.6. Results for selected study endpoints at Week 48 are shown in Table 12.
- Subjects Co-infected with HIV and HBV
- Study AI463038 was a randomized, double-blind, placebo-controlled study of BARACLUDE versus placebo in 68 subjects co-infected with HIV and HBV who experienced recurrence of HBV viremia while receiving a lamivudine-containing highly active antiretroviral (HAART) regimen. Subjects continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day) and were assigned to add either BARACLUDE 1 mg once daily (51 subjects) or placebo (17 subjects) for 24 weeks followed by an open-label phase for an additional 24 weeks where all subjects received BARACLUDE. At baseline, subjects had a mean serum HBV DNA level by PCR of 9.13 log10 copies/mL. Ninety-nine percent of subjects were HBeAg-positive at baseline, with a mean baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2 log10 copies/mL through 24 weeks of blinded therapy. Virologic and biochemical endpoints at Week 24 are shown in Table 13. There are no data in patients with HIV/HBV co-infection who have not received prior lamivudine therapy. BARACLUDE has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment.
- For subjects originally assigned to BARACLUDE, at the end of the open-label phase (Week 48), 8% of subjects had HBV DNA <300 copies/mL by PCR, the mean change from baseline HBV DNA by PCR was −4.20 log10 copies/mL, and 37% of subjects with abnormal ALT at baseline had ALT normalization (≤1 × ULN).
- Beyond 48 Weeks
- The optimal duration of therapy with BARACLUDE is unknown. According to protocol-mandated criteria in the Phase 3 clinical trials, subjects discontinued BARACLUDE or lamivudine treatment after 52 weeks according to a definition of response based on HBV virologic suppression (<0.7 MEq/mL by bDNA assay) and loss of HBeAg (in HBeAg-positive subjects) or ALT <1.25 × ULN (in HBeAg-negative subjects) at Week 48. Subjects who achieved virologic suppression but did not have serologic response (HBeAg-positive) or did not achieve ALT <1.25 × ULN (HBeAg-negative) continued blinded dosing through 96 weeks or until the response criteria were met. These protocol-specified subject management guidelines are not intended as guidance for clinical practice.
- Nucleoside-inhibitor-naïve Subjects
- Among nucleoside-inhibitor-naïve, HBeAg-positive subjects (Study AI463022), 243 (69%) BARACLUDE-treated subjects and 164 (46%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. Of those continuing blinded treatment in Year 2, 180 (74%) BARACLUDE subjects and 60 (37%) lamivudine subjects achieved HBV DNA <300 copies/mL by PCR at the end of dosing (up to 96 weeks). 193 (79%) BARACLUDE subjects achieved ALT ≤1 × ULN compared to 112 (68%) lamivudine subjects, and HBeAg seroconversion occurred in 26 (11%) BARACLUDE subjects and 20 (12%) lamivudine subjects.
- Among nucleoside-inhibitor-naïve, HBeAg-positive subjects, 74 (21%) BARACLUDE subjects and 67 (19%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. Among BARACLUDE responders, 26 (35%) subjects had HBV DNA <300 copies/mL, 55 (74%) subjects had ALT ≤1 × ULN, and 56 (76%) subjects sustained HBeAg seroconversion at the end of follow-up. Among lamivudine responders, 20 (30%) subjects had HBV DNA <300 copies/mL, 41 (61%) subjects had ALT ≤1 × ULN, and 47 (70%) subjects sustained HBeAg seroconversion at the end of follow-up.
- Among nucleoside-inhibitor-naïve, HBeAg-negative subjects (Study AI463027), 26 (8%) BARACLUDE-treated subjects and 28 (9%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. In this small cohort continuing treatment in Year 2, 22 BARACLUDE and 16 lamivudine subjects had HBV DNA <300 copies/mL by PCR, and 7 and 6 subjects, respectively, had ALT ≤1 × ULN at the end of dosing (up to 96 weeks).
- Among nucleoside-inhibitor-naïve, HBeAg-negative subjects, 275 (85%) BARACLUDE subjects and 245 (78%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. In this cohort, very few subjects in each treatment arm had HBV DNA <300 copies/mL by PCR at the end of follow-up. At the end of follow-up, 126 (46%) BARACLUDE subjects and 84 (34%) lamivudine subjects had ALT ≤1 × ULN.
- Lamivudine-refractory Subjects
- Among lamivudine-refractory subjects (Study AI463026), 77 (55%) BARACLUDE-treated subjects and 3 (2%) lamivudine subjects continued blinded treatment for up to 96 weeks. In this cohort of BARACLUDE subjects, 31 (40%) subjects achieved HBV DNA <300 copies/mL, 62 (81%) subjects had ALT ≤1 × ULN, and 8 (10%) subjects demonstrated HBeAg seroconversion at the end of dosing.
- The pharmacokinetics, safety and antiviral activity of BARACLUDE in pediatric subjects were initially assessed in Study AI463028. Twenty-four treatment-naïve and 19 lamivudine-experienced HBeAg-positive pediatric subjects 2 to less than 18 years of age with compensated CHB and elevated ALT were treated with BARACLUDE 0.015 mg/kg (up to 0.5 mg) or 0.03 mg/kg (up to 1 mg) once daily. Fifty-eight percent (14/24) of treatment-naïve subjects and 47% (9/19) of lamivudine-experienced subjects achieved HBV DNA <50 IU/mL at Week 48 and ALT normalized in 83% (20/24) of treatment-naïve and 95% (18/19) of lamivudine-experienced subjects.
- Safety and antiviral efficacy were confirmed in Study AI463189, an ongoing study of BARACLUDE among 180 nucleoside-inhibitor-treatment-naïve pediatric subjects 2 to less than 18 years of age with HBeAg-positive chronic hepatitis B infection, compensated liver disease, and elevated ALT. Subjects were randomized 2:1 to receive blinded treatment with BARACLUDE 0.015 mg/kg up to 0.5 mg/day (N=120) or placebo (N=60). The randomization was stratified by age group (2 to 6 years; >6 to 12 years; and >12 to <18 years). Baseline demographics and HBV disease characteristics were comparable between the 2 treatment arms and across age cohorts. At study entry, the mean HBV DNA was 8.1 log10 IU/mL and mean ALT was 103 U/L. The primary efficacy endpoint was a composite of HBeAg seroconversion and serum HBV DNA <50 IU/mL at Week 48 assessed in the first 123 subjects reaching 48 weeks of blinded treatment. Twenty-four percent (20/82) of subjects in the BARACLUDE-treated group and 2% (1/41) of subjects in the placebo-treated group met the primary endpoint. Forty-six percent (38/82) of BARACLUDE-treated subjects and 2% (1/41) of placebo-treated subjects achieved HBV DNA <50 IU/mL at Week 48. ALT normalization occurred in 67% (55/82) of BARACLUDE-treated subjects and 22% (9/41) of placebo-treated subjects; 24% (20/82) of BARACLUDE-treated subjects and 12% (5/41) of placebo-treated subjects had HBeAg seroconversion.
# How Supplied
- BARACLUDE® (entecavir) Tablets and Oral Solution are available in the following strengths and configurations of plastic bottles with child-resistant closures:
- BARACLUDE Oral Solution is a ready-to-use product; dilution or mixing with water or any other solvent or liquid product is not recommended. Each bottle of the oral solution is accompanied by a dosing spoon that is calibrated in 0.5 mL increments up to 10 mL.
- Storage
- BARACLUDE Tablets should be stored in a tightly closed container at 25°C (77°F); excursions permitted between 15°C and 30°C (59° and 86°F). Store in the outer carton to protect from light.
## Storage
There is limited information regarding Entecavir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Physicians should inform their patients of the following important points when initiating BARACLUDE treatment:
- Patients should remain under the care of a physician while taking BARACLUDE. They should discuss any new symptoms or concurrent medications with their physician.
- Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
- Patients should be advised to take BARACLUDE on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal).
- Patients using the oral solution should be instructed to hold the dosing spoon in a vertical position and fill it gradually to the mark corresponding to the prescribed dose. Rinsing of the dosing spoon with water is recommended after each daily dose. Some patients may find it difficult to accurately measure the prescribed dose using the provided dosing spoon; therefore, patients/caregivers should refer to the steps in the Patient Information section that demonstrate the correct technique of using the provided dosing spoon to measure the prescribed BARACLUDE dose.
- Patients should be advised to take a missed dose as soon as remembered unless it is almost time for the next dose. Patients should not take two doses at the same time.
- Patients should be advised that treatment with BARACLUDE will not cure HBV.
- Patients should be informed that BARACLUDE may lower the amount of HBV in the body, may lower the ability of HBV to multiply and infect new liver cells, and may improve the condition of the liver.
- Patients should be informed that it is not known whether BARACLUDE will reduce their chances of getting liver cancer or cirrhosis.
- Post-treatment Exacerbation of Hepatitis
- Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician.
- HIV/HBV Co-infection
- Patients should be offered HIV antibody testing before starting BARACLUDE therapy. They should be informed that if they have HIV infection and are not receiving effective HIV treatment, BARACLUDE may increase the chance of HIV resistance to HIV medication.
# Precautions with Alcohol
- Alcohol-Entecavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Baraclude®[2]
# Look-Alike Drug Names
There is limited information regarding Entecavir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Baraclude | |
8579cee2ec3c6d7759fd6a51f24ce7971f3d40f7 | wikidoc | Barbicide | Barbicide
Barbicide is a transparent blue disinfectant solution manufactured by King Research. It is used in barber shops and hair salons to disinfect items such as combs and scissors. In many salons each barber or hair stylist has his or her own supply of barbicide displayed on a shelf in a distinctive glass and stainless steel jar.
Barbicide contains quaternary ammonium, perfume, and colouring. It is sold in concentrated solution which salons dilute with water.
Barbicide's creator came up with the name because he hated going to the barber when he was a child. Just as suicide means killing oneself and homicide means killing another, he gave his creation the name Barbicide (meaning killing the barber) as a nod to his childhood. | Barbicide
Barbicide is a transparent blue disinfectant solution manufactured by King Research. It is used in barber shops and hair salons to disinfect items such as combs and scissors. In many salons each barber or hair stylist has his or her own supply of barbicide displayed on a shelf in a distinctive glass and stainless steel jar.
Barbicide contains quaternary ammonium, perfume, and colouring. It is sold in concentrated solution which salons dilute with water.
Barbicide's creator came up with the name because he hated going to the barber when he was a child. Just as suicide means killing oneself and homicide means killing another, he gave his creation the name Barbicide (meaning killing the barber) as a nod to his childhood.
# External links
- King Research
- Barbicide Material Safety Data Sheet
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Barbicide | |
f08119e04fde19615fec3c6f471d3b4902de6b55 | wikidoc | Base pair | Base pair
In molecular biology, two nucleotides on opposite complementary DNA or RNA strands that are connected via hydrogen bonds are called a base pair (often abbreviated bp). In the canonical Watson-Crick base pairing, adenine (A) forms a base pair with thymine (T), as does guanine (G) with cytosine (C) in DNA. In RNA, thymine is replaced by uracil (U). Non-Watson-Crick base pairing with alternate hydrogen bonding patterns also occur, especially in RNA; common such patterns are Hoogsteen base pairs.
Pairing is also the mechanism by which codons on messenger RNA molecules are recognized by anticodons on transfer RNA during protein translation. Some DNA- or RNA-binding enzymes can recognize specific base pairing patterns that identify particular regulatory regions of genes.
The size of an individual gene or an organism's entire genome is often measured in base pairs because DNA is usually double-stranded. Hence, the number of total base pairs is equal to the number of nucleotides in one of the strands (with the exception of non-coding single-stranded regions of telomeres). The haploid human genome (23 chromosomes) is estimated to be about 3 billion base pairs long and to contain 20,000-25,000 distinct genes.
# Examples
The following DNA sequences illustrate pair double-stranded patterns. By convention, the top strand is written from the 5' end to the 3' end; thus the bottom strand is written 3' to 5'.
# Length measurements
The following abbreviations are commonly used to describe the length of a DNA/RNA molecule:
- bp = base pair(s)
- kb (= kbp) = kilo base pairs = 1,000 bp
- Mb = mega base pairs = 1,000,000 bp
- Gb = giga base pairs = 1,000,000,000 bp
In case of single stranded DNA/RNA we talk about nucleotides, abbreviated nt (or knt, Mnt, Gnt), rather than base pairs, as they are not paired.
For distinction between units of computer storage and bases kbp, Mbp, Gbp etc may be used for disambiguation.
The Centimorgan is also often used to imply distance along a chromosome, but the number of base-pairs it corresponds to varies widely. In the Human genome, it is about 1 million base pairs .
# Hydrogen bonding and stability
Hydrogen bonding is the chemical mechanism that underlies the base-pairing rules described above. Appropriate geometrical correspondence of hydrogen bond donors and acceptors allows only the "right" pairs to form stably. The GC base pair has three hydrogen bonds, whereas the AT base pair has only two; as a consequence, the GC pair is more stable.
The larger nucleic acids, adenine and guanine, are members of a class of doubly-ringed chemical structures called purines; the smaller nucleic acids, cytosine and thymine (and uracil), are members of a class of singly-ringed chemical structures called pyrimidines. Purines are only complementary with pyrimidines: pyrimidine-pyrimidine pairings are energetically unfavorable because the molecules are too far apart for hydrogen bonding to be established; purine-purine pairings are energetically unfavorable because the molecules are too close, leading to electrostatic repulsion. The only other possible pairings are GT and AC; these pairings are mismatches because the pattern of hydrogen donors and acceptors do not correspond. (It should be noted that the GU pairing, with two hydrogen bonds, does occur fairly often in RNA but rarely in DNA.)
Paired DNA and RNA molecules are comparatively stable at room temperature but the two nucleotide strands will separate above a melting point that is determined by the length of the molecules, the extent of mispairing (if any), and the GC content. Higher GC content results in higher melting temperatures; it is therefore unsurprising that the genomes of extremophile organisms such as Thermus thermophilus are particularly GC-rich. Conversely, regions of a genome that need to separate frequently - for example, the promoter regions for often-transcribed genes - are comparatively GC-poor (for example, see TATA box). GC content and melting temperature must also be taken into account when designing primers for PCR reactions.
# Base stacking
Base stacking interactions between the pi orbitals of the bases' aromatic rings also contribute to stability, and again GC stacking interactions with adjacent bases tend to be more favorable. (Note, though, that a GC stacking interaction with the next base pair is geometrically different from a CG interaction.) Base stacking effects are especially important in the secondary structure of RNA; for example, RNA stem-loop structures are stabilized by base stacking in the loop region.
# Base analogs and intercalators
Chemical analogs of nucleotides can take the place of proper nucleotides and establish non-canonical base-pairing, leading to errors (mostly point mutations) in DNA replication and DNA transcription. One common mutagenic base analog is 5-bromouracil, which resembles thymine but can base-pair to guanine in its enol form.
Other chemicals, known as DNA intercalators, fit into the gap between adjacent bases on a single strand and induce frameshift mutations by "masquerading" as a base, causing the DNA replication machinery to skip or insert additional nucleotides at the intercalated site. Most intercalators are large polyaromatic compounds and are known or suspected carcinogens. Examples include ethidium bromide and acridine. | Base pair
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
In molecular biology, two nucleotides on opposite complementary DNA or RNA strands that are connected via hydrogen bonds are called a base pair (often abbreviated bp). In the canonical Watson-Crick base pairing, adenine (A) forms a base pair with thymine (T), as does guanine (G) with cytosine (C) in DNA. In RNA, thymine is replaced by uracil (U). Non-Watson-Crick base pairing with alternate hydrogen bonding patterns also occur, especially in RNA; common such patterns are Hoogsteen base pairs.
Pairing is also the mechanism by which codons on messenger RNA molecules are recognized by anticodons on transfer RNA during protein translation. Some DNA- or RNA-binding enzymes can recognize specific base pairing patterns that identify particular regulatory regions of genes.
The size of an individual gene or an organism's entire genome is often measured in base pairs because DNA is usually double-stranded. Hence, the number of total base pairs is equal to the number of nucleotides in one of the strands (with the exception of non-coding single-stranded regions of telomeres). The haploid human genome (23 chromosomes) is estimated to be about 3 billion base pairs long and to contain 20,000-25,000 distinct genes.[1]
# Examples
The following DNA sequences illustrate pair double-stranded patterns. By convention, the top strand is written from the 5' end to the 3' end; thus the bottom strand is written 3' to 5'.
# Length measurements
The following abbreviations are commonly used to describe the length of a DNA/RNA molecule:
- bp = base pair(s)
- kb (= kbp) = kilo base pairs = 1,000 bp
- Mb = mega base pairs = 1,000,000 bp
- Gb = giga base pairs = 1,000,000,000 bp
In case of single stranded DNA/RNA we talk about nucleotides, abbreviated nt (or knt, Mnt, Gnt), rather than base pairs, as they are not paired.
For distinction between units of computer storage and bases kbp, Mbp, Gbp etc may be used for disambiguation.
The Centimorgan is also often used to imply distance along a chromosome, but the number of base-pairs it corresponds to varies widely. In the Human genome, it is about 1 million base pairs[2] [3].
# Hydrogen bonding and stability
Hydrogen bonding is the chemical mechanism that underlies the base-pairing rules described above. Appropriate geometrical correspondence of hydrogen bond donors and acceptors allows only the "right" pairs to form stably. The GC base pair has three hydrogen bonds, whereas the AT base pair has only two; as a consequence, the GC pair is more stable.
The larger nucleic acids, adenine and guanine, are members of a class of doubly-ringed chemical structures called purines; the smaller nucleic acids, cytosine and thymine (and uracil), are members of a class of singly-ringed chemical structures called pyrimidines. Purines are only complementary with pyrimidines: pyrimidine-pyrimidine pairings are energetically unfavorable because the molecules are too far apart for hydrogen bonding to be established; purine-purine pairings are energetically unfavorable because the molecules are too close, leading to electrostatic repulsion. The only other possible pairings are GT and AC; these pairings are mismatches because the pattern of hydrogen donors and acceptors do not correspond. (It should be noted that the GU pairing, with two hydrogen bonds, does occur fairly often in RNA but rarely in DNA.)
Paired DNA and RNA molecules are comparatively stable at room temperature but the two nucleotide strands will separate above a melting point that is determined by the length of the molecules, the extent of mispairing (if any), and the GC content. Higher GC content results in higher melting temperatures; it is therefore unsurprising that the genomes of extremophile organisms such as Thermus thermophilus are particularly GC-rich. Conversely, regions of a genome that need to separate frequently - for example, the promoter regions for often-transcribed genes - are comparatively GC-poor (for example, see TATA box). GC content and melting temperature must also be taken into account when designing primers for PCR reactions.
# Base stacking
Base stacking interactions between the pi orbitals of the bases' aromatic rings also contribute to stability, and again GC stacking interactions with adjacent bases tend to be more favorable. (Note, though, that a GC stacking interaction with the next base pair is geometrically different from a CG interaction.) Base stacking effects are especially important in the secondary structure of RNA; for example, RNA stem-loop structures are stabilized by base stacking in the loop region.
# Base analogs and intercalators
Chemical analogs of nucleotides can take the place of proper nucleotides and establish non-canonical base-pairing, leading to errors (mostly point mutations) in DNA replication and DNA transcription. One common mutagenic base analog is 5-bromouracil, which resembles thymine but can base-pair to guanine in its enol form.
Other chemicals, known as DNA intercalators, fit into the gap between adjacent bases on a single strand and induce frameshift mutations by "masquerading" as a base, causing the DNA replication machinery to skip or insert additional nucleotides at the intercalated site. Most intercalators are large polyaromatic compounds and are known or suspected carcinogens. Examples include ethidium bromide and acridine. | https://www.wikidoc.org/index.php/Base-pair | |
6bcaa58db56608eb5d220cd847db14111fb75151 | wikidoc | Paruresis | Paruresis
Synonyms and keywords: pee shyness; shy kidney; bashful bladder; stage fright; urinophobia; shy bladder syndrome
# Overview
Paruresis (IPA Template:IPA) is a type of social anxiety disorder, that can affect both men and women, in which the sufferer is unable to urinate in the (real or imaginary) presence of others, such as in a public restroom. The analogous condition that affects bowel movement is called parcopresis.
# Historical Perspective
The term Paruresis was coined by Williams and Degenhart (1954) in their paper "Paruresis: a survey of a disorder of micturition" in the Journal of Psychology 51:19-29. They surveyed 1,419 college students and found 14.4% had experienced paruresis, either incidentally or continuously.
# Epidemiology and Demographics
The prevalence among college students is about 14% .
# Natural History, Complications, Prognosis
Many people have brief, isolated episodes of urinary difficulty in situations where other people are in close proximity, and this is sometimes described as "stage fright". However, that is to be distinguished from paruresis.
Paruresis goes beyond simple shyness, embarrassment, or desire for privacy in that it is much more severe and may cause unnecessary inconvenience, because the inability to urinate, although psychological in origin, is physical in its effect, and not under the control of the sufferer. Paruresis can be mild, moderate or severe. In mild cases, paruresis is an occasional event, like a form of subconscious performance anxiety. For example, a man at a public urinal may be surprised to find it difficult to urinate when flanked by other men, possibly because he may be worried about them seeing his penis, while others may find that they are unable to urinate while in moving vehicles. In severe cases, a person with paruresis can urinate only when alone at home.
Although most sufferers report that they developed the condition in their teenage years, it can strike at any age. Also, because of the differing levels of severity from one person to another, some people's first experience of the problem is when, for the first time, they "lock up" attempting to produce a sample for a drug test.
Severe cases of this disorder can have highly restricting effects on a person's life. Severe sufferers may not be willing to travel far from their home. Others cannot urinate even in their own home if someone else can be heard to be there.
There is growing recognition of the condition by the United Kingdom's National Health Service and UK government. The condition is catered for in the rules for mandatory urine testing for drugs in UK prisons, and UK incapacity benefit tribunals also recognise it. It is listed in the NHS on-line encyclopaedia of conditions and disorders. It is now reported to have been accepted as a valid reason for jury service excusal. From 1st August 2005, the guidance on the rules relating to the testing of those on probation in the UK, explicitly cites paruresis as a valid reason for inability to produce a sample which is not to be construed as a refusal.
The condition is recognised by the American Urological Association, who include it in their on-line directory of conditions.
It has, from time to time been the topic of advice columns such as Ann Landers, to which sufferers have written in and been counselled on their problem.
There can be serious difficulties with workplace drug testing where observed urine samples are insisted upon, if the testing regime does not recognise and cater for the condition. In the UK, employees have a general right not to be unfairly dismissed, and so have an arguable defence if this arises, but this is not the case everywhere.
There is growing evidence to suggest that some drug testing authorities find paruresis a nuisance, and some implement "shy bladder procedures" which pay no more than lip service to the condition, and where there is no evidence that they have conducted any real research into the matter.
The codes and procedures for drug testing in sport are set by the World Anti-Doping Agency ("WADA"). Enquiries to WADA reveal that their doping codes do not cater for the condition at all, and they say they have never had any reports of problems with it. It is thought to be remarkable that such a widespread common condition is not experienced by any athletes, and it is believed by some that this is because sufferers avoid activities where they know they will be required to submit to such testing without the right to choose an alternative testing method. If that is correct, then there might well be a vicious circle which would be of the nature of potential world class athletes who are sufferers being deterred by the testing regime, whilst the testing regime does not cater for the condition because it has not encountered sufferers.
# Diagnosis
In DSM-IV TR, it is classified as a social phobia.
# Treatment
There are a number of "work-arounds" that address the symptom and not the problem:
- drinking less fluid and emptying out whenever 'safe' (although this can be dangerous and lead to dehydration)
- avoidance of large or busy public restrooms
- finding less-busy or single-occupancy restrooms
- returning to a specific bathroom or stall which is familiar and feels safer
- using bathrooms on other floors or in other buildings to avoid familiar persons
- timing bathroom visits to avoid the presence of others (solitude)
- timing bathroom visits to correspond to heavy usage by others (masking effect from noise, greater anonimity)
- tickling the buttocks
- running the tap or flushing to mask urination sounds
- thinking about water flowing
- using a catheter
- using a stall instead of a urinal
- closing ones eyes and imagining no one is there
- focusing on a single point or thought (with or without eyes open)
- holding one's breath, forcing urination to begin before the next breath is taken
- combination of two or more of the preceding techniques
Actual treatments for the condition include:
- cognitive behavior therapy,
- training with biofeedback,
- anti-anxiety medications, and
- reducing the level of privacy at which the condition triggers by indulging in graduated exposure therapy. This last can be achieved by sufferers working together at organised events known as workshops. | Paruresis
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: pee shyness; shy kidney; bashful bladder; stage fright; urinophobia; shy bladder syndrome
# Overview
Paruresis (IPA Template:IPA) is a type of social anxiety disorder, that can affect both men and women, in which the sufferer is unable to urinate in the (real or imaginary) presence of others, such as in a public restroom. The analogous condition that affects bowel movement is called parcopresis.
# Historical Perspective
The term Paruresis was coined by Williams and Degenhart (1954) in their paper "Paruresis: a survey of a disorder of micturition" in the Journal of Psychology 51:19-29. They surveyed 1,419 college students and found 14.4% had experienced paruresis, either incidentally or continuously.
# Epidemiology and Demographics
The prevalence among college students is about 14% [1].
# Natural History, Complications, Prognosis
Many people have brief, isolated episodes of urinary difficulty in situations where other people are in close proximity, and this is sometimes described as "stage fright". However, that is to be distinguished from paruresis.
Paruresis goes beyond simple shyness, embarrassment, or desire for privacy in that it is much more severe and may cause unnecessary inconvenience, because the inability to urinate, although psychological in origin, is physical in its effect, and not under the control of the sufferer. Paruresis can be mild, moderate or severe. In mild cases, paruresis is an occasional event, like a form of subconscious performance anxiety. For example, a man at a public urinal may be surprised to find it difficult to urinate when flanked by other men, possibly because he may be worried about them seeing his penis, while others may find that they are unable to urinate while in moving vehicles. In severe cases, a person with paruresis can urinate only when alone at home.[2]
Although most sufferers report that they developed the condition in their teenage years, it can strike at any age. Also, because of the differing levels of severity from one person to another, some people's first experience of the problem is when, for the first time, they "lock up" attempting to produce a sample for a drug test.
Severe cases of this disorder can have highly restricting effects on a person's life. Severe sufferers may not be willing to travel far from their home. Others cannot urinate even in their own home if someone else can be heard to be there.
There is growing recognition of the condition by the United Kingdom's National Health Service and UK government. The condition is catered for in the rules for mandatory urine testing for drugs in UK prisons, and UK incapacity benefit tribunals also recognise it. It is listed in the NHS on-line encyclopaedia of conditions and disorders.[3] It is now reported to have been accepted as a valid reason for jury service excusal.[4] From 1st August 2005, the guidance on the rules relating to the testing of those on probation in the UK, explicitly cites paruresis as a valid reason for inability to produce a sample which is not to be construed as a refusal.
The condition is recognised by the American Urological Association, who include it in their on-line directory of conditions.[5]
It has, from time to time been the topic of advice columns such as Ann Landers, to which sufferers have written in and been counselled on their problem.
There can be serious difficulties with workplace drug testing where observed urine samples are insisted upon, if the testing regime does not recognise and cater for the condition. In the UK, employees have a general right not to be unfairly dismissed, and so have an arguable defence if this arises, but this is not the case everywhere.
There is growing evidence to suggest that some drug testing authorities find paruresis a nuisance, and some implement "shy bladder procedures" which pay no more than lip service to the condition, and where there is no evidence that they have conducted any real research into the matter.
The codes and procedures for drug testing in sport are set by the World Anti-Doping Agency ("WADA"). Enquiries to WADA reveal that their doping codes do not cater for the condition at all, and they say they have never had any reports of problems with it. It is thought to be remarkable that such a widespread common condition is not experienced by any athletes, and it is believed by some that this is because sufferers avoid activities where they know they will be required to submit to such testing without the right to choose an alternative testing method. If that is correct, then there might well be a vicious circle which would be of the nature of potential world class athletes who are sufferers being deterred by the testing regime, whilst the testing regime does not cater for the condition because it has not encountered sufferers.
# Diagnosis
In DSM-IV TR, it is classified as a social phobia.[6]
# Treatment
There are a number of "work-arounds" that address the symptom and not the problem:
- drinking less fluid and emptying out whenever 'safe' (although this can be dangerous and lead to dehydration)
- avoidance of large or busy public restrooms
- finding less-busy or single-occupancy restrooms
- returning to a specific bathroom or stall which is familiar and feels safer
- using bathrooms on other floors or in other buildings to avoid familiar persons
- timing bathroom visits to avoid the presence of others (solitude)
- timing bathroom visits to correspond to heavy usage by others (masking effect from noise, greater anonimity)
- tickling the buttocks
- running the tap or flushing to mask urination sounds
- thinking about water flowing
- using a catheter
- using a stall instead of a urinal
- closing ones eyes and imagining no one is there
- focusing on a single point or thought (with or without eyes open)
- holding one's breath, forcing urination to begin before the next breath is taken
- combination of two or more of the preceding techniques
Actual treatments for the condition include:
- cognitive behavior therapy,
- training with biofeedback,
- anti-anxiety medications, and
- reducing the level of privacy at which the condition triggers by indulging in graduated exposure therapy. This last can be achieved by sufferers working together at organised events known as workshops. | https://www.wikidoc.org/index.php/Bashful_bladder | |
f2ce80651b6858689adcb08b0ab57e1b300ff7cb | wikidoc | Bearberry | Bearberry
Bearberries are three species of dwarf shrubs in the genus Arctostaphylos. Unlike the other species of Arctostaphylos (see Manzanita), they are adapted to arctic and sub-arctic climates, and have a circumpolar distribution in northern North America, Asia and Europe, one with a small highly disjunct population in Central America.
# Species
The name bearberry derives from the edible fruit, said to be greatly enjoyed by bears. The fruit, also called bearberries, are edible and sometimes gathered for food. The leaves of the plant are used in herbal medicine.
- Alpine Bearberry - A. alpina (L.) Spreng (syn. Arctous alpinus (L.) Niedenzu). A procumbent shrub 10-30 cm high. Leaves not winter green, but dead leaves persist on stems for several years. Berries dark purple to black. Distribution: circumpolar, at high latitudes, from Scotland east across Scandinavia, Russia, Alaska, Canada and Greenland; southern limits in Europe in the Pyrenees and the Alps, in Asia to the Altay Mountains, and in North America to British Columbia in the west, and Maine and New Hampshire in the United States in the east.
- Red Bearberry - A. rubra (Rehd. & Wilson) Fernald (syn. Arctous rubra (Rehder and E.H. Wilson) Nakai; Arctous alpinus var. ruber Rehd. and Wilson). A procumbent shrub 10-30 cm high. Leaves deciduous, falling in autumn to leave bare stems. Berries red. Distribution: in the mountains of Sichuan, southwestern China north and east to eastern Siberia, Alaska and northern Canada east to northern Quebec.
- Common Bearberry - A. uva-ursi (L.) Spreng.
Other recorded old English common names include Arberry, Bear's Grape, Crowberry, Foxberry, Hog Cranberry, Kinnikinnick, Mealberry, Mountain Box, Mountain Cranberry, Mountain Tobacco, Red Bearberry, Sandberry, Upland Cranberry, Uva-ursi.
## Medicinal Uses
The plant contains arbutin, methylarbutin, a bitter principle, ursolic acid, tannic acid, gallic acid, some essential oil and resin, hydroquinones (mainly arbutin, up to 17%), tannins (up to 15%), phenolic glycosides and flavonoids.
The leaves are picked any time during the summer and dried for use in infusions, liquid extracts, medicinal tea bags and tablets. The plant has the following claimed properties: anti-lithic, aromatic, astringent, disinfectant, diuretic, lithontripic, sedative (renal), stimulant (mild), tonic, urinary antiseptic. It has been used to treat arthritis, back pain (lower), bed wetting, bile problems, bladder infections, bloating, bright's disease, bronchitis, cararrh of the bladder, cystitis, diabetes (by removing excessive sugar from the blood), diarrhea, fevers, fluid retention, gallstones, gonorrhea, headache (smoked), haemorrhoids, indigestion, kidney stones, kidney infections, liver problems, lung congestion, excessive menstration, nephritis, obesity, pancreatis, prostate gland weakness, rheumatism, chronic urethritis, vaginal discharge, vaginal diseases, and water retention.
It is claimed to strengthen the heart muscle and urinary tract, return the womb to its normal size after childbirth, and prevents uteral infection. It is also claimed to be a powerful tonic for the sphincter muscle of the bladder so it helps with bladder control problems. It has a strong bacteriostatic action against Staphylococci and E. coli. The leaves have strong astringent properties.
Bearberry is relatively safe, though large doses may cause nausea, green urine, bluish-grey skin, vomiting, fever, chills, severe back pain, ringing in the ears (some people can withstand up to 20g and others show signs of poisoning after just 1g); take no more than 7-10 days at a time.
It should not be used by people who are pregnant, breast feeding, nor in the treatment of children (under 12) and patients with kidney disease. Drug interactions have been recorded with diuretics, as well as drugs that make the urine acidic (such as ascorbic acid and Urex).
## History and Folklore
Bearberry was first documented in The Physicians of Myddfai, a 13th century Welsh herbal, it was also described by Clusius in 1601, and recommended for medicinal use in 1763 by Gerhard and others. Often called uva-ursi, from the Latin uva, "grape, berry of the vine", ursi, "bear", i.e. "bear's grape". It first appeared in the London Pharmacopoeia in 1788, though it probably was in use long before.
In Strathnairn, Scotland there is a hill, known in English as Brin Mains, but which is known in Scottish Gaelic as "Cnoc nan Cnàimhseag" which means "The hill of the Bearberries".
Marco Polo reported in 13th century that the Chinese were using it as a diuretic, to treat kidney and urinary problems. Bearberry leaves are used still used medicinally in Poland and other countries.
Native Americans used it with tobacco and other herbs in religious ceremonies; used as a smudge (type of incense) or smoked in a sacred pipe, it carried the smoker's prayers to the Great Spirit. When mixed with tobacco, it was referred to as Kinnikinnick, from the Algonquian for "mixture". Native Americans also used Bearberry tea to treat inflammation of the urinary tract, urethritis, kidney stones, and cystitis. The Cheyenne used the tea to treat back sprains. Some Native American tribes powdered the leaves and applied them to sores. Other tribes drank it to treat venereal diseases. The berries were also made into a tea that was used to ward off obesity. Early European settlers in the Americas used the leaves taken internally as an astringent to treat nephritis, kidney stones and other diseases of the urinary system. | Bearberry
Bearberries are three species of dwarf shrubs in the genus Arctostaphylos. Unlike the other species of Arctostaphylos (see Manzanita), they are adapted to arctic and sub-arctic climates, and have a circumpolar distribution in northern North America, Asia and Europe, one with a small highly disjunct population in Central America.
# Species
The name bearberry derives from the edible fruit, said to be greatly enjoyed by bears. The fruit, also called bearberries, are edible and sometimes gathered for food. The leaves of the plant are used in herbal medicine.
- Alpine Bearberry - A. alpina (L.) Spreng (syn. Arctous alpinus (L.) Niedenzu). A procumbent shrub 10-30 cm high. Leaves not winter green, but dead leaves persist on stems for several years. Berries dark purple to black. Distribution: circumpolar, at high latitudes, from Scotland east across Scandinavia, Russia, Alaska, Canada and Greenland; southern limits in Europe in the Pyrenees and the Alps, in Asia to the Altay Mountains, and in North America to British Columbia in the west, and Maine and New Hampshire in the United States in the east.
- Red Bearberry - A. rubra (Rehd. & Wilson) Fernald (syn. Arctous rubra (Rehder and E.H. Wilson) Nakai; Arctous alpinus var. ruber Rehd. and Wilson). A procumbent shrub 10-30 cm high. Leaves deciduous, falling in autumn to leave bare stems. Berries red. Distribution: in the mountains of Sichuan, southwestern China north and east to eastern Siberia, Alaska and northern Canada east to northern Quebec.
- Common Bearberry - A. uva-ursi (L.) Spreng.
Other recorded old English common names include Arberry, Bear's Grape, Crowberry, Foxberry, Hog Cranberry, Kinnikinnick, Mealberry, Mountain Box, Mountain Cranberry, Mountain Tobacco, Red Bearberry, Sandberry, Upland Cranberry, Uva-ursi.
## Medicinal Uses
The plant contains arbutin, methylarbutin, a bitter principle, ursolic acid, tannic acid, gallic acid, some essential oil and resin, hydroquinones (mainly arbutin, up to 17%), tannins (up to 15%), phenolic glycosides and flavonoids.
The leaves are picked any time during the summer and dried for use in infusions, liquid extracts, medicinal tea bags and tablets. The plant has the following claimed properties: anti-lithic, aromatic, astringent, disinfectant, diuretic, lithontripic, sedative (renal), stimulant (mild), tonic, urinary antiseptic. It has been used to treat arthritis, back pain (lower), bed wetting, bile problems, bladder infections, bloating, bright's disease, bronchitis, cararrh of the bladder, cystitis, diabetes (by removing excessive sugar from the blood), diarrhea, fevers, fluid retention, gallstones, gonorrhea, headache (smoked), haemorrhoids, indigestion, kidney stones, kidney infections, liver problems, lung congestion, excessive menstration, nephritis, obesity, pancreatis, prostate gland weakness, rheumatism, chronic urethritis, vaginal discharge, vaginal diseases, and water retention[citation needed].
It is claimed to strengthen the heart muscle and urinary tract, return the womb to its normal size after childbirth, and prevents uteral infection. It is also claimed to be a powerful tonic for the sphincter muscle of the bladder so it helps with bladder control problems. It has a strong bacteriostatic action against Staphylococci and E. coli. The leaves have strong astringent properties.
Bearberry is relatively safe, though large doses may cause nausea, green urine, bluish-grey skin, vomiting, fever, chills, severe back pain, ringing in the ears (some people can withstand up to 20g and others show signs of poisoning after just 1g); take no more than 7-10 days at a time.
It should not be used by people who are pregnant, breast feeding, nor in the treatment of children (under 12) and patients with kidney disease. Drug interactions have been recorded with diuretics, as well as drugs that make the urine acidic (such as ascorbic acid and Urex).
## History and Folklore
Bearberry was first documented in The Physicians of Myddfai, a 13th century Welsh herbal, it was also described by Clusius in 1601, and recommended for medicinal use in 1763 by Gerhard and others. Often called uva-ursi, from the Latin uva, "grape, berry of the vine", ursi, "bear", i.e. "bear's grape". It first appeared in the London Pharmacopoeia in 1788, though it probably was in use long before.
In Strathnairn, Scotland there is a hill, known in English as Brin Mains, but which is known in Scottish Gaelic as "Cnoc nan Cnàimhseag" which means "The hill of the Bearberries".
Marco Polo reported in 13th century that the Chinese were using it as a diuretic, to treat kidney and urinary problems. Bearberry leaves are used still used medicinally in Poland and other countries.
Native Americans used it with tobacco and other herbs in religious ceremonies; used as a smudge (type of incense) or smoked in a sacred pipe, it carried the smoker's prayers to the Great Spirit. When mixed with tobacco, it was referred to as Kinnikinnick, from the Algonquian for "mixture". Native Americans also used Bearberry tea to treat inflammation of the urinary tract, urethritis, kidney stones, and cystitis. The Cheyenne used the tea to treat back sprains. Some Native American tribes powdered the leaves and applied them to sores. Other tribes drank it to treat venereal diseases. The berries were also made into a tea that was used to ward off obesity. Early European settlers in the Americas used the leaves taken internally as an astringent to treat nephritis, kidney stones and other diseases of the urinary system. | https://www.wikidoc.org/index.php/Bearberry | |
1f0c390e58e2529b7540021d33c46607f37433fc | wikidoc | Cosmetics | Cosmetics
Cosmetics (Template:Audio) are substances used to enhance or protect the appearance or odor of the human body. Cosmetics include skin-care creams, lotions, powders, perfumes, lipsticks, fingernail and toenail polishes, eye and facial makeup, permanent waves, colored contact lenses, hair colors, hair sprays and gels, deodorants, baby products, bath oils, bubble baths, bath salts, butters and many other types of products. Their use is widespread, especially among women in Western countries. A subset of cosmetics is called "make-up," which refers primarily to colored products intended to alter the user’s appearance. Many manufacturers distinguish between decorative cosmetics and care cosmetics.
The manufacture of cosmetics is currently dominated by a small number of multinational corporations that originated in the early 20th century, but the distribution and sale of cosmetics is spread among a wide range of different businesses. The U.S. FDA which regulates cosmetics in the United States defines cosmetics as: "intended to be applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance without affecting the body's structure or functions." This broad definition includes, as well, any material intended for use as a component of a cosmetic product. The FDA specifically excludes soap from this category.
# History
The first archaeological evidence of cosmetics usage is found in Ancient Egypt around 4000 BC. The Ancient Greeks and Romans also used cosmetics. The Romans and Ancient Egyptians used cosmetics containing poisonous mercury and often lead. The ancient kingdom of Israel was influenced by cosmetics as recorded in the Old Testament—2 Kings 9:30 where Jezebel painted her eyes—approximately 840 BC. The Biblical book of Esther describes various beauty treatments as well.
In the western world, the advent of cosmetics was in the middle ages, although typically restricted to use within the upper classes.
Cosmetic use was frowned upon at some points in history. For example, in the 1800s, make-up was used primarily by prostitutes, and Queen Victoria publicly declared makeup improper, vulgar, and acceptable only for use by actors. Adolf Hitler told women that face painting was for clowns and not for the women of the Master Race.
By the middle of the 20th century, cosmetics were in widespread use in nearly all societies around the world.
Cosmetics have been in use for thousands of years. They also attached silk or leather with adhesive to cover a blemish. The absence of regulation of the manufacture and use of cosmetics has led to negative side effects, deformities, blindness, and even death through the ages. Examples of this were the prevalent use of ceruse(white lead), to cover the face during the Renaissance, and blindness caused by the mascara Lash Lure during the early 1900s.
# Industry Today
The worldwide annual expenditures for cosmetics is estimated at U.S. $18 billion. Of the major firms, the oldest and the largest is L'Oréal, which was founded by Eugene Schueller in 1909 as the French Harmless Hair Colouring Company (now owned by Liliane Bettencourt 26% and Nestlé 28%, with the remaining 46% are publicly traded). The market was developed in the USA during the 1910s by Elizabeth Arden, Helena Rubinstein, and Max Factor. These firms were joined by Revlon just before World War II and Estée Lauder just after.
Like most industry, cosmetic companies resist regulation by government agencies like the FDA, and have lobbied against this throughout the years.
# Criticism and controversy
During the 20th century, the popularity of cosmetics increased rapidly. Especially in the United States, cosmetics are used by girls at an increasingly young age. Many companies have catered to this expanding market by introducing more flavored lipsticks and glosses, cosmetics packaged in glittery, sparkly packaging and marketing and advertising using young models. The social consequences of younger and younger beautification has had much attention in the media over the last few years.
Criticism of cosmetics has come from a variety of sources, including feminists, animal rights activists, authors and public interest groups. There is a growing awareness and preference for cosmetics that are without any toxic ingredients, especially those derived from petroleum, sodium lauryl sulfate (SLS), and parabens.
Numerous published reports have raised concern over the safety of a few surfactants. SLS causes a number of skin issues including dermatitis.
Parabens can cause skin irritation and contact dermatitis in individuals with paraben allergies, a small percentage of the general population. Animal experiments have shown that parabens have a weak estrogenic activity, acting as xenoestrogens.
Prolonged use of makeup has also been linked to thinning eyelashes.
Synthetic fragrances are widely used in consumer products. Studies concluded from patch testing show synthetic fragrances are made of many ingredients which cause allergic reactions.
# Makeup Types
- Lipstick, lip gloss, lip liner, lip plumper, lip balm, lip volume, lip luster, lip conditioner and lip boosters.
- Foundation, used to color the face and conceal flaws to produce an impression of health and youth. Usually a liquid, cream, powder or mousse.
- Powder, used to set the foundation, giving a matte finish.
- Rouge, blush or blusher, cheek stain used to color the cheeks and emphasize the cheekbones. This comes in powder, cream and gel forms.
- Bronzer, used to create a more tan look to the skin.
- Mascara and lash extender, lash conditioner used to enhance the eyelashes. Can be of different colors and even waterproof.
- Eye liner and eye shadow, eye shimmer and glitter eye pencils as well as different color pencils used to color and emphasize the eyelids (larger eyes are a sign of youth).
- Eyebrow pencils, creams, waxes, gels and powders are used to fill in and define the brows.
- Nail polish, used to color the fingernails and toenails.
- Concealer, a type of thick opaque makeup used to cover pimples, various spots and inconsistencies in the skin.
Also included in the general category of cosmetics are skin care products. These include creams and lotions to moisturize the face and body, sunscreens to protect the skin from damaging UV radiation, and treatment products to repair or hide skin imperfections (acne, wrinkles, dark circles under eyes, etc.).
Cosmetics can also be described by the form of the product, as well as the area for application.
Cosmetics can be liquid or cream emulsions; powders, both pressed and loose; dispersions; and anhydrous creams or sticks.
# Special Effects
In addition to over-the-counter cosmetic products, recent years have seen an increasing market for prescription or surgical cosmetic procedures. These range from temporary enhancements, such as cosmetic colored contact lenses, to major cosmetic surgery.
To temporary fashionable enhancement belongs application of false eyelashes or eyelash extensions, in order to enhance the natural eyelashes and make eye appearance more attractive.
Many techniques, such as microdermabrasion and physical or chemical peels, remove the oldest, top layers of skin cells. The younger layers of skin left behind appear more plump, youthful, and soft. Permanent application of pigments (tattooing) is also used cosmetically.
# Ingredients
While there is assurance from the largest cosmetic companies that their various ingredients are safe to use, there is a growing preference for cosmetics that are without any "synthetic" ingredients, especially those derived from petroleum. Once a niche market, certified organic products are becoming more mainstream.
Ingredients' listings in cosmetics are highly regulated in many countries. The testing of cosmetic products on animals is a subject of some controversy. It is now illegal in the United Kingdom, the Netherlands, and Belgium, and a ban across the European Union is due to come into effect in 2009.
Organic and Natural Ingredients
Even though many products in cosmetics are regulated, there are many health concerns that come from harmful chemicals in these products. Some products carry carcinogenic contaminant 1,4- dioxane. Not all organic products are better but they don't carry harmful preservatives that could be harmful. Many cosmetic companies are coming out with "All natural" and "Organic" products. All natural products contain mineral and plant ingredients and organic products are made with agricultural products, grown with out pesticides. Products who claim they are organic are not, unless they are certified "USDA Organic." | Cosmetics
Template:Otheruses3
Cosmetics (Template:Audio) are substances used to enhance or protect the appearance or odor of the human body. Cosmetics include skin-care creams, lotions, powders, perfumes, lipsticks, fingernail and toenail polishes, eye and facial makeup, permanent waves, colored contact lenses, hair colors, hair sprays and gels, deodorants, baby products, bath oils, bubble baths, bath salts, butters and many other types of products. Their use is widespread, especially among women in Western countries. A subset of cosmetics is called "make-up," which refers primarily to colored products intended to alter the user’s appearance. Many manufacturers distinguish between decorative cosmetics and care cosmetics.
The manufacture of cosmetics is currently dominated by a small number of multinational corporations that originated in the early 20th century, but the distribution and sale of cosmetics is spread among a wide range of different businesses. The U.S. FDA which regulates cosmetics in the United States[1] defines cosmetics as: "intended to be applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance without affecting the body's structure or functions." This broad definition includes, as well, any material intended for use as a component of a cosmetic product. The FDA specifically excludes soap from this category.[2]
# History
The first archaeological evidence of cosmetics usage is found in Ancient Egypt around 4000 BC.[citation needed] The Ancient Greeks and Romans also used cosmetics. The Romans and Ancient Egyptians used cosmetics containing poisonous mercury and often lead. The ancient kingdom of Israel was influenced by cosmetics as recorded in the Old Testament—2 Kings 9:30 where Jezebel painted her eyes—approximately 840 BC. The Biblical book of Esther describes various beauty treatments as well.
In the western world, the advent of cosmetics was in the middle ages, although typically restricted to use within the upper classes.
Cosmetic use was frowned upon at some points in history. For example, in the 1800s, make-up was used primarily by prostitutes, and Queen Victoria publicly declared makeup improper, vulgar, and acceptable only for use by actors.[3] Adolf Hitler told women that face painting was for clowns and not for the women of the Master Race.[citation needed]
By the middle of the 20th century, cosmetics were in widespread use in nearly all societies around the world.
Cosmetics have been in use for thousands of years. They also attached silk or leather with adhesive to cover a blemish. The absence of regulation of the manufacture and use of cosmetics has led to negative side effects, deformities, blindness, and even death through the ages. Examples of this were the prevalent use of ceruse(white lead), to cover the face during the Renaissance, and blindness caused by the mascara Lash Lure during the early 1900s.
# Industry Today
The worldwide annual expenditures for cosmetics is estimated at U.S. $18 billion.[4] Of the major firms, the oldest and the largest is L'Oréal, which was founded by Eugene Schueller in 1909 as the French Harmless Hair Colouring Company (now owned by Liliane Bettencourt 26% and Nestlé 28%, with the remaining 46% are publicly traded). The market was developed in the USA during the 1910s by Elizabeth Arden, Helena Rubinstein, and Max Factor. These firms were joined by Revlon just before World War II and Estée Lauder just after.
Like most industry, cosmetic companies resist regulation by government agencies like the FDA, and have lobbied against this throughout the years.
# Criticism and controversy
During the 20th century, the popularity of cosmetics increased rapidly. Especially in the United States, cosmetics are used by girls at an increasingly young age. Many companies have catered to this expanding market by introducing more flavored lipsticks and glosses, cosmetics packaged in glittery, sparkly packaging and marketing and advertising using young models. The social consequences of younger and younger beautification has had much attention in the media over the last few years.
Criticism of cosmetics has come from a variety of sources, including feminists, animal rights activists, authors and public interest groups. There is a growing awareness and preference for cosmetics that are without any toxic ingredients, especially those derived from petroleum, sodium lauryl sulfate (SLS), and parabens.[5]
Numerous published reports have raised concern over the safety of a few surfactants. SLS causes a number of skin issues including dermatitis.[6][7][8][9][10]
Parabens can cause skin irritation and contact dermatitis in individuals with paraben allergies, a small percentage of the general population.[11] Animal experiments have shown that parabens have a weak estrogenic activity, acting as xenoestrogens.[12]
Prolonged use of makeup has also been linked to thinning eyelashes.[13]
Synthetic fragrances are widely used in consumer products. Studies concluded from patch testing show synthetic fragrances are made of many ingredients which cause allergic reactions.[14]
# Makeup Types
- Lipstick, lip gloss, lip liner, lip plumper, lip balm, lip volume, lip luster, lip conditioner and lip boosters.[1]
- Foundation, used to color the face and conceal flaws to produce an impression of health and youth. Usually a liquid, cream, powder or mousse.[1]
- Powder, used to set the foundation, giving a matte finish.
- Rouge, blush or blusher, cheek stain used to color the cheeks and emphasize the cheekbones. This comes in powder, cream and gel forms.[1]
- Bronzer, used to create a more tan look to the skin.[1]
- Mascara and lash extender, lash conditioner used to enhance the eyelashes. Can be of different colors and even waterproof. [1]
- Eye liner and eye shadow, eye shimmer and glitter eye pencils as well as different color pencils used to color and emphasize the eyelids (larger eyes are a sign of youth).[1]
- Eyebrow pencils, creams, waxes, gels and powders are used to fill in and define the brows.[1]
- Nail polish, used to color the fingernails and toenails.[1]
- Concealer, a type of thick opaque makeup used to cover pimples, various spots and inconsistencies in the skin.[1]
Also included in the general category of cosmetics are skin care products. These include creams and lotions to moisturize the face and body, sunscreens to protect the skin from damaging UV radiation, and treatment products to repair or hide skin imperfections (acne, wrinkles, dark circles under eyes, etc.).
Cosmetics can also be described by the form of the product, as well as the area for application.
Cosmetics can be liquid or cream emulsions; powders, both pressed and loose; dispersions; and anhydrous creams or sticks.
# Special Effects
In addition to over-the-counter cosmetic products, recent years have seen an increasing market for prescription or surgical cosmetic procedures. These range from temporary enhancements, such as cosmetic colored contact lenses, to major cosmetic surgery.
To temporary fashionable enhancement belongs application of false eyelashes or eyelash extensions, in order to enhance the natural eyelashes and make eye appearance more attractive.
Many techniques, such as microdermabrasion and physical or chemical peels, remove the oldest, top layers of skin cells. The younger layers of skin left behind appear more plump, youthful, and soft. Permanent application of pigments (tattooing) is also used cosmetically.
# Ingredients
While there is assurance from the largest cosmetic companies that their various ingredients are safe to use, there is a growing preference for cosmetics that are without any "synthetic" ingredients, especially those derived from petroleum. Once a niche market, certified organic products are becoming more mainstream.
Ingredients' listings in cosmetics are highly regulated in many countries. The testing of cosmetic products on animals is a subject of some controversy. It is now illegal in the United Kingdom, the Netherlands, and Belgium, and a ban across the European Union is due to come into effect in 2009.
Organic and Natural Ingredients
Even though many products in cosmetics are regulated, there are many health concerns that come from harmful chemicals in these products. Some products carry carcinogenic contaminant 1,4- dioxane. Not all organic products are better but they don't carry harmful preservatives that could be harmful. Many cosmetic companies are coming out with "All natural" and "Organic" products. All natural products contain mineral and plant ingredients and organic products are made with agricultural products, grown with out pesticides. Products who claim they are organic are not, unless they are certified "USDA Organic." [15] | https://www.wikidoc.org/index.php/Beauty | |
82ddb7e134f4c1de3545855bc346c7fc057adc07 | wikidoc | Beclamide | Beclamide
Beclamide (marketed as Chloracon, Hibicon, Posedrine, Nydrane, Seclar, and other names) is a propionate and was used as a sedative and as an anticonvulsant.
Side effects are uncommon but include stomach pain, nervousness, giddiness, skin rash and leukopenia. It is counter-indicated in breast feeding as it is passed in the milk.
Administration is oral, though it has an unpleasant taste. It is quickly absorbed and elimination is renal and complete within 48 hours.
It was studied in the 1950s for its anticonvulsant properties, as a treatment for generalised tonic-clonic seizures. It was not effective for absence seizures. It is no longer used as an AED. Interest in the drug resumed in the 1990s for its psychiatric properties as an adjunct in the treatment of schizophrenia. | Beclamide
Beclamide (marketed as Chloracon, Hibicon, Posedrine, Nydrane, Seclar, and other names) is a propionate and was used as a sedative and as an anticonvulsant.
Side effects are uncommon but include stomach pain, nervousness, giddiness, skin rash and leukopenia. It is counter-indicated in breast feeding as it is passed in the milk.
Administration is oral, though it has an unpleasant taste. It is quickly absorbed and elimination is renal and complete within 48 hours.
It was studied in the 1950s for its anticonvulsant properties, as a treatment for generalised tonic-clonic seizures. It was not effective for absence seizures. It is no longer used as an AED. Interest in the drug resumed in the 1990s for its psychiatric properties as an adjunct in the treatment of schizophrenia. | https://www.wikidoc.org/index.php/Beclamide | |
64bd12a2253f4fd3d1d6fc95430bfbaebb2c31bf | wikidoc | Bee sting | Bee sting
A bee sting strictly means a sting from a bee (honeybee, bumblebee, sweat bee etc). In the vernacular it can mean a sting of a bee, wasp, hornet, yellowjacket or sawfly. Some people may even call the bite of a horsefly a bee sting. It is important to differentiate a bee sting from an insect bite. It is also important to recognize that the venom or toxin of stinging insects is quite different. Therefore, the body's reaction to a bee sting may differ significantly from one species to another.
The most aggressive stinging insects are wasps (including bald-faced hornets) but not in general hornets (the European hornet is gentle). All of these insects aggressively defend their nests, although they have not developed a sting targeted at mammals like the honeybees.
In people who are allergic to bee stings, a sting may trigger a dangerous anaphylactic reaction that is potentially deadly.
# Honeybee stings
A honeybee that is away from the hive foraging for nectar or pollen will rarely sting, except when stepped on or roughly handled. Honeybees will actively seek out and sting when they perceive the hive to be threatened, often being alerted to this by the release of attack pheromones (below).
Although it is widely believed that a worker honeybee can sting only once, this is a misconception: although the stinger is in fact barbed so that it lodges in the victim's skin, tearing loose from the bee's abdomen and leading to its death in minutes, this only happens if the victim is a mammal (or bird). The bee's stinger evolved originally for inter-bee combat between members of different hives, and the barbs evolved later as an anti-mammal defense: a barbed stinger can still penetrate the chitinous plates of another bee's exoskeleton and retract safely. Honeybees are the only hymenoptera with a barbed stinger.
The stinger's injection of apitoxin into the victim is accompanied by the release of alarm pheromones, a process which is accelerated if the bee is fatally injured. Release of alarm pheromones near a hive or swarm may attract other bees to the location, where they will likewise exhibit defensive behaviors until there is no longer a threat (typically because the victim has either fled or been killed). These pheromones do not dissipate nor wash off quickly, and if their target enters water, bees will resume their attack as soon as the target leaves.
(Alarm pheromones have been characterized as having a "dirty socks" smell, which is why amateur beekeepers will often bathe and change into clean clothes before working a hive.)
The larger drone bees do not have stingers. In worker bees, the stinger is a modified ovipositor. The queen bee has a smooth stinger and can, if need be, sting skin-bearing creatures multiple times, but the queen does not leave the hive under normal conditions. Her stinger is not for defense of the hive; she only uses it for dispatching rival queens, ideally before they can finish pupating. Queen breeders who handle multiple queens and have the queen odor on their hands are sometimes stung by a queen.
The main component of bee venom responsible for pain in vertebrates is the toxin melittin; histamine and other biogenic amines may also contribute to pain and itching. In one of the medical uses of honeybee products, apitherapy, bee venom has been used to treat arthritis and other painful conditions.
- Bee sting. The stinger is tearing off and remains in the skin
Bee sting. The stinger is tearing off and remains in the skin
- 2 minutes later
2 minutes later
- 6 minutes later
6 minutes later
- 27 minutes later
27 minutes later
# Treatment
Following a honeybee sting the first step in treatment is removal of the barbed stinger. The stinger should be removed as fast as possible without regard to method: studies have shown the amount of venom delivered does not differ if the stinger is pinched or scraped off and even a delay of a few seconds leads to more venom being injected. Once the stinger is removed, reduce pain and swelling with a cold compress.
Many traditional remedies have been suggested for bee stings including damp pastes of tobacco, salt, baking soda, meat tenderizer, toothpaste, clay, aspirin or even application of copper coins. Bee venom is acidic and these interventions are often recommended to neutralize the venom; however, neutralizing a sting is unlikely to be effective as the venom is injected under the skin and deep into the tissues, where a topically applied alkali is unable to reach, so neutralization is unlikely to occur. In any case, the amount of venom injected is typically very small (between 5 and 50 micrograms of fluid) and placing large amounts of alkali near the sting site is unlikely to produce a perfectly neutral pH to stop the sting hurting. Many people do claim benefit from these home remedies but it is doubtful they have any real physical effect on how much a sting hurts or continues hurting, the effect is probably related to rubbing the area or the mind perceiving benefit. Furthermore, none of these interventions have been proven to be effective in scientific studies and a randomized trial of aspirin paste and topical ice packs showed that aspirin was not effective in reducing the duration of swelling or pain in bee and wasp stings, and significantly increased the duration of redness. The study concluded that ice alone is better treatment for bee and wasp stings than aspirin.
The sting may be painful for a few hours. Swelling and itching may persist for a week. Do not scratch the area as that will only increase the itching and swelling. If a reaction persists for over a week or covers an area greater than 3 or 4 inches, seek medical attention. Also, doctors may recommend a tetanus immunization. For about 2 percent of people, anaphylactic shock from certain proteins in the venom can be life-threatening and requires emergency treatment by a physician. If the victim is allergic to bee stings, the victim must be treated to prevent shock. People known to be highly allergic may carry around epinephrine in the form of a self-injectable Epipen for the treatment of an anaphylactic shock.
For patients who experience severe or life threatening reactions to insect stings, researchers at Johns Hopkins have developed a series of allergy injections composed of increasing concentrations of naturally occurring venom which provide excellent and usually life-long protections against future insect stings. | Bee sting
A bee sting strictly means a sting from a bee (honeybee, bumblebee, sweat bee etc). In the vernacular it can mean a sting of a bee, wasp, hornet, yellowjacket or sawfly. Some people may even call the bite of a horsefly a bee sting. It is important to differentiate a bee sting from an insect bite. It is also important to recognize that the venom or toxin of stinging insects is quite different. Therefore, the body's reaction to a bee sting may differ significantly from one species to another.
The most aggressive stinging insects are wasps (including bald-faced hornets) but not in general hornets (the European hornet is gentle). All of these insects aggressively defend their nests, although they have not developed a sting targeted at mammals like the honeybees.
In people who are allergic to bee stings, a sting may trigger a dangerous anaphylactic reaction that is potentially deadly.
# Honeybee stings
A honeybee that is away from the hive foraging for nectar or pollen will rarely sting, except when stepped on or roughly handled. Honeybees will actively seek out and sting when they perceive the hive to be threatened, often being alerted to this by the release of attack pheromones (below).
Although it is widely believed that a worker honeybee can sting only once, this is a misconception: although the stinger is in fact barbed so that it lodges in the victim's skin, tearing loose from the bee's abdomen and leading to its death in minutes, this only happens if the victim is a mammal (or bird). The bee's stinger evolved originally for inter-bee combat between members of different hives, and the barbs evolved later as an anti-mammal defense: a barbed stinger can still penetrate the chitinous plates of another bee's exoskeleton and retract safely. Honeybees are the only hymenoptera with a barbed stinger.
The stinger's injection of apitoxin into the victim is accompanied by the release of alarm pheromones, a process which is accelerated if the bee is fatally injured. Release of alarm pheromones near a hive or swarm may attract other bees to the location, where they will likewise exhibit defensive behaviors until there is no longer a threat (typically because the victim has either fled or been killed). These pheromones do not dissipate nor wash off quickly, and if their target enters water, bees will resume their attack as soon as the target leaves.
(Alarm pheromones have been characterized as having a "dirty socks" smell, which is why amateur beekeepers will often bathe and change into clean clothes before working a hive.)[citation needed]
The larger drone bees do not have stingers. In worker bees, the stinger is a modified ovipositor. The queen bee has a smooth stinger and can, if need be, sting skin-bearing creatures multiple times, but the queen does not leave the hive under normal conditions. Her stinger is not for defense of the hive; she only uses it for dispatching rival queens, ideally before they can finish pupating. Queen breeders who handle multiple queens and have the queen odor on their hands are sometimes stung by a queen.
The main component of bee venom responsible for pain in vertebrates is the toxin melittin; histamine and other biogenic amines may also contribute to pain and itching.[1] In one of the medical uses of honeybee products, apitherapy, bee venom has been used to treat arthritis and other painful conditions.[2]
- Bee sting. The stinger is tearing off and remains in the skin
Bee sting. The stinger is tearing off and remains in the skin
- 2 minutes later
2 minutes later
- 6 minutes later
6 minutes later
- 27 minutes later
27 minutes later
# Treatment
Following a honeybee sting the first step in treatment is removal of the barbed stinger. The stinger should be removed as fast as possible without regard to method: studies have shown the amount of venom delivered does not differ if the stinger is pinched or scraped off and even a delay of a few seconds leads to more venom being injected.[3] Once the stinger is removed, reduce pain and swelling with a cold compress.[4]
Many traditional remedies have been suggested for bee stings including damp pastes of tobacco, salt, baking soda, meat tenderizer, toothpaste, clay, aspirin or even application of copper coins.[5][6] Bee venom is acidic and these interventions are often recommended to neutralize the venom; however, neutralizing a sting is unlikely to be effective as the venom is injected under the skin and deep into the tissues, where a topically applied alkali is unable to reach, so neutralization is unlikely to occur.[5] In any case, the amount of venom injected is typically very small (between 5 and 50 micrograms of fluid) and placing large amounts of alkali near the sting site is unlikely to produce a perfectly neutral pH to stop the sting hurting.[5] Many people do claim benefit from these home remedies but it is doubtful they have any real physical effect on how much a sting hurts or continues hurting, the effect is probably related to rubbing the area or the mind perceiving benefit.[5] Furthermore, none of these interventions have been proven to be effective in scientific studies and a randomized trial of aspirin paste and topical ice packs showed that aspirin was not effective in reducing the duration of swelling or pain in bee and wasp stings, and significantly increased the duration of redness.[4] The study concluded that ice alone is better treatment for bee and wasp stings than aspirin.[4]
The sting may be painful for a few hours. Swelling and itching may persist for a week. Do not scratch the area as that will only increase the itching and swelling. If a reaction persists for over a week or covers an area greater than 3 or 4 inches, seek medical attention. Also, doctors may recommend a tetanus immunization. For about 2 percent of people, anaphylactic shock from certain proteins in the venom can be life-threatening and requires emergency treatment by a physician.[7] If the victim is allergic to bee stings, the victim must be treated to prevent shock. People known to be highly allergic may carry around epinephrine in the form of a self-injectable Epipen for the treatment of an anaphylactic shock.
For patients who experience severe or life threatening reactions to insect stings, researchers at Johns Hopkins have developed a series of allergy injections composed of increasing concentrations of naturally occurring venom which provide excellent and usually life-long protections against future insect stings. [8] | https://www.wikidoc.org/index.php/Bee_sting | |
8921362b1cc34473cdbd72f1e8a582cd47386c0a | wikidoc | Belimumab | Belimumab
# Disclaimer
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# Overview
Belimumab is a monoclonal antibody that is FDA approved for the treatment of active autoantibody-positive systemic lupus erythematosus. Common adverse reactions include Diarrhea, nausea, infectious disease, infusion reaction, nasopharyngitis, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Systemic Lupus Erythematosus
- For the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.
- Recommended dosage regimen is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter.
- Prior to dosing with belimumab, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions.
- Reconstitute, dilute, and administer as an intravenous infusion only, over a period of 1 hour.
- The infusion rate may be slowed or interrupted if the patient develops an infusion reaction.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Belimumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Belimumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Belimumab 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 Belimumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Belimumab in pediatric patients.
# Contraindications
- Belimumab is contraindicated in patients who have had anaphylaxis with belimumab.
# Warnings
### Mortality
- There were more deaths reported with belimumab than with placebo during the controlled period of the clinical trials.
- Out of 2,133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the groups receiving placebo, belimumab 1 mg/kg, belimumab 4 mg/kg, and belimumab 10 mg/kg, respectively.
- No single cause of death predominated.
- Etiologies included infection, cardiovascular disease, and suicide.
### Serious Infections
- Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including belimumab.
- Physicians should exercise caution when considering the use of belimumab in patients with chronic infections.
- Patients receiving any therapy for chronic infection should not begin therapy with belimumab.
- Consider interrupting therapy with belimumab in patients who develop a new infection while undergoing treatment with belimumab and monitor these patients closely.
- In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with belimumab compared with 67% in patients who received placebo.
- The most frequent infections (>5% of patients receiving belimumab) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with belimumab and in 5.2% of patients who received placebo.
- The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.
- Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving belimumab and 1.0% of patients receiving placebo.
- Infections resulting in death occurred in 0.3% (4/1,458) of patients treated with belimumab and in 0.1% (1/675) of patients receiving placebo.
Progressive Multifocal Leukoencephalopathy (PML):
- Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including belimumab.
- Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function.
- Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated.
- In patients with confirmed PML, consider stopping immunosuppressant therapy, including belimumab.
### Malignancy
- The impact of treatment with belimumab on the development of malignancies is not known.
- In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving belimumab and 0.4% of patients receiving placebo.
- In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1,458) and 0.3% (2/675) of patients receiving belimumab and placebo, respectively.
- The mechanism of action of belimumab could increase the risk for the development of malignancies.
### Hypersensitivity Reactions, including Anaphylaxis
- Acute hypersensitivity reactions, including anaphylaxis and death, have been reported in association with belimumab.
- These events generally occurred within hours of the infusion; however, they may occur later.
- Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema, have been reported and typically occurred up to a week following the most recent infusion.
- Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of belimumab.
- Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of patients receiving belimumab and 11% (76/675) of patients receiving placebo.
- Anaphylaxis was observed in 0.6% (9/1,458) of patients receiving belimumab and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea.
- Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases.
- Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.
- Belimumab should be administered by healthcare providers prepared to manage anaphylaxis.
- In the event of a serious reaction, administration of belimumab must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of belimumab.
- Patients should be informed of the signs and symptoms of an acute hypersensitivity reaction and be instructed to seek immediate medical care should a reaction occur.
### Infusion Reactions
- In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of patients receiving belimumab and 15% (99/675) of patients receiving placebo.
- Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving belimumab and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension.
- The most common infusion reactions (≥3% of patients receiving belimumab) were headache, nausea, and skin reactions.
- Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases.
- Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions.
- Belimumab should be administered by healthcare providers prepared to manage infusion reactions.
- The infusion rate may be slowed or interrupted if the patient develops an infusion reaction.
- Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.
### Depression
- In the controlled clinical trials, psychiatric events were reported more frequently with belimumab (16%) than with placebo (12%), related primarily to depression-related events (6.3% belimumab and 4.7% placebo), insomnia (6.0% belimumab and 5.3% placebo), and anxiety (3.9% belimumab and 2.8% placebo).
- Serious psychiatric events were reported in 0.8% of patients receiving belimumab (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. *Serious depression was reported in 0.4% (6/1,458) of patients receiving belimumab and 0.1% (1/675) of patients receiving placebo.
- Two suicides (0.1%) were reported in patients receiving belimumab.
- The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications.
- It is unknown if treatment with belimumab is associated with increased risk for these events.
- Patients receiving belimumab should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.
### Immunization
- Live vaccines should not be given for 30 days before or concurrently with belimumab as clinical safety has not been established.
- No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving belimumab or the effect of belimumab on new immunizations.
- Because of its mechanism of action, belimumab may interfere with the response to immunizations.
### Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide
- Belimumab has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of belimumab is not recommended in combination with biologic therapies or intravenous cyclophosphamide.
# Adverse Reactions
## Clinical Trials Experience
The data described below reflect exposure to belimumab plus standard of care compared with placebo plus standard of care in 2,133 patients in 3 controlled trials. Patients received belimumab at doses of 1 mg/kg (N = 673), 4 mg/kg (N = 111; Trial 1 only), or 10 mg/kg (N = 674) or placebo (N = 675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In 2 of the trials (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other trial (Trial 2) treatment was given for 72 weeks. Because there was no apparent dose-related increase in the majority of adverse events observed with belimumab, the safety data summarized below are presented for the 3 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo.
The population had a mean age of 39 (range: 18 to 75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with belimumab reported an adverse reaction compared with 92% treated with placebo.
The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving belimumab and placebo, respectively).
The most commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.
The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving belimumab and 7.1% for patients receiving placebo. The most common adverse reactions resulting in discontinuation of treatment (≥1% of patients receiving belimumab or placebo) were infusion reactions (1.6% belimumab and 0.9% placebo), lupus nephritis (0.7% belimumab and 1.2% placebo), and infections (0.7% belimumab and 1.0% placebo).
TABLE 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received belimumab 10 mg/kg and at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies.
### Immunogenicity
In Trials 2 and 3, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving belimumab 10 mg/kg and in 27 of 559 (4.8%) patients receiving belimumab 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving belimumab 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known.
The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of belimumab. 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.
- Fatal anaphylaxis
# Drug Interactions
- Formal drug interaction studies have not been performed with belimumab.
- In clinical trials of patients with SLE, belimumab was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics.
- The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled clinical studies using belimumab in pregnant women. Immunoglobulin G (IgG) antibodies, including belimumab, can cross the placenta. Because animal reproduction studies are not always predictive of human response, belimumab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with belimumab and for at least 4 months after the final treatment.
Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5, and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24%, and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8%, and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of immunoglobulin M (IgM) in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belimumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Belimumab during labor and delivery.
### Nursing Mothers
It is not known whether belimumab is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys. Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness of belimumab have not been established in children.
### Geriatic Use
Clinical studies of belimumab did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients
### Gender
There is no FDA guidance on the use of Belimumab with respect to specific gender populations.
### Race
In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects receiving belimumab relative to black subjects receiving placebo. Use with caution in black/African-American patients.
### Renal Impairment
There is no FDA guidance on the use of Belimumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Belimumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Belimumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Belimumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous infusion
- Belimumab should be administered by healthcare providers prepared to manage anaphylaxis.
- Belimumab should not be infused concomitantly in the same intravenous line with other agents.
- No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of belimumab with other agents.
- The reconstituted solution of belimumab, if not used immediately, should be stored protected from direct sunlight and refrigerated at 2° to 8°C (36° to 46°F).
- Solutions of belimumab diluted in normal saline may be stored at 2° to 8°C (36° to 46°F) or room temperature. The total time from reconstitution of belimumab to completion of infusion should not exceed 8 hours.
### Monitoring
- Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.
# IV Compatibility
Belimumab is provided as a lyophilized powder in a single-use vial for intravenous infusion only and should be reconstituted and diluted by a healthcare professional using aseptic technique as follows:
### Reconstitution Instructions
- Remove belimumab from the refrigerator and allow to stand 10 to 15 minutes for the vial to reach room temperature.
- Reconstitute the belimumab powder with Sterile Water for Injection, USP, as follows. The reconstituted solution will contain a concentration of 80 mg/mL belimumab.
- Reconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.
- Reconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP.
- The stream of sterile water should be directed toward the side of the vial to minimize foaming.
- Gently swirl the vial for 60 seconds.
- Allow the vial to sit at room temperature during reconstitution, gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved.
- Do not shake.
- Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes.
- Protect the reconstituted solution from sunlight.
- If a mechanical reconstitution device (swirler) is used to reconstitute belimumab, it should not exceed 500 rpm and the vial swirled for no longer than 30 minutes.
- Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow, and without particles.
- Small air bubbles, however, are expected and acceptable.
### Dilution Instructions
- Dextrose intravenous solutions are incompatible with belimumab.
- Belimumab should only be diluted in 0.9% Sodium Chloride Injection, USP.
- Dilute the reconstituted product to 250 mL in 0.9% Sodium Chloride Injection, USP (normal saline) for intravenous infusion.
- From a 250-mL infusion bag or bottle of normal saline, withdraw and discard a volume equal to the volume of the reconstituted solution of belimumab required for the patient’s dose. Then add the required volume of the reconstituted solution of belimumab into the infusion bag or bottle.
- Gently invert the bag or bottle to mix the solution. Any unused solution in the vials must be discarded.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Discard the solution if any particulate matter or discoloration is observed.
- The reconstituted solution of belimumab, if not used immediately, should be stored protected from direct sunlight and refrigerated at 2° to 8°C (36° to 46°F).
- Solutions of belimumab diluted in normal saline may be stored at 2° to 8°C (36° to 46°F) or room temperature.
- The total time from reconstitution of belimumab to completion of infusion should not exceed 8 hours.
- No incompatibilities between belimumab and polyvinylchloride or polyolefin bags have been observed.
# Overdosage
- There is no clinical experience with overdosage of belimumab.
- Two doses of up to 20 mg/kg have been given by intravenous infusion to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.
# Pharmacology
## Mechanism of Action
Belimumab is a BLyS-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.
## Structure
Belimumab is a human IgG1λ monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a molecular weight of approximately 147 kDa. Belimumab is produced by recombinant DNA technology in a mammalian cell expression system.
Belimumab is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for intravenous infusion. Upon reconstitution with Sterile Water for Injection, USP, each single-use vial delivers 80 mg/mL belimumab in 0.16 mg/mL citric acid, 0.4 mg/mL polysorbate 80, 2.7 mg/mL sodium citrate, and 80 mg/mL sucrose, with a pH of 6.5.
## Pharmacodynamics
In Trial 1 and Trial 2 in which B cells were measured, treatment with belimumab significantly reduced circulating CD19+, CD20+, naïve, and activated B cells, plasmacytoid cells, and the SLE B-cell subset at Week 52. Reductions in naïve and the SLE B-cell subset were observed as early as Week 8 and were sustained to Week 52. Memory cells increased initially and slowly declined toward baseline levels by Week 52. The clinical relevance of these effects on B cells has not been established.
Treatment with belimumab led to reductions in IgG and anti-dsDNA, and increases in complement (C3 and C4). These changes were observed as early as Week 8 and were sustained through Week 52. The clinical relevance of normalizing these biomarkers has not been definitively established.
## Pharmacokinetics
The pharmacokinetic parameters displayed in TABLE 2 are based on population parameter estimates which are specific to the 563 patients who received belimumab 10 mg/kg in Trials 2 and 3.
Drug Interactions: No formal drug interaction studies have been conducted with belimumab. Concomitant use of mycophenolate, azathioprine, methotrexate, antimalarials, NSAIDs, aspirin, and HMG-CoA reductase inhibitors did not significantly influence belimumab pharmacokinetics. Coadministration of steroids and angiotensin-converting enzyme (ACE) inhibitors resulted in an increase of systemic clearance of belimumab that was not clinically significant because the magnitude was well within the range of normal variability of clearance. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated.
Special Populations: The following information is based on the population pharmacokinetic analysis.
Age: Age did not significantly influence belimumab pharmacokinetics in the trial population, where the majority of subjects (70%) were aged between 18 and 45 years. No pharmacokinetic data are available in pediatric patients. Limited pharmacokinetic data are available for elderly patients as only 1.4% of the subjects included in the pharmacokinetic analysis were aged 65 years or older.
Gender: Gender did not significantly influence belimumab pharmacokinetics in the largely (94%) female trial population.
Race: Race did not significantly influence belimumab pharmacokinetics. The racial distribution was 53% white/Caucasian, 16% Asian, 16% Alaska native/American Indian, and 14% black/African-American.
Renal Impairment: No formal trials were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. Belimumab has been studied in a limited number of patients with SLE and renal impairment (261 subjects with moderate renal impairment, creatinine clearance ≥30 and 2 g/day) increased belimumab clearance, these effects were within the expected range of variability. Therefore, dosage adjustment in patients with renal impairment is not recommended.
Hepatic Impairment: No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Baseline ALT and AST levels did not significantly influence belimumab pharmacokinetics.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of belimumab. The mutagenic potential of belimumab was not evaluated.
Effects on male and female fertility have not been directly evaluated in animal studies.
# Clinical Studies
The safety and effectiveness of belimumab were evaluated in 3 randomized, double-blind, placebo-controlled trials involving 2,133 patients with SLE according to the American College of Rheumatology criteria (Trial 1, 2, and 3). Patients with severe active lupus nephritis and severe active CNS lupus were excluded. Patients were on a stable standard of care SLE treatment regimen comprising any of the following (alone or in combination): corticosteroids, antimalarials, NSAIDs, and immunosuppressives. Use of other biologics and intravenous cyclophosphamide were not permitted.
```Trial 1: belimumab 1 mg/kg, 4 mg/kg, 10 mg/kg
Trial 1 enrolled 449 patients and evaluated doses of 1, 4, and 10 mg/kg belimumab plus standard of care compared with placebo plus standard of care over 52 weeks in patients with SLE. Patients had to have a SELENA-SLEDAI score of ≥4 at baseline and a history of autoantibodies (anti-nuclear antibody and/or anti-double-stranded DNA ), but 28% of the population was autoantibody negative at baseline. The co-primary endpoints were percent change in SELENA-SLEDAI score at Week 24 and time to first flare over 52 weeks. No significant differences between any of the groups receiving belimumab and the group receiving placebo were observed. Exploratory analysis of this trial identified a subgroup of patients (72%), who were autoantibody positive, in whom belimumab appeared to offer benefit. The results of this trial informed the design of Trials 2 and 3 and led to the selection of a target population and indication that is limited to autoantibody-positive SLE patients.
Trials 2 and 3: belimumab 1 mg/kg and 10 mg/kg
Trials 2 and 3 were randomized, double-blind, placebo-controlled trials in patients with SLE that were similar in design except duration - Trial 2 was 76 weeks duration and Trial 3 was 52 weeks duration. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score ≥6, and positive autoantibody test results at screening. Patients were excluded from the trial if they had ever received treatment with a B-cell targeted agent or if they were currently receiving other biologic agents. Intravenous cyclophosphamide was not permitted within the previous 6 months or during the trial. Trial 2 was conducted primarily in North America and Europe. Trial 3 was conducted in South America, Eastern Europe, Asia, and Australia.
Baseline concomitant medications included corticosteroids (Trial 2: 76%, Trial 3: 96%), immunosuppressives (Trial 2: 56%, Trial 3: 42%; including azathioprine, methotrexate and mycophenolate), and antimalarials (Trial 2: 63%, Trial 3: 67%). Most patients (>70%) were receiving 2 or more classes of SLE medications.
In Trial 2 and Trial 3, more than 50% of patients had 3 or more active organ systems at baseline. The most common active organ systems at baseline based on SELENA-SLEDAI were mucocutaneous (82% in both trials); immune (Trial 2: 74%, Trial 3: 85%); and musculoskeletal (Trial 2: 73%, Trial 3: 59%). Less than 16% of patients had some degree of renal activity and less than 7% of patients had activity in the vascular, cardio-respiratory, or CNS systems.
At screening, patients were stratified by disease severity based on their SELENA-SLEDAI score (≤9 vs. ≥10), proteinuria level (<2 g/24 hr vs. ≥2 g/24 hr), and race (African or Indigenous-American descent vs. other), and then randomly assigned to receive belimumab 1 mg/kg, belimumab 10 mg/kg, or placebo in addition to standard of care. The patients were administered trial medication intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for 48 weeks in Trial 3 and for 72 weeks in Trial 2.
The primary efficacy endpoint was a composite endpoint (SLE Responder Index or SRI) that defined response as meeting each of the following criteria at Week 52 compared with baseline:
- ≥4-point reduction in the SELENA-SLEDAI score, and
- no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores, and
- no worsening (<0.30-point increase) in Physician’s Global Assessment (PGA) score.
The SRI uses the SELENA-SLEDAI score as an objective measure of reduction in global disease activity; the BILAG index to ensure no significant worsening in any specific organ system; and the PGA to ensure that improvements in disease activity are not accompanied by worsening of the patient’s condition overall.
In both Trials 2 and 3, the proportion of SLE patients achieving an SRI response, as defined for the primary endpoint, was significantly higher in the group receiving belimumab 10 mg/kg than in the group receiving placebo. The effect on the SRI was not consistently significantly different for patients receiving belimumab 1 mg/kg relative to placebo in both trials. The 1 mg/kg dose is not recommended. The trends in comparisons between the treatment groups for the rates of response for the individual components of the endpoint were generally consistent with that of the SRI (Table 3). At Week 76 in Trial 2, the SRI response rate with belimumab 10 mg/kg was not significantly different from that of placebo (39% and 32%, respectively).
The reduction in disease activity seen in the SRI was related primarily to improvement in the most commonly involved organ systems namely, mucocutaneous, musculoskeletal, and immune.
Effect in Black/African-American Patients: Exploratory sub-group analyses of SRI response rate in patients of black race were performed. In Trial 2 and Trial 3 combined, the SRI response rate in black patients (N = 148) in groups receiving belimumab was less than that in the group receiving placebo (22/50 or 44% for placebo, 15/48 or 31% for belimumab 1 mg/kg, and 18/50 or 36% for belimumab 10 mg/kg). In Trial 1, black patients (N = 106) in the groups receiving belimumab did not appear to have a different response than the rest of the trial population. Although no definitive conclusions can be drawn from these subgroup analyses, caution should be used when considering treatment with belimumab in black/African-American SLE patients.
Effect on Concomitant Steroid Treatment: In Trial 2 and Trial 3, 46% and 69% of patients, respectively, were receiving prednisone at doses >7.5 mg/day at baseline. The proportion of patients able to reduce their average prednisone dose by at least 25% to ≤7.5 mg/day during Weeks 40 through 52 was not consistently significantly different for belimumab relative to placebo in both trials. In Trial 2, 17% of patients receiving belimumab 10 mg/kg and 19% of patients receiving belimumab 1 mg/kg achieved this level of steroid reduction compared with 13% of patients receiving placebo. In Trial 3, 19%, 21%, and 12% of patients receiving belimumab 10 mg/kg, belimumab 1 mg/kg, and placebo, respectively, achieved this level of steroid reduction.
Effect on Severe SLE Flares: The probability of experiencing a severe SLE flare, as defined by a modification of the SELENA Trial flare criteria which excluded severe flares triggered only by an increase of the SELENA-SLEDAI score to >12, was calculated for both Trials 2 and 3. The proportion of patients having at least 1 severe flare over 52 weeks was not consistently significantly different for belimumab relative to placebo in both trials. In Trial 2, 18% of patients receiving belimumab 10 mg/kg and 16% of patients receiving belimumab 1 mg/kg had a severe flare compared with 24% of patients receiving placebo. In Trial 3, 14%, 18%, and 23% of patients receiving belimumab 10 mg/kg, belimumab 1 mg/kg and placebo, respectively, had a severe flare.
# How Supplied
- Belimumab is a sterile, preservative-free, lyophilized powder for reconstitution, dilution, and intravenous infusion provided in single-use glass vials with a rubber stopper (not made with natural rubber latex) and a flip-off seal.
- Each 5-mL vial contains 120 mg of belimumab.
- Each 20-mL vial contains 400 mg of belimumab.
Belimumab is supplied as follows:
## Storage
- Store vials of belimumab refrigerated between 2° to 8°C (36° to 46°F).
- Vials should be protected from light and stored in the original carton until use.
- Do not freeze.
- Avoid exposure to heat.
- Do not use beyond the expiration date.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advice for the Patient
- Give patients the Medication Guide for belimumab and provide them an opportunity to read it prior to each treatment session.
- It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be discussed.
Mortality: Advise patients that more patients receiving belimumab in the main clinical trials died than did patients receiving placebo treatment
Serious Infections: Advise patients that belimumab may decrease their ability to fight infections. Ask patients if they have a history of chronic infections and if they are currently on any therapy for an infection. Instruct patients to tell their healthcare provider if they develop signs or symptoms of an infection.
Progressive Multifocal Leukoencephalopathy (PML): Advise patients to contact their healthcare professional if they experience new or worsening neurological symptoms such as memory loss, confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems.
Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of hypersensitivity and infusion reactions, including wheezing, difficulty breathing, angioedema, rash, hypotension, bradycardia, and headache. Instruct patients to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of belimumab. Inform patients to tell their healthcare provider about possible reactions that may include a combination of symptoms such as rash, nausea, fatigue, muscle aches, headache, and/or facial swelling and may occur after administration of belimumab.
Depression: Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes.
Immunizations: Inform patients that they should not receive live vaccines while taking belimumab. Response to vaccinations could be impaired by belimumab.
Pregnancy and Nursing Mothers: Inform patients that belimumab has not been studied in pregnant women or nursing mothers so the effects of belimumab on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant. Encourage pregnant patients to enroll in the pregnancy registry for belimumab. Instruct patients to tell their healthcare provider if they plan to breastfeed their infant.
# Precautions with Alcohol
Alcohol-Belimumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Benlysta
# Look-Alike Drug Names
There is limited information regarding Belimumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Belimumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]
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# Overview
Belimumab is a monoclonal antibody that is FDA approved for the treatment of active autoantibody-positive systemic lupus erythematosus. Common adverse reactions include Diarrhea, nausea, infectious disease, infusion reaction, nasopharyngitis, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Systemic Lupus Erythematosus
- For the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus (SLE) who are receiving standard therapy.
- Recommended dosage regimen is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter.
- Prior to dosing with belimumab, consider administering premedication for prophylaxis against infusion reactions and hypersensitivity reactions.
- Reconstitute, dilute, and administer as an intravenous infusion only, over a period of 1 hour.
- The infusion rate may be slowed or interrupted if the patient develops an infusion reaction.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Belimumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Belimumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Belimumab 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 Belimumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Belimumab in pediatric patients.
# Contraindications
- Belimumab is contraindicated in patients who have had anaphylaxis with belimumab.
# Warnings
### Mortality
- There were more deaths reported with belimumab than with placebo during the controlled period of the clinical trials.
- Out of 2,133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the groups receiving placebo, belimumab 1 mg/kg, belimumab 4 mg/kg, and belimumab 10 mg/kg, respectively.
- No single cause of death predominated.
- Etiologies included infection, cardiovascular disease, and suicide.
### Serious Infections
- Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including belimumab.
- Physicians should exercise caution when considering the use of belimumab in patients with chronic infections.
- Patients receiving any therapy for chronic infection should not begin therapy with belimumab.
- Consider interrupting therapy with belimumab in patients who develop a new infection while undergoing treatment with belimumab and monitor these patients closely.
- In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with belimumab compared with 67% in patients who received placebo.
- The most frequent infections (>5% of patients receiving belimumab) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with belimumab and in 5.2% of patients who received placebo.
- The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis.
- Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving belimumab and 1.0% of patients receiving placebo.
- Infections resulting in death occurred in 0.3% (4/1,458) of patients treated with belimumab and in 0.1% (1/675) of patients receiving placebo.
Progressive Multifocal Leukoencephalopathy (PML):
- Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including belimumab.
- Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function.
- Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated.
- In patients with confirmed PML, consider stopping immunosuppressant therapy, including belimumab.
### Malignancy
- The impact of treatment with belimumab on the development of malignancies is not known.
- In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving belimumab and 0.4% of patients receiving placebo.
- In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1,458) and 0.3% (2/675) of patients receiving belimumab and placebo, respectively.
- The mechanism of action of belimumab could increase the risk for the development of malignancies.
### Hypersensitivity Reactions, including Anaphylaxis
- Acute hypersensitivity reactions, including anaphylaxis and death, have been reported in association with belimumab.
- These events generally occurred within hours of the infusion; however, they may occur later.
- Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema, have been reported and typically occurred up to a week following the most recent infusion.
- Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of belimumab.
- Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of patients receiving belimumab and 11% (76/675) of patients receiving placebo.
- Anaphylaxis was observed in 0.6% (9/1,458) of patients receiving belimumab and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea.
- Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases.
- Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.
- Belimumab should be administered by healthcare providers prepared to manage anaphylaxis.
- In the event of a serious reaction, administration of belimumab must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of belimumab.
- Patients should be informed of the signs and symptoms of an acute hypersensitivity reaction and be instructed to seek immediate medical care should a reaction occur.
### Infusion Reactions
- In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of patients receiving belimumab and 15% (99/675) of patients receiving placebo.
- Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving belimumab and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension.
- The most common infusion reactions (≥3% of patients receiving belimumab) were headache, nausea, and skin reactions.
- Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases.
- Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions.
- Belimumab should be administered by healthcare providers prepared to manage infusion reactions.
- The infusion rate may be slowed or interrupted if the patient develops an infusion reaction.
- Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.
### Depression
- In the controlled clinical trials, psychiatric events were reported more frequently with belimumab (16%) than with placebo (12%), related primarily to depression-related events (6.3% belimumab and 4.7% placebo), insomnia (6.0% belimumab and 5.3% placebo), and anxiety (3.9% belimumab and 2.8% placebo).
- Serious psychiatric events were reported in 0.8% of patients receiving belimumab (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. *Serious depression was reported in 0.4% (6/1,458) of patients receiving belimumab and 0.1% (1/675) of patients receiving placebo.
- Two suicides (0.1%) were reported in patients receiving belimumab.
- The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications.
- It is unknown if treatment with belimumab is associated with increased risk for these events.
- Patients receiving belimumab should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.
### Immunization
- Live vaccines should not be given for 30 days before or concurrently with belimumab as clinical safety has not been established.
- No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving belimumab or the effect of belimumab on new immunizations.
- Because of its mechanism of action, belimumab may interfere with the response to immunizations.
### Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide
- Belimumab has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of belimumab is not recommended in combination with biologic therapies or intravenous cyclophosphamide.
# Adverse Reactions
## Clinical Trials Experience
The data described below reflect exposure to belimumab plus standard of care compared with placebo plus standard of care in 2,133 patients in 3 controlled trials. Patients received belimumab at doses of 1 mg/kg (N = 673), 4 mg/kg (N = 111; Trial 1 only), or 10 mg/kg (N = 674) or placebo (N = 675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In 2 of the trials (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other trial (Trial 2) treatment was given for 72 weeks. Because there was no apparent dose-related increase in the majority of adverse events observed with belimumab, the safety data summarized below are presented for the 3 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo.
The population had a mean age of 39 (range: 18 to 75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with belimumab reported an adverse reaction compared with 92% treated with placebo.
The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving belimumab and placebo, respectively).
The most commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.
The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving belimumab and 7.1% for patients receiving placebo. The most common adverse reactions resulting in discontinuation of treatment (≥1% of patients receiving belimumab or placebo) were infusion reactions (1.6% belimumab and 0.9% placebo), lupus nephritis (0.7% belimumab and 1.2% placebo), and infections (0.7% belimumab and 1.0% placebo).
TABLE 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received belimumab 10 mg/kg and at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies.
### Immunogenicity
In Trials 2 and 3, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving belimumab 10 mg/kg and in 27 of 559 (4.8%) patients receiving belimumab 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving belimumab 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known.
The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of belimumab. 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.
- Fatal anaphylaxis
# Drug Interactions
- Formal drug interaction studies have not been performed with belimumab.
- In clinical trials of patients with SLE, belimumab was administered concomitantly with other drugs, including corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate, and mycophenolate), angiotensin pathway antihypertensives, HMG-CoA reductase inhibitors (statins), and NSAIDs without evidence of a clinically meaningful effect of these concomitant medications on belimumab pharmacokinetics.
- The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled clinical studies using belimumab in pregnant women. Immunoglobulin G (IgG) antibodies, including belimumab, can cross the placenta. Because animal reproduction studies are not always predictive of human response, belimumab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment with belimumab and for at least 4 months after the final treatment.
Nonclinical reproductive studies have been performed in pregnant cynomolgus monkeys receiving belimumab at doses of 0, 5, and 150 mg/kg by intravenous infusion (the high dose was approximately 9 times the anticipated maximum human exposure) every 2 weeks from gestation day 20 to 150. Belimumab was shown to cross the placenta. Belimumab was not associated with direct or indirect teratogenicity under the conditions tested. Fetal deaths were observed in 14%, 24%, and 15% of pregnant females in the 0, 5 and 150 mg/kg groups, respectively. Infant deaths occurred with an incidence of 0%, 8%, and 5%. The cause of fetal and infant deaths is not known. The relevance of these findings to humans is not known. Other treatment-related findings were limited to the expected reversible reduction of B cells in both dams and infants and reversible reduction of immunoglobulin M (IgM) in infant monkeys. B-cell numbers recovered after the cessation of belimumab treatment by about 1 year post-partum in adult monkeys and by 3 months of age in infant monkeys. IgM levels in infants exposed to belimumab in utero recovered by 6 months of age.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belimumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Belimumab during labor and delivery.
### Nursing Mothers
It is not known whether belimumab is excreted in human milk or absorbed systemically after ingestion. However, belimumab was excreted into the milk of cynomolgus monkeys. Because maternal antibodies are excreted in human breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of breastfeeding to the infant and the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness of belimumab have not been established in children.
### Geriatic Use
Clinical studies of belimumab did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Use with caution in elderly patients
### Gender
There is no FDA guidance on the use of Belimumab with respect to specific gender populations.
### Race
In Trial 2 and Trial 3, response rates for the primary endpoint were lower for black subjects receiving belimumab relative to black subjects receiving placebo. Use with caution in black/African-American patients.
### Renal Impairment
There is no FDA guidance on the use of Belimumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Belimumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Belimumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Belimumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous infusion
- Belimumab should be administered by healthcare providers prepared to manage anaphylaxis.
- Belimumab should not be infused concomitantly in the same intravenous line with other agents.
- No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of belimumab with other agents.
- The reconstituted solution of belimumab, if not used immediately, should be stored protected from direct sunlight and refrigerated at 2° to 8°C (36° to 46°F).
- Solutions of belimumab diluted in normal saline may be stored at 2° to 8°C (36° to 46°F) or room temperature. The total time from reconstitution of belimumab to completion of infusion should not exceed 8 hours.
### Monitoring
- Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.
# IV Compatibility
Belimumab is provided as a lyophilized powder in a single-use vial for intravenous infusion only and should be reconstituted and diluted by a healthcare professional using aseptic technique as follows:
### Reconstitution Instructions
- Remove belimumab from the refrigerator and allow to stand 10 to 15 minutes for the vial to reach room temperature.
- Reconstitute the belimumab powder with Sterile Water for Injection, USP, as follows. The reconstituted solution will contain a concentration of 80 mg/mL belimumab.
- Reconstitute the 120-mg vial with 1.5 mL Sterile Water for Injection, USP.
- Reconstitute the 400-mg vial with 4.8 mL Sterile Water for Injection, USP.
- The stream of sterile water should be directed toward the side of the vial to minimize foaming.
- Gently swirl the vial for 60 seconds.
- Allow the vial to sit at room temperature during reconstitution, gently swirling the vial for 60 seconds every 5 minutes until the powder is dissolved.
- Do not shake.
- Reconstitution is typically complete within 10 to 15 minutes after the sterile water has been added, but it may take up to 30 minutes.
- Protect the reconstituted solution from sunlight.
- If a mechanical reconstitution device (swirler) is used to reconstitute belimumab, it should not exceed 500 rpm and the vial swirled for no longer than 30 minutes.
- Once reconstitution is complete, the solution should be opalescent and colorless to pale yellow, and without particles.
- Small air bubbles, however, are expected and acceptable.
### Dilution Instructions
- Dextrose intravenous solutions are incompatible with belimumab.
- Belimumab should only be diluted in 0.9% Sodium Chloride Injection, USP.
- Dilute the reconstituted product to 250 mL in 0.9% Sodium Chloride Injection, USP (normal saline) for intravenous infusion.
- From a 250-mL infusion bag or bottle of normal saline, withdraw and discard a volume equal to the volume of the reconstituted solution of belimumab required for the patient’s dose. Then add the required volume of the reconstituted solution of belimumab into the infusion bag or bottle.
- Gently invert the bag or bottle to mix the solution. Any unused solution in the vials must be discarded.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Discard the solution if any particulate matter or discoloration is observed.
- The reconstituted solution of belimumab, if not used immediately, should be stored protected from direct sunlight and refrigerated at 2° to 8°C (36° to 46°F).
- Solutions of belimumab diluted in normal saline may be stored at 2° to 8°C (36° to 46°F) or room temperature.
- The total time from reconstitution of belimumab to completion of infusion should not exceed 8 hours.
- No incompatibilities between belimumab and polyvinylchloride or polyolefin bags have been observed.
# Overdosage
- There is no clinical experience with overdosage of belimumab.
- Two doses of up to 20 mg/kg have been given by intravenous infusion to humans with no increase in incidence or severity of adverse reactions compared with doses of 1, 4, or 10 mg/kg.
# Pharmacology
## Mechanism of Action
Belimumab is a BLyS-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.
## Structure
Belimumab is a human IgG1λ monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a molecular weight of approximately 147 kDa. Belimumab is produced by recombinant DNA technology in a mammalian cell expression system.
Belimumab is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for intravenous infusion. Upon reconstitution with Sterile Water for Injection, USP, each single-use vial delivers 80 mg/mL belimumab in 0.16 mg/mL citric acid, 0.4 mg/mL polysorbate 80, 2.7 mg/mL sodium citrate, and 80 mg/mL sucrose, with a pH of 6.5.
## Pharmacodynamics
In Trial 1 and Trial 2 in which B cells were measured, treatment with belimumab significantly reduced circulating CD19+, CD20+, naïve, and activated B cells, plasmacytoid cells, and the SLE B-cell subset at Week 52. Reductions in naïve and the SLE B-cell subset were observed as early as Week 8 and were sustained to Week 52. Memory cells increased initially and slowly declined toward baseline levels by Week 52. The clinical relevance of these effects on B cells has not been established.
Treatment with belimumab led to reductions in IgG and anti-dsDNA, and increases in complement (C3 and C4). These changes were observed as early as Week 8 and were sustained through Week 52. The clinical relevance of normalizing these biomarkers has not been definitively established.
## Pharmacokinetics
The pharmacokinetic parameters displayed in TABLE 2 are based on population parameter estimates which are specific to the 563 patients who received belimumab 10 mg/kg in Trials 2 and 3.
Drug Interactions: No formal drug interaction studies have been conducted with belimumab. Concomitant use of mycophenolate, azathioprine, methotrexate, antimalarials, NSAIDs, aspirin, and HMG-CoA reductase inhibitors did not significantly influence belimumab pharmacokinetics. Coadministration of steroids and angiotensin-converting enzyme (ACE) inhibitors resulted in an increase of systemic clearance of belimumab that was not clinically significant because the magnitude was well within the range of normal variability of clearance. The effect of belimumab on the pharmacokinetics of other drugs has not been evaluated.
Special Populations: The following information is based on the population pharmacokinetic analysis.
Age: Age did not significantly influence belimumab pharmacokinetics in the trial population, where the majority of subjects (70%) were aged between 18 and 45 years. No pharmacokinetic data are available in pediatric patients. Limited pharmacokinetic data are available for elderly patients as only 1.4% of the subjects included in the pharmacokinetic analysis were aged 65 years or older.
Gender: Gender did not significantly influence belimumab pharmacokinetics in the largely (94%) female trial population.
Race: Race did not significantly influence belimumab pharmacokinetics. The racial distribution was 53% white/Caucasian, 16% Asian, 16% Alaska native/American Indian, and 14% black/African-American.
Renal Impairment: No formal trials were conducted to examine the effects of renal impairment on the pharmacokinetics of belimumab. Belimumab has been studied in a limited number of patients with SLE and renal impairment (261 subjects with moderate renal impairment, creatinine clearance ≥30 and <60 mL/min; 14 subjects with severe renal impairment, creatinine clearance ≥15 and <30 mL/min). Although increases in creatinine clearance and proteinuria (>2 g/day) increased belimumab clearance, these effects were within the expected range of variability. Therefore, dosage adjustment in patients with renal impairment is not recommended.
Hepatic Impairment: No formal trials were conducted to examine the effects of hepatic impairment on the pharmacokinetics of belimumab. Baseline ALT and AST levels did not significantly influence belimumab pharmacokinetics.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of belimumab. The mutagenic potential of belimumab was not evaluated.
Effects on male and female fertility have not been directly evaluated in animal studies.
# Clinical Studies
The safety and effectiveness of belimumab were evaluated in 3 randomized, double-blind, placebo-controlled trials involving 2,133 patients with SLE according to the American College of Rheumatology criteria (Trial 1, 2, and 3). Patients with severe active lupus nephritis and severe active CNS lupus were excluded. Patients were on a stable standard of care SLE treatment regimen comprising any of the following (alone or in combination): corticosteroids, antimalarials, NSAIDs, and immunosuppressives. Use of other biologics and intravenous cyclophosphamide were not permitted.
```Trial 1: belimumab 1 mg/kg, 4 mg/kg, 10 mg/kg
Trial 1 enrolled 449 patients and evaluated doses of 1, 4, and 10 mg/kg belimumab plus standard of care compared with placebo plus standard of care over 52 weeks in patients with SLE. Patients had to have a SELENA-SLEDAI score of ≥4 at baseline and a history of autoantibodies (anti-nuclear antibody [ANA] and/or anti-double-stranded DNA [anti-dsDNA]), but 28% of the population was autoantibody negative at baseline. The co-primary endpoints were percent change in SELENA-SLEDAI score at Week 24 and time to first flare over 52 weeks. No significant differences between any of the groups receiving belimumab and the group receiving placebo were observed. Exploratory analysis of this trial identified a subgroup of patients (72%), who were autoantibody positive, in whom belimumab appeared to offer benefit. The results of this trial informed the design of Trials 2 and 3 and led to the selection of a target population and indication that is limited to autoantibody-positive SLE patients.
Trials 2 and 3: belimumab 1 mg/kg and 10 mg/kg
Trials 2 and 3 were randomized, double-blind, placebo-controlled trials in patients with SLE that were similar in design except duration - Trial 2 was 76 weeks duration and Trial 3 was 52 weeks duration. Eligible patients had active SLE disease, defined as a SELENA-SLEDAI score ≥6, and positive autoantibody test results at screening. Patients were excluded from the trial if they had ever received treatment with a B-cell targeted agent or if they were currently receiving other biologic agents. Intravenous cyclophosphamide was not permitted within the previous 6 months or during the trial. Trial 2 was conducted primarily in North America and Europe. Trial 3 was conducted in South America, Eastern Europe, Asia, and Australia.
Baseline concomitant medications included corticosteroids (Trial 2: 76%, Trial 3: 96%), immunosuppressives (Trial 2: 56%, Trial 3: 42%; including azathioprine, methotrexate and mycophenolate), and antimalarials (Trial 2: 63%, Trial 3: 67%). Most patients (>70%) were receiving 2 or more classes of SLE medications.
In Trial 2 and Trial 3, more than 50% of patients had 3 or more active organ systems at baseline. The most common active organ systems at baseline based on SELENA-SLEDAI were mucocutaneous (82% in both trials); immune (Trial 2: 74%, Trial 3: 85%); and musculoskeletal (Trial 2: 73%, Trial 3: 59%). Less than 16% of patients had some degree of renal activity and less than 7% of patients had activity in the vascular, cardio-respiratory, or CNS systems.
At screening, patients were stratified by disease severity based on their SELENA-SLEDAI score (≤9 vs. ≥10), proteinuria level (<2 g/24 hr vs. ≥2 g/24 hr), and race (African or Indigenous-American descent vs. other), and then randomly assigned to receive belimumab 1 mg/kg, belimumab 10 mg/kg, or placebo in addition to standard of care. The patients were administered trial medication intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days for 48 weeks in Trial 3 and for 72 weeks in Trial 2.
The primary efficacy endpoint was a composite endpoint (SLE Responder Index or SRI) that defined response as meeting each of the following criteria at Week 52 compared with baseline:
- ≥4-point reduction in the SELENA-SLEDAI score, and
- no new British Isles Lupus Assessment Group (BILAG) A organ domain score or 2 new BILAG B organ domain scores, and
- no worsening (<0.30-point increase) in Physician’s Global Assessment (PGA) score.
The SRI uses the SELENA-SLEDAI score as an objective measure of reduction in global disease activity; the BILAG index to ensure no significant worsening in any specific organ system; and the PGA to ensure that improvements in disease activity are not accompanied by worsening of the patient’s condition overall.
In both Trials 2 and 3, the proportion of SLE patients achieving an SRI response, as defined for the primary endpoint, was significantly higher in the group receiving belimumab 10 mg/kg than in the group receiving placebo. The effect on the SRI was not consistently significantly different for patients receiving belimumab 1 mg/kg relative to placebo in both trials. The 1 mg/kg dose is not recommended. The trends in comparisons between the treatment groups for the rates of response for the individual components of the endpoint were generally consistent with that of the SRI (Table 3). At Week 76 in Trial 2, the SRI response rate with belimumab 10 mg/kg was not significantly different from that of placebo (39% and 32%, respectively).
The reduction in disease activity seen in the SRI was related primarily to improvement in the most commonly involved organ systems namely, mucocutaneous, musculoskeletal, and immune.
Effect in Black/African-American Patients: Exploratory sub-group analyses of SRI response rate in patients of black race were performed. In Trial 2 and Trial 3 combined, the SRI response rate in black patients (N = 148) in groups receiving belimumab was less than that in the group receiving placebo (22/50 or 44% for placebo, 15/48 or 31% for belimumab 1 mg/kg, and 18/50 or 36% for belimumab 10 mg/kg). In Trial 1, black patients (N = 106) in the groups receiving belimumab did not appear to have a different response than the rest of the trial population. Although no definitive conclusions can be drawn from these subgroup analyses, caution should be used when considering treatment with belimumab in black/African-American SLE patients.
Effect on Concomitant Steroid Treatment: In Trial 2 and Trial 3, 46% and 69% of patients, respectively, were receiving prednisone at doses >7.5 mg/day at baseline. The proportion of patients able to reduce their average prednisone dose by at least 25% to ≤7.5 mg/day during Weeks 40 through 52 was not consistently significantly different for belimumab relative to placebo in both trials. In Trial 2, 17% of patients receiving belimumab 10 mg/kg and 19% of patients receiving belimumab 1 mg/kg achieved this level of steroid reduction compared with 13% of patients receiving placebo. In Trial 3, 19%, 21%, and 12% of patients receiving belimumab 10 mg/kg, belimumab 1 mg/kg, and placebo, respectively, achieved this level of steroid reduction.
Effect on Severe SLE Flares: The probability of experiencing a severe SLE flare, as defined by a modification of the SELENA Trial flare criteria which excluded severe flares triggered only by an increase of the SELENA-SLEDAI score to >12, was calculated for both Trials 2 and 3. The proportion of patients having at least 1 severe flare over 52 weeks was not consistently significantly different for belimumab relative to placebo in both trials. In Trial 2, 18% of patients receiving belimumab 10 mg/kg and 16% of patients receiving belimumab 1 mg/kg had a severe flare compared with 24% of patients receiving placebo. In Trial 3, 14%, 18%, and 23% of patients receiving belimumab 10 mg/kg, belimumab 1 mg/kg and placebo, respectively, had a severe flare.
# How Supplied
- Belimumab is a sterile, preservative-free, lyophilized powder for reconstitution, dilution, and intravenous infusion provided in single-use glass vials with a rubber stopper (not made with natural rubber latex) and a flip-off seal.
- Each 5-mL vial contains 120 mg of belimumab.
- Each 20-mL vial contains 400 mg of belimumab.
Belimumab is supplied as follows:
## Storage
- Store vials of belimumab refrigerated between 2° to 8°C (36° to 46°F).
- Vials should be protected from light and stored in the original carton until use.
- Do not freeze.
- Avoid exposure to heat.
- Do not use beyond the expiration date.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advice for the Patient
- Give patients the Medication Guide for belimumab and provide them an opportunity to read it prior to each treatment session.
- It is important that the patient’s overall health be assessed at each infusion visit and any questions resulting from the patient’s reading of the Medication Guide be discussed.
Mortality: Advise patients that more patients receiving belimumab in the main clinical trials died than did patients receiving placebo treatment
Serious Infections: Advise patients that belimumab may decrease their ability to fight infections. Ask patients if they have a history of chronic infections and if they are currently on any therapy for an infection. Instruct patients to tell their healthcare provider if they develop signs or symptoms of an infection.
Progressive Multifocal Leukoencephalopathy (PML): Advise patients to contact their healthcare professional if they experience new or worsening neurological symptoms such as memory loss, confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems.
Hypersensitivity/Anaphylactic and Infusion Reactions: Educate patients on the signs and symptoms of hypersensitivity and infusion reactions, including wheezing, difficulty breathing, angioedema, rash, hypotension, bradycardia, and headache. Instruct patients to immediately tell their healthcare provider if they experience symptoms of an allergic reaction during or after the administration of belimumab. Inform patients to tell their healthcare provider about possible reactions that may include a combination of symptoms such as rash, nausea, fatigue, muscle aches, headache, and/or facial swelling and may occur after administration of belimumab.
Depression: Instruct patients to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes.
Immunizations: Inform patients that they should not receive live vaccines while taking belimumab. Response to vaccinations could be impaired by belimumab.
Pregnancy and Nursing Mothers: Inform patients that belimumab has not been studied in pregnant women or nursing mothers so the effects of belimumab on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare provider if they are pregnant, become pregnant, or are thinking about becoming pregnant. Encourage pregnant patients to enroll in the pregnancy registry for belimumab. Instruct patients to tell their healthcare provider if they plan to breastfeed their infant.
# Precautions with Alcohol
Alcohol-Belimumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Benlysta[1]
# Look-Alike Drug Names
There is limited information regarding Belimumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Belimumab | |
ee236d27aafd4e587f20d5cc7df2f687f80ef8bf | wikidoc | Bemegride | Bemegride
# Overview
Bemegride (also marketed as Megimide) is a central nervous system stimulant and antidote for barbiturate poisoning as its chemoreceptor agonism increases mean tidal volume, thereby increasing respiration and the concentration of O2 in blood although it may be theoretically used as a supportive measure in treating any depressant overdose. The drug's synthesis was invented in 1911.
# John Bodkin Adams case
Bemegride is notable in legal history as the drug suspected serial killer Dr John Bodkin Adams failed to prescribe correctly to his patient Gertrude Hullett. Hullett took an overdose of barbiturates on 19 July 1956 but Adams only gave her a single 10cc dose of bemegride three days later on the 22nd, despite having acquired 100cc for her treatment. Hullett died the next day on 23 July 1956. Adams was charged but never tried for her murder.
# Animal use
Bemegride is also used to induce convulsions in experimental animals.
# Synthesis
The original synthesis involves first the condensation of methylethylketone with two equivalents of cyanoacetamide. The product can be rationalized by assuming first aldol condensation of ketone and active methylene compound followed by dehydration to give 3. Conjugate addition of a second molecule of cyanoacetamide would afford 4. Addition of one of the amide amines to the nitrile would then afford the iminonitrile 5. The observed product 6 can be rationalized by assuming loss of the carboxamide under strongly basic conditions. Decarboxylative hydrolysis of 6 then leads to bemigride 7. | Bemegride
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bemegride (also marketed as Megimide) is a central nervous system stimulant and antidote for barbiturate poisoning[1] as its chemoreceptor agonism increases mean tidal volume, thereby increasing respiration and the concentration of O2 in blood although it may be theoretically used as a supportive measure in treating any depressant overdose. The drug's synthesis was invented in 1911.[2]
# John Bodkin Adams case
Bemegride is notable in legal history as the drug suspected serial killer Dr John Bodkin Adams failed to prescribe correctly to his patient Gertrude Hullett. Hullett took an overdose of barbiturates on 19 July 1956 but Adams only gave her a single 10cc dose of bemegride three days later on the 22nd, despite having acquired 100cc for her treatment. Hullett died the next day on 23 July 1956. Adams was charged but never tried for her murder.[3]
# Animal use
Bemegride is also used to induce convulsions in experimental animals.[4]
# Synthesis
The original synthesis involves first the condensation of methylethylketone with two equivalents of cyanoacetamide. The product can be rationalized by assuming first aldol condensation of ketone and active methylene compound followed by dehydration to give 3. Conjugate addition of a second molecule of cyanoacetamide would afford 4. Addition of one of the amide amines to the nitrile would then afford the iminonitrile 5. The observed product 6 can be rationalized by assuming loss of the carboxamide under strongly basic conditions. Decarboxylative hydrolysis of 6 then leads to bemigride 7. | https://www.wikidoc.org/index.php/Bemegride | |
e9fd6d997c43639593f3bf0eb8844f59a2b7f59f | wikidoc | Mydriasis | Mydriasis
Synonyms and keywords: Pupillary dilation; dilated pupil
# Overview
Mydriasis is an excessive dilation of the pupil due to disease, trauma or drugs. Normally, the pupil dilates in the dark and constricts in the light. A mydriatic pupil will remain excessively large, even in a bright environment. Sometimes colloquially referred to as a "blown pupil."
The opposite, constriction of the pupil, is called miosis.
# Pathophysiology
There are two types of muscle that control the size of the iris: circular muscle and radial muscle. The former is innervated by the parasympathetic nervous system, the latter by the sympathetic nervous system. Sympathetic stimulation of α1 adrenergic receptors causes the contraction of the radial muscle, and subsequent dilation of the pupil. Conversely, parasympathetic stimulation cause contraction of the circular muscle and constriction of the iris.
The mechanism of mydriasis depends on the agent being used. It usually involves either a disruption of the parasympathetic nerve supply to the eye (which causes contraction of the pupil), or over activity of the sympathetic nervous system (SNS).
# Causes
## Common Causes
- Adregenic agents
- Amphetamines
- Antihistamines
- Antipsychotic agents
- Apraclonidine
- Atropine
- Chlorpheniramine
- Chlorpromazine
- Cinnarizine
- Cocaine
- Cyclopentolate
- Diphenhydramine
- Dipivefrin
- Disopyramide
- Dopram injection
- Doxapram hydrochloride
- Hallucinogens
- Hexamethonium
- Hydroxyzine
- Lachesine
- Levomepromazine
- Lysergic acid diethylamide
- Mdma
- Mescaline
- Naphazoline
- Noradrenaline
- Opiate
- Oxcarbazepine
- Perazine
- Phenelzine
- Phenylephrine
- Pipothiazine
- Pizotifen
- Prochlorperazine
- Psychedelic mushrooms
- Sibutramine
- Systemic anticholinergics
- Tetrahydrozoline
- Tricyclic antidepressants
- Tropicamide
## Causes by Organ System
## Causes in Alphabetical Order
## Causes in Alphabetical Order
- 3rd cranial nerve disorder
- Acute closed angle glaucoma
- Adie's tonic pupil
- Adregenic agents
- Amphetamines
- Antihistamines
- Antipsychotic agents
- Apraclonidine
- Atropine
- Autonomic seizure
- Benign episodic mydriasis
- Brain death
- Cerebral oedema
- Chlorpheniramine
- Chlorpromazine
- Cinnarizine
- Cocaine
- Coma
- Congenital mydriasis
- Cyclopentolate
- Diphenhydramine
- Dipivefrin
- Disopyramide
- Dopram injection
- Doxapram hydrochloride
- Hallucinogens
- Hexamethonium
- Hydroxyzine
- Lachesine
- Levomepromazine
- Lysergic acid diethylamide
- Mdma
- Mescaline
- Naphazoline
- Noradrenaline
- Opiate
- Oxcarbazepine
- Perazine
- Phenelzine
- Phenylephrine
- Pipothiazine
- Pizotifen
- Pourfour du petit syndrome
- Prochlorperazine
- Psychedelic mushrooms
- Raised intracranial pressure
- Seizures
- Serotonin syndrome
- Sibutramine
- Systemic anticholinergics
- Tetrahydrozoline
- Third nerve palsy
- Trauma
- Tricyclic antidepressants
- Tropicamide
- Weber syndrome
# Diagnostic Findings
## History and Symptoms
- Complete history with special attention to:
- Neurologic
- Ophthalmologic
- Otolaryngologic
## Physical Examination
## Eyes
- Pupil dilated using anaesthetic and muscle relaxant
- Pupillary response
- Pupil size (light & dark)
- Pupil response to light and convergence
- Lid position
## MRI
- MRI to check for third cranial nerve palsy
# Treatment
## Medical Therapy
- Adie's pupil - Pilcarpine .125% BID-QID
- Migraines - pain meds, antidepressants, anticonvulsants, beta blockers, calcium channel blockers
## Primary Prevention
- Remove causative medication
- Sunglasses to decrease light sensitivity
# Related Chapters
- Miosis
- Anisocoria | Mydriasis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.
Synonyms and keywords: Pupillary dilation; dilated pupil
# Overview
Mydriasis is an excessive dilation of the pupil due to disease, trauma or drugs. Normally, the pupil dilates in the dark and constricts in the light. A mydriatic pupil will remain excessively large, even in a bright environment. Sometimes colloquially referred to as a "blown pupil."
The opposite, constriction of the pupil, is called miosis.
# Pathophysiology
There are two types of muscle that control the size of the iris: circular muscle and radial muscle. The former is innervated by the parasympathetic nervous system, the latter by the sympathetic nervous system. Sympathetic stimulation of α1 adrenergic receptors causes the contraction of the radial muscle, and subsequent dilation of the pupil. Conversely, parasympathetic stimulation cause contraction of the circular muscle and constriction of the iris.
The mechanism of mydriasis depends on the agent being used. It usually involves either a disruption of the parasympathetic nerve supply to the eye (which causes contraction of the pupil), or over activity of the sympathetic nervous system (SNS).
# Causes
## Common Causes
- Adregenic agents
- Amphetamines
- Antihistamines
- Antipsychotic agents
- Apraclonidine
- Atropine
- Chlorpheniramine
- Chlorpromazine
- Cinnarizine
- Cocaine
- Cyclopentolate
- Diphenhydramine
- Dipivefrin
- Disopyramide
- Dopram injection
- Doxapram hydrochloride
- Hallucinogens
- Hexamethonium
- Hydroxyzine
- Lachesine
- Levomepromazine
- Lysergic acid diethylamide
- Mdma
- Mescaline
- Naphazoline
- Noradrenaline
- Opiate
- Oxcarbazepine
- Perazine
- Phenelzine
- Phenylephrine
- Pipothiazine
- Pizotifen
- Prochlorperazine
- Psychedelic mushrooms
- Sibutramine
- Systemic anticholinergics
- Tetrahydrozoline
- Tricyclic antidepressants
- Tropicamide
## Causes by Organ System
## Causes in Alphabetical Order
## Causes in Alphabetical Order
- 3rd cranial nerve disorder
- Acute closed angle glaucoma
- Adie's tonic pupil
- Adregenic agents
- Amphetamines
- Antihistamines
- Antipsychotic agents
- Apraclonidine
- Atropine
- Autonomic seizure
- Benign episodic mydriasis
- Brain death
- Cerebral oedema
- Chlorpheniramine
- Chlorpromazine
- Cinnarizine
- Cocaine
- Coma
- Congenital mydriasis
- Cyclopentolate
- Diphenhydramine
- Dipivefrin
- Disopyramide
- Dopram injection
- Doxapram hydrochloride
- Hallucinogens
- Hexamethonium
- Hydroxyzine
- Lachesine
- Levomepromazine
- Lysergic acid diethylamide
- Mdma
- Mescaline
- Naphazoline
- Noradrenaline
- Opiate
- Oxcarbazepine
- Perazine
- Phenelzine
- Phenylephrine
- Pipothiazine
- Pizotifen
- Pourfour du petit syndrome
- Prochlorperazine
- Psychedelic mushrooms
- Raised intracranial pressure
- Seizures
- Serotonin syndrome
- Sibutramine
- Systemic anticholinergics
- Tetrahydrozoline
- Third nerve palsy
- Trauma
- Tricyclic antidepressants
- Tropicamide
- Weber syndrome
# Diagnostic Findings
## History and Symptoms
- Complete history with special attention to:
- Neurologic
- Ophthalmologic
- Otolaryngologic
## Physical Examination
## Eyes
- Pupil dilated using anaesthetic and muscle relaxant
- Pupillary response
- Pupil size (light & dark)
- Pupil response to light and convergence
- Lid position
## MRI
- MRI to check for third cranial nerve palsy
# Treatment
## Medical Therapy
- Adie's pupil - Pilcarpine .125% BID-QID
- Migraines - pain meds, antidepressants, anticonvulsants, beta blockers, calcium channel blockers
## Primary Prevention
- Remove causative medication
- Sunglasses to decrease light sensitivity
# Related Chapters
- Miosis
- Anisocoria | https://www.wikidoc.org/index.php/Benign_episodic_mydriasis | |
0f0265a70f446009565664cc591b13c29b71c1fd | wikidoc | Benzidine | Benzidine
# Overview
Benzidine is the trivial name for 4,4'-diaminobiphenyl, a carcinogenic aromatic amine which has been used as part of a test for cyanide and also in the synthesis of dyes. It has been linked to bladder cancer and pancreatic cancer.
In common with benzidine some other aromatic amines such as 2-aminonaphthalene have been withdrawn from use in almost all industries because they are so carcinogenic.
In the past a common test for blood used benzidine but this has largely been replaced by tests using phenolphthalein / hydrogen peroxide and luminol. An enzyme in blood causes the benzidine to be oxidized to a polymer which is blue coloured. The test for cyanide uses similar chemistry to give the blue colour.
Benzidine is a known human carcinogen.
# Benzidine rearrangement
In a classic rearrangement reaction called the benzidine rearrangement benzidine is formed by reaction of the 1,2-diphenylhydrazine (PhNHNHPh) with acids. One plausible reaction mechanism has both hydrazine nitrogen atoms protonated after which a sigmatropic reaction takes place . | Benzidine
Template:Chembox new
# Overview
Benzidine is the trivial name for 4,4'-diaminobiphenyl, a carcinogenic aromatic amine which has been used as part of a test for cyanide and also in the synthesis of dyes. It has been linked to bladder cancer and pancreatic cancer.
In common with benzidine some other aromatic amines such as 2-aminonaphthalene have been withdrawn from use in almost all industries because they are so carcinogenic.
In the past a common test for blood used benzidine but this has largely been replaced by tests using phenolphthalein / hydrogen peroxide and luminol. An enzyme in blood causes the benzidine to be oxidized to a polymer which is blue coloured. The test for cyanide uses similar chemistry to give the blue colour.
Benzidine is a known human carcinogen. [1]
# Benzidine rearrangement
In a classic rearrangement reaction called the benzidine rearrangement benzidine is formed by reaction of the 1,2-diphenylhydrazine (PhNHNHPh) with acids. One plausible reaction mechanism has both hydrazine nitrogen atoms protonated after which a sigmatropic reaction takes place [2].
# External links
- | https://www.wikidoc.org/index.php/Benzidine | |
13f9f7c3c9abf290e049be0056f7f17ded738949 | wikidoc | Beractant | Beractant
# 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
Beractant is a Lung Surfactant that is FDA approved for the treatment of Respiratory distress syndrome (RDS) (hyaline membrane disease) in premature infants. Common adverse reactions include Transient bradycardia, Oxygen desaturation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- SURVANTA is indicated for prevention and treatment (“rescue”) of Respiratory distress syndrome (RDS) (hyaline membrane disease) in premature infants. SURVANTA significantly reduces the incidence of RDS, mortality due to RDS and air leak complications.
- In premature infants less than 1250 g birth weight or with evidence of surfactant deficiency, give SURVANTA as soon as possible, preferably within 15 minutes of birth.
- To treat infants with RDS confirmed by x-ray and requiring mechanical ventilation, give SURVANTA as soon as possible, preferably by 8 hours of age.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Beractant in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Beractant in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- SURVANTA is indicated for prevention and treatment (“rescue”) of Respiratory Distress Syndrome (RDS) (hyaline membrane disease) in premature infants. SURVANTA significantly reduces the incidence of RDS, mortality due to RDS and air leak complications.
- In premature infants less than 1250 g birth weight or with evidence of surfactant deficiency, give SURVANTA as soon as possible, preferably within 15 minutes of birth.
- To treat infants with RDS confirmed by x-ray and requiring mechanical ventilation, give SURVANTA as soon as possible, preferably by 8 hours of age.
### Dosage
- For intratracheal administration only.
- SURVANTA should be administered by or under the supervision of clinicians experienced in intubation, ventilator management, and general care of premature infants.
- Marked improvements in oxygenation may occur within minutes of administration of SURVANTA. Therefore, frequent and careful clinical observation and monitoring of systemic oxygenation are essential to avoid hyperoxia.
- Review of audiovisual instructional materials describing dosage and administration procedures is recommended before using SURVANTA. Materials are available upon request from AbbVie Inc.
- Each dose of SURVANTA is 100 mg of phospholipids/kg birth weight (4 mL/kg). The SURVANTA Dosing Chart shows the total dosage for a range of birth weights.
- Four doses of SURVANTA can be administered in the first 48 hours of life. Doses should be given no more frequently than every 6 hours.
- SURVANTA should be inspected visually for discoloration prior to administration. The color of SURVANTA is off-white to light brown. If settling occurs during storage, swirl the vial gently to redisperse. Some foaming at the surface may occur during handling and is inherent in the nature of the product.
- SURVANTA is stored refrigerated (2-8°C). Date and time need to be recorded in the box on front of the carton or vial, whenever SURVANTA is removed from the refrigerator. Before administration, SURVANTA should be warmed by standing at room temperature for at least 20 minutes or warmed in the hand for at least 8 minutes. Artificial warming methods should not be used. If a prevention dose is to be given, preparation of SURVANTA should begin before the infant’s birth.
- Unopened, unused vials of SURVANTA that have been warmed to room temperature may be returned to the refrigerator within 24 hours of warming, and stored for future use. SURVANTA SHOULD NOT BE REMOVED FROM THE REFRIGERATOR FOR MORE THAN 24 HOURS. SURVANTA SHOULD NOT BE WARMED AND RETURNED TO THE REFRIGERATOR MORE THAN ONCE. Each single-use vial of SURVANTA should be entered only once. Used vials with residual drug should be discarded.
- SURVANTA does not require reconstitution or sonication before use.
### DOSING PROCEDURES
- SURVANTA is administered intratracheally by instillation through a 5 French end-hole catheter. The catheter can be inserted into the infant’s endotracheal tube without interrupting ventilation by passing the catheter through a neonatal suction valve attached to the endotracheal tube. Alternatively, SURVANTA can be instilled through the catheter by briefly disconnecting the endotracheal tube from the ventilator.
- The neonatal suction valve used for administering SURVANTA should be a type that allows entry of the catheter into the endotracheal tube without interrupting ventilation and also maintains a closed airway circuit system by sealing the valve around the catheter.
- If the neonatal suction valve is used, the catheter should be rigid enough to pass easily into the endotracheal tube. A very soft and pliable catheter may twist or curl within the neonatal suction valve. The length of the catheter should be shortened so that the tip of the catheter protrudes just beyond the end of the endotracheal tube above the infant’s carina. SURVANTA should not be instilled into a mainstem bronchus.
- To ensure homogenous distribution of SURVANTA throughout the lungs, each dose is divided into four quarter-doses.
- Each quarter-dose is administered with the infant in a different position. The recommended positions are:
- Head and body inclined 5-10° down, head turned to the right
- Head and body inclined 5-10° down, head turned to the left
- Head and body inclined 5-10° up, head turned to the right
- Head and body inclined 5-10° up, head turned to the left
- The dosing procedure is facilitated if one person administers the dose while another person positions and monitors the infant.
- First Dose
- Determine the total dose of SURVANTA from the SURVANTA dosing chart based on the infant’s birth weight. Slowly withdraw the entire contents of the vial into a plastic syringe through a large-gauge needle (eg, at least 20 gauge). Do not filter SURVANTA and avoid shaking.
- Attach the premeasured 5 French end-hole catheter to the syringe. Fill the catheter with SURVANTA. Discard excess SURVANTA through the catheter so that only the total dose to be given remains in the syringe.
- Before administering SURVANTA, assure proper placement and patency of the endotracheal tube. At the discretion of the clinician, the endotracheal tube may be suctioned before administering SURVANTA. The infant should be allowed to stabilize before proceeding with dosing.
- In the prevention strategy, weigh, intubate and stabilize the infant. Administer the dose as soon as possible after birth, preferably within 15 minutes. Position the infant appropriately and gently inject the first quarter-dose through the catheter over 2-3 seconds.
- After administration of the first quarter-dose, remove the catheter from the endotracheal tube. Manually ventilate with a hand-bag with sufficient oxygen to prevent cyanosis, at a rate of 60 breaths/minute, and sufficient positive pressure to provide adequate air exchange and chest wall excursion.
- In the rescue strategy, the first dose should be given as soon as possible after the infant is placed on a ventilator for management of RDS. In the clinical trials, immediately before instilling the first quarter-dose, the infant’s ventilator settings were changed to rate 60/minute, inspiratory time 0.5 second, and FiO2 1.0.
- Position the infant appropriately and gently inject the first quarter-dose through the catheter over 2-3 seconds. After administration of the first quarter-dose, remove the catheter from the endotracheal tube and continue mechanical ventilation.
- In both strategies, ventilate the infant for at least 30 seconds or until stable. Reposition the infant for instillation of the next quarter-dose.
- Instill the remaining quarter-doses using the same procedures. After instillation of each quarter-dose, remove the catheter and ventilate for at least
- 30 seconds or until the infant is stabilized. After instillation of the final quarter-dose, remove the catheter without flushing it. Do not suction the infant for 1 hour after dosing unless signs of significant airway obstruction occur.
- After completion of the dosing procedure, resume usual ventilator management and clinical care.
- Repeat Doses
- The dosage of SURVANTA for repeat doses is also 100 mg phospholipids/kg and is based on the infant’s birth weight. The infant should not be reweighed for determination of the SURVANTA dosage. Use the SURVANTA Dosing Chart to determine the total dosage.
- The need for additional doses of SURVANTA is determined by evidence of continuing respiratory distress. Using the following criteria for redosing, significant reductions in mortality due to RDS were observed in the multiple-dose clinical trials with SURVANTA.
- Dose no sooner than 6 hours after the preceding dose if the infant remains intubated and requires at least 30% inspired oxygen to maintain a PaO2 less than or equal to 80 torr.
- Radiographic confirmation of RDS should be obtained before administering additional doses to those who received a prevention dose.
- Prepare SURVANTA and position the infant for administration of each quarter-dose as previously described. After instillation of each quarter-dose, remove the dosing catheter from the endotracheal tube and ventilate the infant for at least 30 seconds or until stable.
- In the clinical studies, ventilator settings used to administer repeat doses were different than those used for the first dose. For repeat doses, the FiO2 was increased by 0.20 or an amount sufficient to prevent cyanosis. The ventilator delivered a rate of 30/minute with an inspiratory time less than
- 1.0 second. If the infant’s pretreatment rate was 30 or greater, it was left unchanged during SURVANTA instillation.
- Manual hand-bag ventilation should not be used to administer repeat doses. During the dosing procedure, ventilator settings may be adjusted at the discretion of the clinician to maintain appropriate oxygenation and ventilation.
- After completion of the dosing procedure, resume usual ventilator management and clinical care.
- If an infant experiences bradycardia or oxygen desaturation during the dosing procedure, stop the dosing procedure and initiate appropriate measures to alleviate the condition. After the infant has stabilized, resume the dosing procedure.
- Rales and moist breath sounds can occur transiently after administration of SURVANTA. Endotracheal suctioning or other remedial action is unnecessary unless clear-cut signs of airway obstruction are present.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Beractant in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Beractant in pediatric patients.
# Contraindications
- None known.
# Warnings
- SURVANTA is intended for intratracheal use only.
- SURVANTA can rapidly affect oxygenation and lung compliance. Therefore, its use should be restricted to a highly supervised clinical setting with immediate availability of clinicians experienced with intubation, ventilator management, and general care of premature infants. Infants receiving SURVANTA should be frequently monitored with arterial or transcutaneous measurement of systemic oxygen and carbon dioxide.
- During the dosing procedure, transient episodes of bradycardia and decreased oxygen saturation have been reported. If these occur, stop the dosing procedure and initiate appropriate measures to alleviate the condition. After stabilization, resume the dosing procedure.
### Precautions
- Rales and moist breath sounds can occur transiently after administration. Endotracheal suctioning or other remedial action is not necessary unless clear-cut signs of airway obstruction are present.
- Increased probability of post-treatment nosocomial sepsis in SURVANTA-treated infants was observed in the controlled clinical trials (Table 3). The increased risk for sepsis among SURVANTA-treated infants was not associated with increased mortality among these infants. The causative organisms were similar in treated and control infants. There was no significant difference between groups in the rate of post-treatment infections other than sepsis.
- Use of SURVANTA in infants less than 600 g birth weight or greater than 1750 g birth weight has not been evaluated in controlled trials. There is no controlled experience with use of SURVANTA in conjunction with experimental therapies for RDS (eg, high-frequency ventilation or extracorporeal membrane oxygenation).
- No information is available on the effects of doses other than 100 mg phospholipids/kg, more than four doses, dosing more frequently than every 6 hours, or administration after 48 hours of age.
# Adverse Reactions
## Clinical Trials Experience
- The most commonly reported adverse experiences were associated with the dosing procedure. In the multiple-dose controlled clinical trials, each dose of SURVANTA was divided into four quarter-doses which were instilled through a catheter inserted into the endotracheal tube by briefly disconnecting the endotracheal tube from the ventilator. Transient bradycardia occurred with 11.9% of doses. Oxygen desaturation occurred with 9.8% of doses.
- Other reactions during the dosing procedure occurred with fewer than 1% of doses and included endotracheal tube reflux, pallor, vasoconstriction, hypotension, endotracheal tube blockage, hypertension, hypocarbia, hypercarbia, and apnea. No deaths occurred during the dosing procedure, and all reactions resolved with symptomatic treatment.
- The occurrence of concurrent illnesses common in premature infants was evaluated in the controlled trials. The rates in all controlled studies are in Table 3.
- When all controlled studies were pooled, there was no difference in intracranial hemorrhage. However, in one of the single-dose rescue studies and one of the multiple-dose prevention studies, the rate of intracranial hemorrhage was significantly higher in SURVANTA patients than control patients (63.3% v 30.8%, P = 0.001; and 48.8% v 34.2%, P = 0.047, respectively). The rate in a Treatment IND involving approximately 8100 infants was lower than in the controlled trials.
- In the controlled clinical trials, there was no effect of SURVANTA on results of common laboratory tests: white blood cell count and serum sodium, potassium, bilirubin, and creatinine.
- More than 4300 pretreatment and post-treatment serum samples from approximately 1500 patients were tested by Western Blot Immunoassay for antibodies to surfactant-associated proteins SP-B and SP-C. No IgG or IgM antibodies were detected.
- Several other complications are known to occur in premature infants. The following conditions were reported in the controlled clinical studies. The rates of the complications were not different in treated and control infants, and none of the complications were attributed to SURVANTA.
- lung consolidation, blood from the endotracheal tube, deterioration after weaning, respiratory decompensation, subglottic stenosis, paralyzed diaphragm, respiratory failure.
- hypotension, hypertension, tachycardia, ventricular tachycardia, aortic thrombosis, cardiac failure, cardio-respiratory arrest, increased apical pulse, persistent fetal circulation, air embolism, total anomalous pulmonary venous return.
- abdominal distention, hemorrhage, intestinal perforations, volvulus, bowel infarct, feeding intolerance, hepatic failure, stress ulcer.
- renal failure, hematuria.
- coagulopathy, thrombocytopenia, disseminated intravascular coagulation.
- seizures
- adrenal hemorrhage, inappropriate ADH secretion, hyperphosphatemia.
- inguinal hernia.
- fever, deterioration.
- To date, no long-term complications or sequelae of SURVANTA therapy have been found.
- Six-month adjusted-age follow-up evaluations of 232 infants (115 treated) demonstrated no clinically important differences between treatment groups in pulmonary and neurologic sequelae, incidence or severity of retinopathy of prematurity, rehospitalizations, growth, or allergic manifestations.
- Six-month adjusted age follow-up evaluations have been completed in 631 (345 treated) of 916 surviving infants. There were significantly less cerebral palsy and need for supplemental oxygen in SURVANTA infants than controls. Wheezing at the time of examination was significantly more frequent among SURVANTA infants, although there was no difference in bronchodilator therapy.
- Final twelve-month follow-up data from the multiple-dose studies are available from 521 (272 treated) of 909 surviving infants. There was significantly less wheezing in SURVANTA infants than controls, in contrast to the six-month results. There was no difference in the incidence of cerebral palsy at twelve months.
- Twenty-four month adjusted age evaluations were completed in 429 (226 treated) of 906 surviving infants. There were significantly fewer SURVANTA infants with rhonchi, wheezing, and tachypnea at the time of examination. No other differences were found.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Beractant in the drug label.
# Drug Interactions
There is limited information regarding Beractant Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Beractant in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Beractant during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Beractant with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Beractant with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Beractant with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Beractant with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Beractant with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Beractant in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Beractant in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Beractant in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Beractant in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- intratracheal
### Monitoring
- Infants receiving SURVANTA should be frequently monitored with arterial or transcutaneous measurement of systemic oxygen and carbon dioxide.
# IV Compatibility
There is limited information regarding IV Compatibility of Beractant in the drug label.
# Overdosage
- Overdosage with SURVANTA has not been reported. Based on animal data, overdosage might result in acute airway obstruction. Treatment should be symptomatic and supportive.
- Rales and moist breath sounds can transiently occur after SURVANTA is given, and do not indicate overdosage. Endotracheal suctioning or other remedial action is not required unless clear-cut signs of airway obstruction are present.
# Pharmacology
## Mechanism of Action
- Endogenous pulmonary surfactant lowers surface tension on alveolar surfaces during respiration and stabilizes the alveoli against collapse at resting transpulmonary pressures. Deficiency of pulmonary surfactant causes Respiratory Distress Syndrome (RDS) in premature infants. SURVANTA replenishes surfactant and restores surface activity to the lungs of these infants.
## Structure
- SURVANTA ® (beractant) Intratracheal Suspension is a sterile, non-pyrogenic pulmonary surfactant intended for intratracheal use only. It is a natural bovine lung extract containing phospholipids, neutral lipids, fatty acids, and surfactant-associated proteins to which colfosceril palmitate (dipalmitoylphosphatidylcholine), palmitic acid, and tripalmitin are added to standardize the composition and to mimic surface-tension lowering properties of natural lung surfactant. The resulting composition provides 25 mg/mL phospholipids (including 11.0-15.5 mg/mL disaturated phosphatidylcholine), 0.5-1.75 mg/mL triglycerides, 1.4-3.5 mg/mL free fatty acids, and less than 1.0 mg/mL protein. It is suspended in 0.9% sodium chloride solution, and heat-sterilized. SURVANTA contains no preservatives. Its protein content consists of two hydrophobic, low molecular weight, surfactant-associated proteins commonly known as SP-B and SP-C. It does not contain the hydrophilic, large molecular weight surfactant-associated protein known as SP-A.
- Each mL of SURVANTA contains 25 mg of phospholipids. It is an off-white to light brown liquid supplied in single-use glass vials containing 4 mL (100 mg phospholipids) or 8 mL (200 mg phospholipids).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Beractant in the drug label.
## Pharmacokinetics
- In vitro, SURVANTA reproducibly lowers minimum surface tension to less than 8 dynes/cm as measured by the pulsating bubble surfactometer and Wilhelmy Surface Balance. In situ, SURVANTA restores pulmonary compliance to excised rat lungs artificially made surfactant-deficient. In vivo, single SURVANTA doses improve lung pressure-volume measurements, lung compliance, and oxygenation in premature rabbits and sheep.
- SURVANTA is administered directly to the target organ, the lungs, where biophysical effects occur at the alveolar surface. In surfactant-deficient premature rabbits and lambs, alveolar clearance of radio-labelled lipid components of SURVANTA is rapid. Most of the dose becomes lung-associated within hours of administration, and the lipids enter endogenous surfactant pathways of reutilization and recycling. In surfactant-sufficient adult animals, SURVANTA clearance is more rapid than in premature and young animals. There is less reutilization and recycling of surfactant in adult animals.
- Limited animal experiments have not found effects of SURVANTA on endogenous surfactant metabolism. Precursor incorporation and subsequent secretion of saturated phosphatidylcholine in premature sheep are not changed by SURVANTA treatments.
- No information is available about the metabolic fate of the surfactant-associated proteins in SURVANTA. The metabolic disposition in humans has not been studied.
## Nonclinical Toxicology
- Carcinogenicity studies have not been performed with SURVANTA. SURVANTA was negative when tested in the Ames test for mutagenicity. Using the maximum feasible dose volume, SURVANTA up to 500 mg phospholipids/kg/day (approximately one-third the premature infant dose based on mg/m2/day) was administered subcutaneously to newborn rats for 5 days. The rats reproduced normally and there were no observable adverse effects in their offspring.
# Clinical Studies
- Clinical effects of SURVANTA were demonstrated in six single-dose and four multiple-dose randomized, multi-center, controlled clinical trials involving approximately 1700 infants. Three open trials, including a Treatment IND, involved more than 8500 infants. Each dose of SURVANTA in all studies was 100 mg phospholipids/kg birth weight and was based on published experience with Surfactant TA, a lyophilized powder dosage form of SURVANTA having the same composition.
- Infants of 600-1250 g birth weight and 23 to 29 weeks estimated gestational age were enrolled in two multiple-dose studies. A dose of SURVANTA was given within 15 minutes of birth to prevent the development of RDS. Up to three additional doses in the first 48 hours, as often as every 6 hours, were given if RDS subsequently developed and infants required mechanical ventilation with an FiO2 ≥ 0.30. Results of the studies at 28 days of age are shown in Table 1.
- Infants of 600-1750 g birth weight with RDS requiring mechanical ventilation and an FiO2 ≥ 0.40 were enrolled in two multiple-dose rescue studies. The initial dose of SURVANTA was given after RDS developed and before 8 hours of age. Infants could receive up to three additional doses in the first 48 hours, as often as every 6 hours, if they required mechanical ventilation and an FiO2 ≥ 0.30. Results of the studies at 28 days of age are shown in Table 2.
- Marked improvements in oxygenation may occur within minutes of administration of SURVANTA.
- All controlled clinical studies with SURVANTA provided information regarding the acute effects of SURVANTA on the arterial-alveolar oxygen ratio (a/APO2), FiO2, and mean airway pressure (MAP) during the first 48 to 72 hours of life. Significant improvements in these variables were sustained for 48-72 hours in SURVANTA-treated infants in four single-dose and two multiple-dose rescue studies and in two multiple-dose prevention studies. In the single-dose prevention studies, the FiO2 improved significantly.
# How Supplied
- SURVANTA (beractant) Intratracheal Suspension is supplied in single-use glass vials containing 4 mL (NDC 0074-1040-04) or 8 mL of SURVANTA (NDC 0074-1040-08). Each milliliter contains 25 mg of phospholipids suspended in 0.9% sodium chloride solution. The color is off-white to light brown.
## Storage
- Store unopened vials at refrigeration temperature (2-8°C). Protect from light. Store vials in carton until ready for use. Vials are for single use only. Upon opening, discard unused drug.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Beractant in the drug label.
# Precautions with Alcohol
- Alcohol-Beractant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Survanta®
# Look-Alike Drug Names
There is limited information regarding Beractant Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Beractant
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Overview
Beractant is a Lung Surfactant that is FDA approved for the treatment of Respiratory distress syndrome (RDS) (hyaline membrane disease) in premature infants. Common adverse reactions include Transient bradycardia, Oxygen desaturation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- SURVANTA is indicated for prevention and treatment (“rescue”) of Respiratory distress syndrome (RDS) (hyaline membrane disease) in premature infants. SURVANTA significantly reduces the incidence of RDS, mortality due to RDS and air leak complications.
- In premature infants less than 1250 g birth weight or with evidence of surfactant deficiency, give SURVANTA as soon as possible, preferably within 15 minutes of birth.
- To treat infants with RDS confirmed by x-ray and requiring mechanical ventilation, give SURVANTA as soon as possible, preferably by 8 hours of age.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Beractant in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Beractant in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- SURVANTA is indicated for prevention and treatment (“rescue”) of Respiratory Distress Syndrome (RDS) (hyaline membrane disease) in premature infants. SURVANTA significantly reduces the incidence of RDS, mortality due to RDS and air leak complications.
- In premature infants less than 1250 g birth weight or with evidence of surfactant deficiency, give SURVANTA as soon as possible, preferably within 15 minutes of birth.
- To treat infants with RDS confirmed by x-ray and requiring mechanical ventilation, give SURVANTA as soon as possible, preferably by 8 hours of age.
### Dosage
- For intratracheal administration only.
- SURVANTA should be administered by or under the supervision of clinicians experienced in intubation, ventilator management, and general care of premature infants.
- Marked improvements in oxygenation may occur within minutes of administration of SURVANTA. Therefore, frequent and careful clinical observation and monitoring of systemic oxygenation are essential to avoid hyperoxia.
- Review of audiovisual instructional materials describing dosage and administration procedures is recommended before using SURVANTA. Materials are available upon request from AbbVie Inc.
- Each dose of SURVANTA is 100 mg of phospholipids/kg birth weight (4 mL/kg). The SURVANTA Dosing Chart shows the total dosage for a range of birth weights.
- Four doses of SURVANTA can be administered in the first 48 hours of life. Doses should be given no more frequently than every 6 hours.
- SURVANTA should be inspected visually for discoloration prior to administration. The color of SURVANTA is off-white to light brown. If settling occurs during storage, swirl the vial gently to redisperse. Some foaming at the surface may occur during handling and is inherent in the nature of the product.
- SURVANTA is stored refrigerated (2-8°C). Date and time need to be recorded in the box on front of the carton or vial, whenever SURVANTA is removed from the refrigerator. Before administration, SURVANTA should be warmed by standing at room temperature for at least 20 minutes or warmed in the hand for at least 8 minutes. Artificial warming methods should not be used. If a prevention dose is to be given, preparation of SURVANTA should begin before the infant’s birth.
- Unopened, unused vials of SURVANTA that have been warmed to room temperature may be returned to the refrigerator within 24 hours of warming, and stored for future use. SURVANTA SHOULD NOT BE REMOVED FROM THE REFRIGERATOR FOR MORE THAN 24 HOURS. SURVANTA SHOULD NOT BE WARMED AND RETURNED TO THE REFRIGERATOR MORE THAN ONCE. Each single-use vial of SURVANTA should be entered only once. Used vials with residual drug should be discarded.
- SURVANTA does not require reconstitution or sonication before use.
### DOSING PROCEDURES
- SURVANTA is administered intratracheally by instillation through a 5 French end-hole catheter. The catheter can be inserted into the infant’s endotracheal tube without interrupting ventilation by passing the catheter through a neonatal suction valve attached to the endotracheal tube. Alternatively, SURVANTA can be instilled through the catheter by briefly disconnecting the endotracheal tube from the ventilator.
- The neonatal suction valve used for administering SURVANTA should be a type that allows entry of the catheter into the endotracheal tube without interrupting ventilation and also maintains a closed airway circuit system by sealing the valve around the catheter.
- If the neonatal suction valve is used, the catheter should be rigid enough to pass easily into the endotracheal tube. A very soft and pliable catheter may twist or curl within the neonatal suction valve. The length of the catheter should be shortened so that the tip of the catheter protrudes just beyond the end of the endotracheal tube above the infant’s carina. SURVANTA should not be instilled into a mainstem bronchus.
- To ensure homogenous distribution of SURVANTA throughout the lungs, each dose is divided into four quarter-doses.
- Each quarter-dose is administered with the infant in a different position. The recommended positions are:
- Head and body inclined 5-10° down, head turned to the right
- Head and body inclined 5-10° down, head turned to the left
- Head and body inclined 5-10° up, head turned to the right
- Head and body inclined 5-10° up, head turned to the left
- The dosing procedure is facilitated if one person administers the dose while another person positions and monitors the infant.
- First Dose
- Determine the total dose of SURVANTA from the SURVANTA dosing chart based on the infant’s birth weight. Slowly withdraw the entire contents of the vial into a plastic syringe through a large-gauge needle (eg, at least 20 gauge). Do not filter SURVANTA and avoid shaking.
- Attach the premeasured 5 French end-hole catheter to the syringe. Fill the catheter with SURVANTA. Discard excess SURVANTA through the catheter so that only the total dose to be given remains in the syringe.
- Before administering SURVANTA, assure proper placement and patency of the endotracheal tube. At the discretion of the clinician, the endotracheal tube may be suctioned before administering SURVANTA. The infant should be allowed to stabilize before proceeding with dosing.
- In the prevention strategy, weigh, intubate and stabilize the infant. Administer the dose as soon as possible after birth, preferably within 15 minutes. Position the infant appropriately and gently inject the first quarter-dose through the catheter over 2-3 seconds.
- After administration of the first quarter-dose, remove the catheter from the endotracheal tube. Manually ventilate with a hand-bag with sufficient oxygen to prevent cyanosis, at a rate of 60 breaths/minute, and sufficient positive pressure to provide adequate air exchange and chest wall excursion.
- In the rescue strategy, the first dose should be given as soon as possible after the infant is placed on a ventilator for management of RDS. In the clinical trials, immediately before instilling the first quarter-dose, the infant’s ventilator settings were changed to rate 60/minute, inspiratory time 0.5 second, and FiO2 1.0.
- Position the infant appropriately and gently inject the first quarter-dose through the catheter over 2-3 seconds. After administration of the first quarter-dose, remove the catheter from the endotracheal tube and continue mechanical ventilation.
- In both strategies, ventilate the infant for at least 30 seconds or until stable. Reposition the infant for instillation of the next quarter-dose.
- Instill the remaining quarter-doses using the same procedures. After instillation of each quarter-dose, remove the catheter and ventilate for at least
- 30 seconds or until the infant is stabilized. After instillation of the final quarter-dose, remove the catheter without flushing it. Do not suction the infant for 1 hour after dosing unless signs of significant airway obstruction occur.
- After completion of the dosing procedure, resume usual ventilator management and clinical care.
- Repeat Doses
- The dosage of SURVANTA for repeat doses is also 100 mg phospholipids/kg and is based on the infant’s birth weight. The infant should not be reweighed for determination of the SURVANTA dosage. Use the SURVANTA Dosing Chart to determine the total dosage.
- The need for additional doses of SURVANTA is determined by evidence of continuing respiratory distress. Using the following criteria for redosing, significant reductions in mortality due to RDS were observed in the multiple-dose clinical trials with SURVANTA.
- Dose no sooner than 6 hours after the preceding dose if the infant remains intubated and requires at least 30% inspired oxygen to maintain a PaO2 less than or equal to 80 torr.
- Radiographic confirmation of RDS should be obtained before administering additional doses to those who received a prevention dose.
- Prepare SURVANTA and position the infant for administration of each quarter-dose as previously described. After instillation of each quarter-dose, remove the dosing catheter from the endotracheal tube and ventilate the infant for at least 30 seconds or until stable.
- In the clinical studies, ventilator settings used to administer repeat doses were different than those used for the first dose. For repeat doses, the FiO2 was increased by 0.20 or an amount sufficient to prevent cyanosis. The ventilator delivered a rate of 30/minute with an inspiratory time less than
- 1.0 second. If the infant’s pretreatment rate was 30 or greater, it was left unchanged during SURVANTA instillation.
- Manual hand-bag ventilation should not be used to administer repeat doses. During the dosing procedure, ventilator settings may be adjusted at the discretion of the clinician to maintain appropriate oxygenation and ventilation.
- After completion of the dosing procedure, resume usual ventilator management and clinical care.
- If an infant experiences bradycardia or oxygen desaturation during the dosing procedure, stop the dosing procedure and initiate appropriate measures to alleviate the condition. After the infant has stabilized, resume the dosing procedure.
- Rales and moist breath sounds can occur transiently after administration of SURVANTA. Endotracheal suctioning or other remedial action is unnecessary unless clear-cut signs of airway obstruction are present.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Beractant in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Beractant in pediatric patients.
# Contraindications
- None known.
# Warnings
- SURVANTA is intended for intratracheal use only.
- SURVANTA can rapidly affect oxygenation and lung compliance. Therefore, its use should be restricted to a highly supervised clinical setting with immediate availability of clinicians experienced with intubation, ventilator management, and general care of premature infants. Infants receiving SURVANTA should be frequently monitored with arterial or transcutaneous measurement of systemic oxygen and carbon dioxide.
- During the dosing procedure, transient episodes of bradycardia and decreased oxygen saturation have been reported. If these occur, stop the dosing procedure and initiate appropriate measures to alleviate the condition. After stabilization, resume the dosing procedure.
### Precautions
- Rales and moist breath sounds can occur transiently after administration. Endotracheal suctioning or other remedial action is not necessary unless clear-cut signs of airway obstruction are present.
- Increased probability of post-treatment nosocomial sepsis in SURVANTA-treated infants was observed in the controlled clinical trials (Table 3). The increased risk for sepsis among SURVANTA-treated infants was not associated with increased mortality among these infants. The causative organisms were similar in treated and control infants. There was no significant difference between groups in the rate of post-treatment infections other than sepsis.
- Use of SURVANTA in infants less than 600 g birth weight or greater than 1750 g birth weight has not been evaluated in controlled trials. There is no controlled experience with use of SURVANTA in conjunction with experimental therapies for RDS (eg, high-frequency ventilation or extracorporeal membrane oxygenation).
- No information is available on the effects of doses other than 100 mg phospholipids/kg, more than four doses, dosing more frequently than every 6 hours, or administration after 48 hours of age.
# Adverse Reactions
## Clinical Trials Experience
- The most commonly reported adverse experiences were associated with the dosing procedure. In the multiple-dose controlled clinical trials, each dose of SURVANTA was divided into four quarter-doses which were instilled through a catheter inserted into the endotracheal tube by briefly disconnecting the endotracheal tube from the ventilator. Transient bradycardia occurred with 11.9% of doses. Oxygen desaturation occurred with 9.8% of doses.
- Other reactions during the dosing procedure occurred with fewer than 1% of doses and included endotracheal tube reflux, pallor, vasoconstriction, hypotension, endotracheal tube blockage, hypertension, hypocarbia, hypercarbia, and apnea. No deaths occurred during the dosing procedure, and all reactions resolved with symptomatic treatment.
- The occurrence of concurrent illnesses common in premature infants was evaluated in the controlled trials. The rates in all controlled studies are in Table 3.
- When all controlled studies were pooled, there was no difference in intracranial hemorrhage. However, in one of the single-dose rescue studies and one of the multiple-dose prevention studies, the rate of intracranial hemorrhage was significantly higher in SURVANTA patients than control patients (63.3% v 30.8%, P = 0.001; and 48.8% v 34.2%, P = 0.047, respectively). The rate in a Treatment IND involving approximately 8100 infants was lower than in the controlled trials.
- In the controlled clinical trials, there was no effect of SURVANTA on results of common laboratory tests: white blood cell count and serum sodium, potassium, bilirubin, and creatinine.
- More than 4300 pretreatment and post-treatment serum samples from approximately 1500 patients were tested by Western Blot Immunoassay for antibodies to surfactant-associated proteins SP-B and SP-C. No IgG or IgM antibodies were detected.
- Several other complications are known to occur in premature infants. The following conditions were reported in the controlled clinical studies. The rates of the complications were not different in treated and control infants, and none of the complications were attributed to SURVANTA.
- lung consolidation, blood from the endotracheal tube, deterioration after weaning, respiratory decompensation, subglottic stenosis, paralyzed diaphragm, respiratory failure.
- hypotension, hypertension, tachycardia, ventricular tachycardia, aortic thrombosis, cardiac failure, cardio-respiratory arrest, increased apical pulse, persistent fetal circulation, air embolism, total anomalous pulmonary venous return.
- abdominal distention, hemorrhage, intestinal perforations, volvulus, bowel infarct, feeding intolerance, hepatic failure, stress ulcer.
- renal failure, hematuria.
- coagulopathy, thrombocytopenia, disseminated intravascular coagulation.
- seizures
- adrenal hemorrhage, inappropriate ADH secretion, hyperphosphatemia.
- inguinal hernia.
- fever, deterioration.
- To date, no long-term complications or sequelae of SURVANTA therapy have been found.
- Six-month adjusted-age follow-up evaluations of 232 infants (115 treated) demonstrated no clinically important differences between treatment groups in pulmonary and neurologic sequelae, incidence or severity of retinopathy of prematurity, rehospitalizations, growth, or allergic manifestations.
- Six-month adjusted age follow-up evaluations have been completed in 631 (345 treated) of 916 surviving infants. There were significantly less cerebral palsy and need for supplemental oxygen in SURVANTA infants than controls. Wheezing at the time of examination was significantly more frequent among SURVANTA infants, although there was no difference in bronchodilator therapy.
- Final twelve-month follow-up data from the multiple-dose studies are available from 521 (272 treated) of 909 surviving infants. There was significantly less wheezing in SURVANTA infants than controls, in contrast to the six-month results. There was no difference in the incidence of cerebral palsy at twelve months.
- Twenty-four month adjusted age evaluations were completed in 429 (226 treated) of 906 surviving infants. There were significantly fewer SURVANTA infants with rhonchi, wheezing, and tachypnea at the time of examination. No other differences were found.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Beractant in the drug label.
# Drug Interactions
There is limited information regarding Beractant Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Beractant in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Beractant during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Beractant with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Beractant with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Beractant with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Beractant with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Beractant with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Beractant in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Beractant in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Beractant in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Beractant in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- intratracheal
### Monitoring
- Infants receiving SURVANTA should be frequently monitored with arterial or transcutaneous measurement of systemic oxygen and carbon dioxide.
# IV Compatibility
There is limited information regarding IV Compatibility of Beractant in the drug label.
# Overdosage
- Overdosage with SURVANTA has not been reported. Based on animal data, overdosage might result in acute airway obstruction. Treatment should be symptomatic and supportive.
- Rales and moist breath sounds can transiently occur after SURVANTA is given, and do not indicate overdosage. Endotracheal suctioning or other remedial action is not required unless clear-cut signs of airway obstruction are present.
# Pharmacology
## Mechanism of Action
- Endogenous pulmonary surfactant lowers surface tension on alveolar surfaces during respiration and stabilizes the alveoli against collapse at resting transpulmonary pressures. Deficiency of pulmonary surfactant causes Respiratory Distress Syndrome (RDS) in premature infants. SURVANTA replenishes surfactant and restores surface activity to the lungs of these infants.
## Structure
- SURVANTA ® (beractant) Intratracheal Suspension is a sterile, non-pyrogenic pulmonary surfactant intended for intratracheal use only. It is a natural bovine lung extract containing phospholipids, neutral lipids, fatty acids, and surfactant-associated proteins to which colfosceril palmitate (dipalmitoylphosphatidylcholine), palmitic acid, and tripalmitin are added to standardize the composition and to mimic surface-tension lowering properties of natural lung surfactant. The resulting composition provides 25 mg/mL phospholipids (including 11.0-15.5 mg/mL disaturated phosphatidylcholine), 0.5-1.75 mg/mL triglycerides, 1.4-3.5 mg/mL free fatty acids, and less than 1.0 mg/mL protein. It is suspended in 0.9% sodium chloride solution, and heat-sterilized. SURVANTA contains no preservatives. Its protein content consists of two hydrophobic, low molecular weight, surfactant-associated proteins commonly known as SP-B and SP-C. It does not contain the hydrophilic, large molecular weight surfactant-associated protein known as SP-A.
- Each mL of SURVANTA contains 25 mg of phospholipids. It is an off-white to light brown liquid supplied in single-use glass vials containing 4 mL (100 mg phospholipids) or 8 mL (200 mg phospholipids).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Beractant in the drug label.
## Pharmacokinetics
- In vitro, SURVANTA reproducibly lowers minimum surface tension to less than 8 dynes/cm as measured by the pulsating bubble surfactometer and Wilhelmy Surface Balance. In situ, SURVANTA restores pulmonary compliance to excised rat lungs artificially made surfactant-deficient. In vivo, single SURVANTA doses improve lung pressure-volume measurements, lung compliance, and oxygenation in premature rabbits and sheep.
- SURVANTA is administered directly to the target organ, the lungs, where biophysical effects occur at the alveolar surface. In surfactant-deficient premature rabbits and lambs, alveolar clearance of radio-labelled lipid components of SURVANTA is rapid. Most of the dose becomes lung-associated within hours of administration, and the lipids enter endogenous surfactant pathways of reutilization and recycling. In surfactant-sufficient adult animals, SURVANTA clearance is more rapid than in premature and young animals. There is less reutilization and recycling of surfactant in adult animals.
- Limited animal experiments have not found effects of SURVANTA on endogenous surfactant metabolism. Precursor incorporation and subsequent secretion of saturated phosphatidylcholine in premature sheep are not changed by SURVANTA treatments.
- No information is available about the metabolic fate of the surfactant-associated proteins in SURVANTA. The metabolic disposition in humans has not been studied.
## Nonclinical Toxicology
- Carcinogenicity studies have not been performed with SURVANTA. SURVANTA was negative when tested in the Ames test for mutagenicity. Using the maximum feasible dose volume, SURVANTA up to 500 mg phospholipids/kg/day (approximately one-third the premature infant dose based on mg/m2/day) was administered subcutaneously to newborn rats for 5 days. The rats reproduced normally and there were no observable adverse effects in their offspring.
# Clinical Studies
- Clinical effects of SURVANTA were demonstrated in six single-dose and four multiple-dose randomized, multi-center, controlled clinical trials involving approximately 1700 infants. Three open trials, including a Treatment IND, involved more than 8500 infants. Each dose of SURVANTA in all studies was 100 mg phospholipids/kg birth weight and was based on published experience with Surfactant TA, a lyophilized powder dosage form of SURVANTA having the same composition.
- Infants of 600-1250 g birth weight and 23 to 29 weeks estimated gestational age were enrolled in two multiple-dose studies. A dose of SURVANTA was given within 15 minutes of birth to prevent the development of RDS. Up to three additional doses in the first 48 hours, as often as every 6 hours, were given if RDS subsequently developed and infants required mechanical ventilation with an FiO2 ≥ 0.30. Results of the studies at 28 days of age are shown in Table 1.
- Infants of 600-1750 g birth weight with RDS requiring mechanical ventilation and an FiO2 ≥ 0.40 were enrolled in two multiple-dose rescue studies. The initial dose of SURVANTA was given after RDS developed and before 8 hours of age. Infants could receive up to three additional doses in the first 48 hours, as often as every 6 hours, if they required mechanical ventilation and an FiO2 ≥ 0.30. Results of the studies at 28 days of age are shown in Table 2.
- Marked improvements in oxygenation may occur within minutes of administration of SURVANTA.
- All controlled clinical studies with SURVANTA provided information regarding the acute effects of SURVANTA on the arterial-alveolar oxygen ratio (a/APO2), FiO2, and mean airway pressure (MAP) during the first 48 to 72 hours of life. Significant improvements in these variables were sustained for 48-72 hours in SURVANTA-treated infants in four single-dose and two multiple-dose rescue studies and in two multiple-dose prevention studies. In the single-dose prevention studies, the FiO2 improved significantly.
# How Supplied
- SURVANTA (beractant) Intratracheal Suspension is supplied in single-use glass vials containing 4 mL (NDC 0074-1040-04) or 8 mL of SURVANTA (NDC 0074-1040-08). Each milliliter contains 25 mg of phospholipids suspended in 0.9% sodium chloride solution. The color is off-white to light brown.
## Storage
- Store unopened vials at refrigeration temperature (2-8°C). Protect from light. Store vials in carton until ready for use. Vials are for single use only. Upon opening, discard unused drug.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Beractant in the drug label.
# Precautions with Alcohol
- Alcohol-Beractant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Survanta®[1]
# Look-Alike Drug Names
There is limited information regarding Beractant Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Beractant | |
b0cb6dea60eff482996ac4c31cc0a410a0090fc0 | wikidoc | Dipeptide | Dipeptide
A dipeptide is a molecule consisting of two amino acids joined by a single peptide bond.
Dipeptides are produced from polypeptides by the action of the hydrolase enzyme dipeptidyl peptidase. Dietary proteins are digested to dipeptides and amino acids, and the dipeptides are absorbed more rapidly than the amino acids, because their uptake involves a separate mechanism. Dipeptides activate G-cells found in the stomach to secrete gastrin.
The Bergmann azlactone peptide synthesis is a classic organic synthesis for the preparation of dipeptides.
# Examples of dipeptides
- Carnosine (beta-alanyl-L-histidine) is highly concentrated in muscle and brain tissues.
- Anserine (beta-alanyl-N-methyl histidine) is found in the skeletal muscle and brain of mammals.
- Homoanserine (N-(4-Aminobutyryl)-L-histidine) is another dipeptide identified in the brain and muscles of mammals.
- Kyotorphin (L-tyrosyl-L-arginine) is a neuroactive dipeptide which plays a role in pain regulation in the brain.
- Balenine (or ophidine) (beta-alanyl-N tau-methyl histidine) has been identified in the muscles of several species of mammal (including man), and the chicken.
- Aspartame (N-L-a-aspartyl-L-phenylalanine 1-methyl ester) is an artificial sweetener.
- Glorin (N- propionyl-γ-L-glutamyl-L-ornithine-δ-lac ethyl ester) is a chemotactic dipeptide for the slime-mould Polysphondylium violaceum.
- Barettin (cyclo-) is a cyclic dipeptide from the marine sponge Geodia barretti.
- Pseudoproline | Dipeptide
A dipeptide is a molecule consisting of two amino acids joined by a single peptide bond.
Dipeptides are produced from polypeptides by the action of the hydrolase enzyme dipeptidyl peptidase. Dietary proteins are digested to dipeptides and amino acids, and the dipeptides are absorbed more rapidly than the amino acids, because their uptake involves a separate mechanism. Dipeptides activate G-cells found in the stomach to secrete gastrin.
The Bergmann azlactone peptide synthesis is a classic organic synthesis for the preparation of dipeptides. [1] [2]
# Examples of dipeptides
- Carnosine (beta-alanyl-L-histidine) is highly concentrated in muscle and brain tissues.
- Anserine (beta-alanyl-N-methyl histidine) is found in the skeletal muscle and brain of mammals.
- Homoanserine (N-(4-Aminobutyryl)-L-histidine) is another dipeptide identified in the brain and muscles of mammals.
- Kyotorphin (L-tyrosyl-L-arginine) is a neuroactive dipeptide which plays a role in pain regulation in the brain.
- Balenine (or ophidine) (beta-alanyl-N tau-methyl histidine) has been identified in the muscles of several species of mammal (including man), and the chicken.
- Aspartame (N-L-a-aspartyl-L-phenylalanine 1-methyl ester) is an artificial sweetener.
- Glorin (N- propionyl-γ-L-glutamyl-L-ornithine-δ-lac ethyl ester) is a chemotactic dipeptide for the slime-mould Polysphondylium violaceum.
- Barettin (cyclo-[(6-bromo-8-en-tryptophan)-arginine]) is a cyclic dipeptide from the marine sponge Geodia barretti.
- Pseudoproline | https://www.wikidoc.org/index.php/Bergmann_azlactone_peptide_synthesis | |
201210c713b5533ac55b8fda79f552ef69b37c73 | wikidoc | Beryllium | Beryllium
# Overview
Beryllium (Template:PronEng) is a chemical element with the symbol Be and atomic number 4. A bivalent element, beryllium is a steel grey, strong, light-weight yet brittle, alkaline earth metal. It is primarily used as a hardening agent in alloys, most notably beryllium copper.
# Properties
- It has one of the highest melting points of the light metals. The modulus of elasticity of beryllium is approximately 1/3 greater than that of steel. It has excellent thermal conductivity, conducts sound with the highest velocity of any solid , and is nonmagnetic.
- It is highly permeable to X-rays, and neutrons are liberated when it is hit by alpha particles, as from radium or polonium (about 30 neutrons/million alpha particles).
- At standard temperature and pressures beryllium resists oxidation when exposed to air (although its ability to scratch glass is probably due to the formation of a thin layer of the oxide).It resists attack by concentrated nitric acid.
# History
This element was discovered by Louis-Nicolas Vauquelin in 1798 as the oxide in beryl and in emeralds. Friedrich Wöhler and A. A. Bussy independently isolated the metal in 1828 by reacting potassium and beryllium chloride.
# Etymology
The name beryllium comes from the Greek βερυλλος, beryllos, beryl, from Prakrit veruliya, from Pāli veuriya; akin or perhaps akin to Tamil language veiru or, viar, "to become pale," in reference to the pale semiprecious gemstone beryl At one time beryllium was referred to as glucinium (from Greek, sweet), due to the sweet taste of its salts (with the accompanying chemical symbol "Gl") .
# Applications
## Mechanical
- Due to its stiffness, light weight, and dimensional stability over a wide temperature range, Beryllium metal is used in the defense and aerospace industries as light-weight structural materials in high-speed aircraft, missiles, space vehicles, and communication satellites. For example, many high-quality liquid fueled rockets use nozzles of pure Be, an example being the Saturn V.
- Beryllium is used as an alloying agent in the production of beryllium copper, which contains up to 2.5% beryllium. Beryllium-copper alloys are used in a wide variety of applications because of their combination of high electrical and thermal conductivity, high strength and hardness, nonmagnetic properties, along with good corrosion and fatigue resistance. These applications include the making of spot-welding electrodes, springs, non-sparking tools and electrical contacts.
- In the telecommunications industry, tools made of beryllium are used to tune the highly magnetic klystrons used for high power microwave applications.
- Beryllium copper is used in electrical spring contacts.
- Beryllium is used in the making of gyroscopes, computer equipment, watch springs and instruments where light-weight, rigidity and dimensional stability are needed.
- The James Webb Space Telescope will have 18 hexagonal beryllium sections for its mirrors. Because JWST will face a temperature of −240 degrees Celsius (33 kelvins), the mirror is made of beryllium, a material capable of handling extreme cold better than glass. Beryllium contracts and deforms less than glass — and thus remains more uniform — in such temperatures. For the same reason, the optics of the Spitzer Space Telescope are entirely built of beryllium metal.
- Beryllium has been used in tweeter and mid-range audio loudspeaker construction as an alternative to titanium and aluminium, largely due to its lower density and greater rigidity.
## Radiation
- Thin sheets of beryllium foil are used as windows in X-ray detectors to filter out visible light and allow only X-rays to be detected.
- Sheets of beryllium ranging from 3 millimetres (0.1181102361 in) thick down to 25 (Expression error: Missing operand for *. in) thick are used as the output window in x-ray tubes, allowing x-rays to leave the tube while keeping a vacuum on the inside of the tube.
- In the field of X-ray lithography beryllium is used for the reproduction of microscopic integrated circuits.
- Because of its low atomic number beryllium is almost transparent to energetic electrically charged particles. Therefore it is used to build the beam pipe around the collision region in collider particle physics experiments. Notably all four main detector experiments at the Large Hadron Collider accelerator (ALICE, ATLAS, CMS, LHCb) use a beryllium beam-pipe.
## Nuclear
- Beryllium is a good neutron moderator because it has a low neutron absorption cross section, and because light nuclei are more effective at slowing down neutrons than heavy nuclei. It has been used in some nuclear reactors; see Category:Beryllium moderated reactors.
- Beryllium is used in nuclear weapon designs, where it is a good pusher and the best possible neutron reflector, reducing the critical mass needed for a fission chain reaction, while adding relatively little mass to the weapon itself. It is a poor tamper because of its low mass, but tamping is less important in fusion-boosted fission weapons. Its transparency to X-rays also lets the energy from a primary fission explosion escape for use in radiation implosion of a secondary fusion stage.
- Beryllium is sometimes used in neutron sources, in which the beryllium is mixed with an alpha emitter such as 210Po, 226Ra, 239Pu or 241Am.
- Beryllium is used in the Joint European Torus fusion research facility and will be used in ITER, to condition the plasma facing components.
# Compounds
- Beryllium is an effective p-type dopant in III-V compound semiconductors. It is widely used in materials such as GaAs, AlGaAs, InGaAs, and InAlAs grown by molecular beam epitaxy (MBE).
- Beryllium oxide is useful for many applications that require an excellent heat conductor, with high strength and hardness, with a very high melting point, and that acts as an electrical insulator. It is being studied for use in increasing the thermal conductivity of uranium dioxide nuclear fuel pellets.
- Beryllium compounds were once used in fluorescent lighting tubes, but this use was discontinued because of berylliosis in the workers manufacturing the tubes (see below).
See also Beryllium compounds.
# Occurrence on Earth
Beryllium is an essential constituent of about 100 out of about 4000 known minerals, the most important of which are bertrandite (Be4Si2O7(OH)2), beryl (Al2Be3Si6O18), chrysoberyl (Al2BeO4), and phenakite (Be2SiO4). Precious forms of beryl are aquamarine and emerald.
The most important commercial sources of beryllium and its compounds are beryl and bertrandite. Beryllium metal did not become readily available until 1957. Currently, most production of this metal is accomplished by reducing beryllium fluoride with magnesium metal. The price on the US market for vacuum-cast beryllium ingots was 338 US$ per pound ($745/kg) in 2001.
See also beryllium minerals.
# Isotopes
Of beryllium's isotopes, only 9Be is stable. Cosmogenic 10Be is produced in the atmosphere by cosmic ray spallation of oxygen and nitrogen. Because beryllium tends to exist in solutions below about pH 5.5 (and most rainwater has a pH less than 5), it will dissolve and be transported to the Earth's surface via rainwater. As the precipitation quickly becomes more alkaline, beryllium drops out of solution. Cosmogenic 10Be thereby accumulates at the soil surface, where its relatively long half-life (1.51 million years) permits a long residence time before decaying to 10B. 10Be and its daughter products have been used to examine soil erosion, soil formation from regolith, the development of lateritic soils, as well as variations in solar activity and the age of ice cores. It is also formed in nuclear explosions by a reaction of fast neutrons with 13C in the carbon dioxide in air, and is one of the historical indicators of past activity at nuclear test sites.
The fact that 7Be and 8Be are unstable has profound cosmological consequences as it means that elements heavier than beryllium could not be produced by nuclear fusion in the Big Bang. However, Fred Hoyle showed that the energy levels of 8Be and 12C favour carbon production by the triple-alpha process in helium burning stars, thus making life possible. (See also Big Bang nucleosynthesis).
The shortest-lived known isotope of beryllium is 13Be which decays through neutron emission. It has a half-life of 2.7 × 10-21 second. 6Be is also very short-lived with a half-life of 5.0 × 10-21 second.
The exotics 11Be and 14Be are known to exhibit a nuclear halo.
# Precautions
According to the International Agency for Research on Cancer (IARC), beryllium and beryllium compounds are Category 1 carcinogens; they are carcinogenic to both animals and humans. Chronic berylliosis is a pulmonary and systemic granulomatous disease caused by exposure to beryllium. Acute beryllium disease in the form of chemical pneumonitis was first reported in Europe in 1933 and in the United States in 1943. Cases of chronic berylliosis were first described in 1946 among workers in plants manufacturing fluorescent lamps in Massachusetts. Chronic berylliosis resembles sarcoidosis in many respects, and the differential diagnosis is often difficult.
Although the use of beryllium compounds in fluorescent lighting tubes was discontinued in 1949, potential for exposure to beryllium exists in the nuclear and aerospace industries and in the refining of beryllium metal and melting of beryllium-containing alloys, the manufacturing of electronic devices, and the handling of other beryllium-containing material.
Early researchers tasted beryllium and its various compounds for sweetness in order to verify its presence. Modern diagnostic equipment no longer necessitates this highly risky procedure and no attempt should be made to ingest this highly toxic substance. Beryllium and its compounds should be handled with great care and special precautions must be taken when carrying out any activity which could result in the release of beryllium dust (lung cancer is a possible result of prolonged exposure to beryllium laden dust).
This substance can be handled safely if certain procedures are followed. No attempt should be made to work with beryllium before familiarization with correct handling procedures.
A successful test for beryllium on different surface areas has been recently developed. The procedure uses fluorescence when beryllium is bound to sulfonated hydroxybenzoquinoline to detect up to 10 times lower than the recommended limit for beryllium concentration in the work place. Fluorescence increases with increasing beryllium concentration. The new procedure has been successfully tested on a variety of surfaces.
## Inhalation
Beryllium can be harmful if inhaled and the effects depend on period of exposure. If beryllium concentrations in air are high enough (greater than 100 µg/m³), an acute condition can result, called acute beryllium disease, which resembles pneumonia. Occupational and community air standards are effective in preventing most acute lung damage. Long term exposure to beryllium can increase the risk of developing lung cancer. The more common and serious health hazard from beryllium today is chronic beryllium disease (CBD), discussed below. It continues to occur in industries as diverse as metal recycling, dental laboratories, alloy manufacturing, nuclear weapons production, defense industries, and metal machine shops that work with alloys containing small amounts of beryllium.
### Chronic beryllium disease (CBD)
Some people (1-15%) become sensitive to beryllium. These individuals may develop an inflammatory reaction that principally targets the respiratory system and skin. This condition is called chronic beryllium disease (CBD), and can occur within a few months or many years after exposure to higher than normal levels of beryllium (greater than 0.02 µg/m³). This disease causes fatigue, weakness, night sweats and can cause difficulty in breathing and a persistent dry cough. It can result in anorexia, weight loss, and may also lead to right-side heart enlargement and heart disease in advanced cases. Some people who are sensitized to beryllium may not have any symptoms. The disease is treatable, but not curable with traditional drugs and medicine. CBD occurs when the body's immune system recognizes beryllium particles as foreign material and mounts an immune system attack against the particles. Because these particles are typically inhaled into the lungs, the lungs become the major site where the immune system responds, they become inflamed and fill with large numbers of white blood cells that accumulate wherever beryllium particles are found. These cells form balls around the beryllium particles called “granulomas.” When enough of these develop, they interfere with the normal function of the organ. Over time, the lungs become stiff and lose their ability to help transfer oxygen from the air into the bloodstream. Patients with CBD develop difficulty inhaling and exhaling sufficient amounts of air, and the amount of oxygen in their bloodstreams falls. Treatment of such patients includes use of oxygen and medicines that try to suppress the immune system’s over-reaction to beryllium. A class of immunosuppressive medicines called glucocorticoids (example: prednisone) is most commonly used as treatment. The general population is unlikely to develop acute or chronic beryllium disease because ambient air levels of beryllium are normally very low (0.00003-0.0002 µg/m³).
## Ingestion
Swallowing beryllium has not been reported to cause effects in humans because very little beryllium is absorbed from the stomach and intestines. Ulcers have been seen in dogs ingesting beryllium in their
diet.
## Dermatological effects
Beryllium can cause contact dermatitis. Beryllium contact with skin that has been scraped or cut may cause rashes, ulcers, or bumps under the skin called granulomas.
## Effects on children
There are no studies on the health effects of children exposed to beryllium, although individual cases of CBD have been reported in children of beryllium workers from the 1940s. It is likely that the health effects seen in children exposed to beryllium will be similar to the effects seen in adults. It is unknown whether children differ from adults in their susceptibility to beryllium. It is unclear whether beryllium is teratogenic.
## Detection in the body
Beryllium can be measured in the urine and blood. The amount of beryllium in blood or urine may not indicate time or quantity of exposure. Beryllium levels can also be measured in lung and skin samples. While such measurements may help establish that exposure has occurred, other tests are used to determine if that exposure has resulted in health effects. A blood test, the blood beryllium lymphocyte proliferation test (BeLPT), identifies beryllium sensitization and has predictive value for CBD. The BeLPT has become the standard test for detecting beryllium sensitization and CBD in individuals who are suspected of having CBD and to help distinguish it from similar conditions such as sarcoidosis. It is also the main test used in industry health programs to monitor whether disease is occurring among current and former workers who have been exposed to beryllium on the job. The test can detect disease that is at an early stage, or can detect disease at more advanced stages of illness as well. The BeLPT can also be performed using cells obtained from a person's lung by a procedure called "bronchoscopy."
## Industrial release and occupational exposure limits
Typical levels of beryllium that industries may release into the air are of the order of 0.01 µg/m³, averaged over a 30-day period, or 2 µg/m³ of workroom air for an 8-hour work shift. Compliance with the current U.S. Occupational Safety and Health Administration (OSHA) permissible exposure limit for beryllium of 2 µg/m³ has been determined to be inadequate to protect workers from developing beryllium sensitization and CBD. The American Conference of Governmental Industrial Hygienists (ACGIH), which is an independent organization of experts in the field of occupational health, has proposed a threshold limit value (TLV) of 0.05 µg/m³ in a 2006 Notice of Intended Change (NIC). This TLV is 40 times lower than the current OHSA permissible exposure limit, reflecting the ACGIH analysis of best available peer-reviewed research data concerning how little airborne beryllium is required to cause sensitization and CBD. Because it can be difficult to control industrial exposures to beryllium, it is advisable to use any methods possible to reduce airborne and surface contamination by beryllium, to minimize the use of beryllium and beryllium-containing alloys whenever possible, and to educate people about the potential hazards if they are likely to encounter beryllium dust or fumes. | Beryllium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Beryllium (Template:PronEng) is a chemical element with the symbol Be and atomic number 4. A bivalent element, beryllium is a steel grey, strong, light-weight yet brittle, alkaline earth metal. It is primarily used as a hardening agent in alloys, most notably beryllium copper.
# Properties
- It has one of the highest melting points of the light metals. The modulus of elasticity of beryllium is approximately 1/3 greater than that of steel. It has excellent thermal conductivity, conducts sound with the highest velocity of any solid [2], and is nonmagnetic.
- It is highly permeable to X-rays, and neutrons are liberated when it is hit by alpha particles, as from radium or polonium (about 30 neutrons/million alpha particles).
- At standard temperature and pressures beryllium resists oxidation when exposed to air (although its ability to scratch glass is probably due to the formation of a thin layer of the oxide).It resists attack by concentrated nitric acid.
# History
This element was discovered by Louis-Nicolas Vauquelin in 1798 as the oxide in beryl and in emeralds. Friedrich Wöhler and A. A. Bussy independently isolated the metal in 1828 by reacting potassium and beryllium chloride.
# Etymology
The name beryllium comes from the Greek βερυλλος, beryllos, beryl, from Prakrit veruliya, from Pāli veuriya; akin or perhaps akin to Tamil language veiru or, viar, "to become pale," in reference to the pale semiprecious gemstone beryl[1] At one time beryllium was referred to as glucinium (from Greek, sweet), due to the sweet taste of its salts (with the accompanying chemical symbol "Gl"[2]) .
# Applications
## Mechanical
- Due to its stiffness, light weight, and dimensional stability over a wide temperature range, Beryllium metal is used in the defense and aerospace industries as light-weight structural materials in high-speed aircraft, missiles, space vehicles, and communication satellites. For example, many high-quality liquid fueled rockets use nozzles of pure Be, an example being the Saturn V.
- Beryllium is used as an alloying agent in the production of beryllium copper, which contains up to 2.5% beryllium. Beryllium-copper alloys are used in a wide variety of applications because of their combination of high electrical and thermal conductivity, high strength and hardness, nonmagnetic properties, along with good corrosion and fatigue resistance. These applications include the making of spot-welding electrodes, springs, non-sparking tools and electrical contacts.
- In the telecommunications industry, tools made of beryllium are used to tune the highly magnetic klystrons used for high power microwave applications.
- Beryllium copper is used in electrical spring contacts.
- Beryllium is used in the making of gyroscopes, computer equipment, watch springs and instruments where light-weight, rigidity and dimensional stability are needed.
- The James Webb Space Telescope[3] will have 18 hexagonal beryllium sections for its mirrors. Because JWST will face a temperature of −240 degrees Celsius (33 kelvins), the mirror is made of beryllium, a material capable of handling extreme cold better than glass. Beryllium contracts and deforms less than glass — and thus remains more uniform — in such temperatures. For the same reason, the optics of the Spitzer Space Telescope are entirely built of beryllium metal.
- Beryllium has been used in tweeter and mid-range audio loudspeaker construction as an alternative to titanium and aluminium, largely due to its lower density and greater rigidity.
## Radiation
- Thin sheets of beryllium foil are used as windows in X-ray detectors to filter out visible light and allow only X-rays to be detected.
- Sheets of beryllium ranging from 3 millimetres (0.1181102361 in) thick down to 25 (Expression error: Missing operand for *. in) thick are used as the output window in x-ray tubes, allowing x-rays to leave the tube while keeping a vacuum on the inside of the tube.
- In the field of X-ray lithography beryllium is used for the reproduction of microscopic integrated circuits.
- Because of its low atomic number beryllium is almost transparent to energetic electrically charged particles. Therefore it is used to build the beam pipe around the collision region in collider particle physics experiments. Notably all four main detector experiments at the Large Hadron Collider accelerator (ALICE, ATLAS, CMS, LHCb) use a beryllium beam-pipe.
## Nuclear
- Beryllium is a good neutron moderator because it has a low neutron absorption cross section, and because light nuclei are more effective at slowing down neutrons than heavy nuclei. It has been used in some nuclear reactors; see Category:Beryllium moderated reactors.
- Beryllium is used in nuclear weapon designs, where it is a good pusher and the best possible neutron reflector, reducing the critical mass needed for a fission chain reaction, while adding relatively little mass to the weapon itself. It is a poor tamper because of its low mass, but tamping is less important in fusion-boosted fission weapons. Its transparency to X-rays also lets the energy from a primary fission explosion escape for use in radiation implosion of a secondary fusion stage.
- Beryllium is sometimes used in neutron sources, in which the beryllium is mixed with an alpha emitter such as 210Po, 226Ra, 239Pu or 241Am.
- Beryllium is used in the Joint European Torus fusion research facility and will be used in ITER, to condition the plasma facing components.[4]
# Compounds
- Beryllium is an effective p-type dopant in III-V compound semiconductors. It is widely used in materials such as GaAs, AlGaAs, InGaAs, and InAlAs grown by molecular beam epitaxy (MBE).
- Beryllium oxide is useful for many applications that require an excellent heat conductor, with high strength and hardness, with a very high melting point, and that acts as an electrical insulator. It is being studied for use in increasing the thermal conductivity of uranium dioxide nuclear fuel pellets.[5]
- Beryllium compounds were once used in fluorescent lighting tubes, but this use was discontinued because of berylliosis in the workers manufacturing the tubes (see below).
See also Beryllium compounds.
# Occurrence on Earth
Beryllium is an essential constituent of about 100 out of about 4000 known minerals, the most important of which are bertrandite (Be4Si2O7(OH)2), beryl (Al2Be3Si6O18), chrysoberyl (Al2BeO4), and phenakite (Be2SiO4). Precious forms of beryl are aquamarine and emerald.
The most important commercial sources of beryllium and its compounds are beryl and bertrandite. Beryllium metal did not become readily available until 1957. Currently, most production of this metal is accomplished by reducing beryllium fluoride with magnesium metal. The price on the US market for vacuum-cast beryllium ingots was 338 US$ per pound ($745/kg) in 2001.[6]
See also beryllium minerals.
# Isotopes
Of beryllium's isotopes, only 9Be is stable. Cosmogenic 10Be is produced in the atmosphere by cosmic ray spallation of oxygen and nitrogen. Because beryllium tends to exist in solutions below about pH 5.5 (and most rainwater has a pH less than 5), it will dissolve and be transported to the Earth's surface via rainwater. As the precipitation quickly becomes more alkaline, beryllium drops out of solution. Cosmogenic 10Be thereby accumulates at the soil surface, where its relatively long half-life (1.51 million years) permits a long residence time before decaying to 10B. 10Be and its daughter products have been used to examine soil erosion, soil formation from regolith, the development of lateritic soils, as well as variations in solar activity and the age of ice cores. It is also formed in nuclear explosions by a reaction of fast neutrons with 13C in the carbon dioxide in air, and is one of the historical indicators of past activity at nuclear test sites.
The fact that 7Be and 8Be are unstable has profound cosmological consequences as it means that elements heavier than beryllium could not be produced by nuclear fusion in the Big Bang. However, Fred Hoyle showed that the energy levels of 8Be and 12C favour carbon production by the triple-alpha process in helium burning stars, thus making life possible. (See also Big Bang nucleosynthesis).
The shortest-lived known isotope of beryllium is 13Be which decays through neutron emission. It has a half-life of 2.7 × 10-21 second. 6Be is also very short-lived with a half-life of 5.0 × 10-21 second.
The exotics 11Be and 14Be are known to exhibit a nuclear halo.
# Precautions
According to the International Agency for Research on Cancer (IARC), beryllium and beryllium compounds are Category 1 carcinogens; they are carcinogenic to both animals and humans.[7] Chronic berylliosis is a pulmonary and systemic granulomatous disease caused by exposure to beryllium. Acute beryllium disease in the form of chemical pneumonitis was first reported in Europe in 1933 and in the United States in 1943. Cases of chronic berylliosis were first described in 1946 among workers in plants manufacturing fluorescent lamps in Massachusetts. Chronic berylliosis resembles sarcoidosis in many respects, and the differential diagnosis is often difficult.
Although the use of beryllium compounds in fluorescent lighting tubes was discontinued in 1949, potential for exposure to beryllium exists in the nuclear and aerospace industries and in the refining of beryllium metal and melting of beryllium-containing alloys, the manufacturing of electronic devices, and the handling of other beryllium-containing material.
Early researchers tasted beryllium and its various compounds for sweetness in order to verify its presence. Modern diagnostic equipment no longer necessitates this highly risky procedure and no attempt should be made to ingest this highly toxic substance. Beryllium and its compounds should be handled with great care and special precautions must be taken when carrying out any activity which could result in the release of beryllium dust (lung cancer is a possible result of prolonged exposure to beryllium laden dust).
This substance can be handled safely if certain procedures are followed. No attempt should be made to work with beryllium before familiarization with correct handling procedures.
A successful test for beryllium on different surface areas has been recently developed. The procedure uses fluorescence when beryllium is bound to sulfonated hydroxybenzoquinoline to detect up to 10 times lower than the recommended limit for beryllium concentration in the work place. Fluorescence increases with increasing beryllium concentration. The new procedure has been successfully tested on a variety of surfaces.
## Inhalation
Beryllium can be harmful if inhaled and the effects depend on period of exposure. If beryllium concentrations in air are high enough (greater than 100 µg/m³), an acute condition can result, called acute beryllium disease, which resembles pneumonia. Occupational and community air standards are effective in preventing most acute lung damage. Long term exposure to beryllium can increase the risk of developing lung cancer. The more common and serious health hazard from beryllium today is chronic beryllium disease (CBD), discussed below. It continues to occur in industries as diverse as metal recycling, dental laboratories, alloy manufacturing, nuclear weapons production, defense industries, and metal machine shops that work with alloys containing small amounts of beryllium.
### Chronic beryllium disease (CBD)
Some people (1-15%) become sensitive to beryllium. These individuals may develop an inflammatory reaction that principally targets the respiratory system and skin. This condition is called chronic beryllium disease (CBD), and can occur within a few months or many years after exposure to higher than normal levels of beryllium (greater than 0.02 µg/m³). This disease causes fatigue, weakness, night sweats and can cause difficulty in breathing and a persistent dry cough. It can result in anorexia, weight loss, and may also lead to right-side heart enlargement and heart disease in advanced cases. Some people who are sensitized to beryllium may not have any symptoms. The disease is treatable, but not curable with traditional drugs and medicine. CBD occurs when the body's immune system recognizes beryllium particles as foreign material and mounts an immune system attack against the particles. Because these particles are typically inhaled into the lungs, the lungs become the major site where the immune system responds, they become inflamed and fill with large numbers of white blood cells that accumulate wherever beryllium particles are found. These cells form balls around the beryllium particles called “granulomas.” When enough of these develop, they interfere with the normal function of the organ. Over time, the lungs become stiff and lose their ability to help transfer oxygen from the air into the bloodstream. Patients with CBD develop difficulty inhaling and exhaling sufficient amounts of air, and the amount of oxygen in their bloodstreams falls. Treatment of such patients includes use of oxygen and medicines that try to suppress the immune system’s over-reaction to beryllium. A class of immunosuppressive medicines called glucocorticoids (example: prednisone) is most commonly used as treatment. The general population is unlikely to develop acute or chronic beryllium disease because ambient air levels of beryllium are normally very low (0.00003-0.0002 µg/m³).
## Ingestion
Swallowing beryllium has not been reported to cause effects in humans because very little beryllium is absorbed from the stomach and intestines. Ulcers have been seen in dogs ingesting beryllium in their
diet.
## Dermatological effects
Beryllium can cause contact dermatitis. Beryllium contact with skin that has been scraped or cut may cause rashes, ulcers, or bumps under the skin called granulomas.
## Effects on children
There are no studies on the health effects of children exposed to beryllium, although individual cases of CBD have been reported in children of beryllium workers from the 1940s. It is likely that the health effects seen in children exposed to beryllium will be similar to the effects seen in adults. It is unknown whether children differ from adults in their susceptibility to beryllium. It is unclear whether beryllium is teratogenic.
## Detection in the body
Beryllium can be measured in the urine and blood. The amount of beryllium in blood or urine may not indicate time or quantity of exposure. Beryllium levels can also be measured in lung and skin samples. While such measurements may help establish that exposure has occurred, other tests are used to determine if that exposure has resulted in health effects. A blood test, the blood beryllium lymphocyte proliferation test (BeLPT), identifies beryllium sensitization and has predictive value for CBD. The BeLPT has become the standard test for detecting beryllium sensitization and CBD in individuals who are suspected of having CBD and to help distinguish it from similar conditions such as sarcoidosis. It is also the main test used in industry health programs to monitor whether disease is occurring among current and former workers who have been exposed to beryllium on the job. The test can detect disease that is at an early stage, or can detect disease at more advanced stages of illness as well. The BeLPT can also be performed using cells obtained from a person's lung by a procedure called "bronchoscopy."
## Industrial release and occupational exposure limits
Typical levels of beryllium that industries may release into the air are of the order of 0.01 µg/m³, averaged over a 30-day period, or 2 µg/m³ of workroom air for an 8-hour work shift. Compliance with the current U.S. Occupational Safety and Health Administration (OSHA) permissible exposure limit for beryllium of 2 µg/m³ has been determined to be inadequate to protect workers from developing beryllium sensitization and CBD. The American Conference of Governmental Industrial Hygienists (ACGIH), which is an independent organization of experts in the field of occupational health, has proposed a threshold limit value (TLV) of 0.05 µg/m³ in a 2006 Notice of Intended Change (NIC). This TLV is 40 times lower than the current OHSA permissible exposure limit, reflecting the ACGIH analysis of best available peer-reviewed research data concerning how little airborne beryllium is required to cause sensitization and CBD. Because it can be difficult to control industrial exposures to beryllium, it is advisable to use any methods possible to reduce airborne and surface contamination by beryllium, to minimize the use of beryllium and beryllium-containing alloys whenever possible, and to educate people about the potential hazards if they are likely to encounter beryllium dust or fumes. | https://www.wikidoc.org/index.php/Beryllium | |
a1deb45a6acca924a52e0bc02e813c67d5e9f21b | wikidoc | Galactose | Galactose
Galactose (Gal) (also called brain sugar) is a type of sugar which is less sweet than glucose and not very water-soluble. It is considered a nutritive sweetener because it has food energy.
Galactan is a polymer of the sugar galactose. It is found in hemicellulose and can be converted to galactose by hydrolysis.
# Sources
It is found in dairy products, in sugar beets and other gums and mucilages.
It is also synthesized by the body, where it forms part of glycolipids and glycoproteins in several tissues.
# Relationship to lactose
Galactose is a monosaccharide constituent, together with glucose, of the disaccharide lactose. The hydrolysis of lactose to glucose and galactose is catalyzed by the enzyme lactase, a β-galactosidase. In the human body, glucose is changed into galactose in order to enable the mammary glands to secrete lactose.
Galactose and glucose are produced by hydrolysis of lactose by β-galactosidase. This enzyme is produced by the lac operon in Escherichia coli (E. coli).
# Clinical significance
Two studies have suggested a possible link between galactose in milk and ovarian cancer. Other studies show no correlation, even in the presence of defective galactose metabolism. More recently, pooled analysis done by the Harvard School of Public Health showed no specific correlation between lactose containing foods and ovarian cancer, and showed statistically insignificant increases in risk for consumption of lactose at ≥30 g/d. More research is necessary to ascertain possible risks.
There are some ongoing studies which suggest that galactose may have a role in treatment of focal segmental glomerulosclerosis (a kidney disease resulting in kidney failure and proteinuria). This effect is likely to be a result of binding of galactose to FSGS factor.
# Structure and isomerism
The first and last -OH groups point the same way and the second and third -OH groups point the other way. D-Galactose has the same configuration at its penultimate carbon as D-glyceraldehyde.
Galactose is a diastereomer of glucose.
# Liver galactose metabolism
In the liver, galactose is converted to glucose 1-phosphate. Glucose 1-phosphate is later on converted to glucose 6-phosphate by the action of the enzyme phosphoglucomutase. Shown below is a diagram depicting galactose metabolism and the different enzymes involved in it.
# Metabolic disorders
There are 3 important disorders involving galactose depending on the type of deficient enzyme: | Galactose
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Editor help
Galactose (Gal) (also called brain sugar[1]) is a type of sugar which is less sweet than glucose and not very water-soluble. It is considered a nutritive sweetener because it has food energy.
Galactan is a polymer of the sugar galactose. It is found in hemicellulose and can be converted to galactose by hydrolysis.
# Sources
It is found in dairy products, in sugar beets and other gums and mucilages.
It is also synthesized by the body, where it forms part of glycolipids and glycoproteins in several tissues.
# Relationship to lactose
Galactose is a monosaccharide constituent, together with glucose, of the disaccharide lactose. The hydrolysis of lactose to glucose and galactose is catalyzed by the enzyme lactase, a β-galactosidase. In the human body, glucose is changed into galactose in order to enable the mammary glands to secrete lactose.
Galactose and glucose are produced by hydrolysis of lactose by β-galactosidase. This enzyme is produced by the lac operon in Escherichia coli (E. coli).
# Clinical significance
Two studies have suggested a possible link between galactose in milk and ovarian cancer.[2][3] Other studies show no correlation, even in the presence of defective galactose metabolism.[4][5] More recently, pooled analysis done by the Harvard School of Public Health showed no specific correlation between lactose containing foods and ovarian cancer, and showed statistically insignificant increases in risk for consumption of lactose at ≥30 g/d.[6] More research is necessary to ascertain possible risks.
There are some ongoing studies which suggest that galactose may have a role in treatment of focal segmental glomerulosclerosis (a kidney disease resulting in kidney failure and proteinuria). This effect is likely to be a result of binding of galactose to FSGS factor.
# Structure and isomerism
The first and last -OH groups point the same way and the second and third -OH groups point the other way. D-Galactose has the same configuration at its penultimate carbon as D-glyceraldehyde.
Galactose is a diastereomer of glucose.
# Liver galactose metabolism
In the liver, galactose is converted to glucose 1-phosphate. Glucose 1-phosphate is later on converted to glucose 6-phosphate by the action of the enzyme phosphoglucomutase. Shown below is a diagram depicting galactose metabolism and the different enzymes involved in it.
# Metabolic disorders
There are 3 important disorders involving galactose depending on the type of deficient enzyme: | https://www.wikidoc.org/index.php/Beta-D-galactose | |
8b449181b815cbe6fd4efc75f590244d0dec815a | wikidoc | Beta cell | Beta cell
# Overview
Beta cells (beta-cells, β-cells) are a type of cell in the pancreas in areas called the islets of Langerhans. They make up 65-80% of the cells in the islets.
# Function
Beta cells make and release insulin, a hormone that controls the level of glucose in the blood. There is a baseline level of insulin maintained by the pancreas, but it can respond quickly to spikes in blood glucose by releasing stored insulin while simultaneously producing more. The response time is fairly quick, taking approximately 10 minutes.
Apart from insulin, beta cells release C-peptide, a byproduct of insulin production, into the bloodstream in equimolar quantities. Measuring the levels of C-peptide can give a practitioner an idea of the viable beta cell mass.
β-cells also produce amylin, also known as IAPP, islet amyloid polypeptide, a protein with unknown function.
# Pathology
- Diabetes mellitus type 1 is caused by the destruction or dysfunction of insulin-producing beta cells by the cells of the immune system.
- In Diabetes mellitus type 2, by contrast, beta cells decline gradually over time, and insulin resistance plays at least as large a role in the disease
- Insulinoma is a rare tumor (usually benign) derived from beta cells. It results in recurrent and prolonged attacks of hypoglycemia.
# Research
Much research is being done in the field of beta-cell physiology and pathology. One major research topic is its effects on diabetes. Many researchers are trying to find ways to use these beta-cells to help control or prevent diabetes. A major topic is the replication of adult beta-cells and the application of these to diabetes. The Larry L. Hillblom Islet Research Center at UCLA is a leading research center in the field, within the Diabetes and Endocrinology Research Center, directed by Dr.
Peter Butler.
A team science effort also exists, known as the Beta Cell Biology Consortium (BCBC). The BCBC is responsible for facilitating interdisciplinary approaches that will advance the understanding of pancreatic islet development and function. The long-term goal of the BCBC is to develop a cell-based therapy for insulin delivery. | Beta cell
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Beta cells (beta-cells, β-cells) are a type of cell in the pancreas in areas called the islets of Langerhans. They make up 65-80% of the cells in the islets.
# Function
Beta cells make and release insulin, a hormone that controls the level of glucose in the blood. There is a baseline level of insulin maintained by the pancreas, but it can respond quickly to spikes in blood glucose by releasing stored insulin while simultaneously producing more. The response time is fairly quick, taking approximately 10 minutes.
Apart from insulin, beta cells release C-peptide, a byproduct of insulin production, into the bloodstream in equimolar quantities. Measuring the levels of C-peptide can give a practitioner an idea of the viable beta cell mass.[1]
β-cells also produce amylin,[2] also known as IAPP, islet amyloid polypeptide, a protein with unknown function.
# Pathology
- Diabetes mellitus type 1 is caused by the destruction or dysfunction of insulin-producing beta cells by the cells of the immune system.
- In Diabetes mellitus type 2, by contrast, beta cells decline gradually over time, and insulin resistance plays at least as large a role in the disease [3][4]
- Insulinoma is a rare tumor (usually benign) derived from beta cells. It results in recurrent and prolonged attacks of hypoglycemia.
# Research
Much research is being done in the field of beta-cell physiology and pathology. One major research topic is its effects on diabetes. Many researchers are trying to find ways to use these beta-cells to help control or prevent diabetes. A major topic is the replication of adult beta-cells and the application of these to diabetes. The Larry L. Hillblom Islet Research Center at UCLA[5] is a leading research center in the field, within the Diabetes and Endocrinology Research Center[6], directed by Dr.
Peter Butler. [7]
A team science effort also exists, known as the Beta Cell Biology Consortium (BCBC).[8] The BCBC is responsible for facilitating interdisciplinary approaches that will advance the understanding of pancreatic islet development and function. The long-term goal of the BCBC is to develop a cell-based therapy for insulin delivery. | https://www.wikidoc.org/index.php/Beta-cells | |
88f139d5f11ca0eff4b5347e604d2914fafda743 | wikidoc | Betel nut | Betel nut
# Overview
Betel nut (Bettlenut), also known as Paaku, Pinang, Areca nut or Cau in Vietnamese and Supari in Bengali language, is the seed of the Betel palm (Areca catechu). Betel nuts can be chewed for their effects as a mildly euphoric stimulant, attributed to the presence of relatively high levels of psychoactive alkaloids. Chewing it increases the capacity to work, also causes a hot sensation in the body; heightened alertness and sweating are an important and popular cultural activity in many Asian countries. It is also used as an offering in Hinduism. In East and Nort-east India, Betel nut is chewed with Paan (Betel leaf). Betel nut and betel leaves are different in chemical compositions. Betel nuts contain arecaidine and guacine whereas the betel leaf oil contains a number of terpeneols.
# Uses
## Modern day consumption
In India (the largest consumer of betel nut), the betel nut is cut into small pieces using a special instrument called sarota, and the husk is wrapped in a "betel leaf" along with lime and may include clove, cardamom, catechu (kattha), etc. for extra flavouring. Betel leaf has a fresh, peppery taste, but, depending on the variety of betel pepper from which it comes, it can be very bitter. Experienced chewers might mix the betel nut with tobacco (the drug effect of the nicotine in tobacco resembles that of betel nut). This preparation of betel leaf with or without betel nut is commonly referred to as paan in India and Pakistan, and is available everywhere.
Betel nut is also sold in ready-to-eat pouches called Pan Masala. It is a mixture of many spices whose primary base is betel nut crushed into very small pieces. Sometimes Pan Masala also includes a small quantity of tobacco; in this case, the product is called gutka.
Betel leaf is a different species of plant than the betel nut, and not in the areca family, but the Piper family (same as pepper and Kava).
## Tradition
Betel chewing is a tradition which dates back thousands of years. The bitter poultice is an acquired taste, and, although it is not clear why the people of the Pacific originally began to chew betelnut, the habit has been passed down through the generations and now provides a cultural link to their past.
The betel and betel juice play an important role in many countries including Myanmar (where it is called kunya), the Solomon Islands and Vietnam. The betel leaves and areca juices are used ceremonially in Vietnamese weddings. Betel leaves and areca juices start the talk between the groom's parents and the bride's parents about the young couple's marriage. The betel and areca are such important symbols of love and marriage that in Vietnamese the phrase "matters of betel and areca" (chuyện trầu cau) is synonymous with marriage. There is a folk tale explaining the origin of this Vietnamese tradition.
In northeast India Betel leaves (pan) with a bit of lime and raw betel nut (called Tamul in Assamese, Sopari in Gujarati, and Kwai in Khasi) are consumed by a majority of the people. In Assam it is a tradition to offer Pan-tamul (Betel leaves and raw betel nut) to guests after tea or meals in a brass plate with stands called a Bota. In Assam betel nuts also have a variety of uses during religious and marriage ceremonies, where it takes on fertility symbolisms. It is also a tradition, especially in Upper Assam, to invite guests to wedding receptions by offering a few betel nuts with leaves. During Bihu, the husori players are offered betel nuts and leaves by each household and their blessings are solicited.
The city Guwahati (guwa betel nut; haat market-place in Assamese) in Assam is named after this nut.
- Chamorro: pugua (Areca catechu), papulu (Piper betel), åfok (lime)
## Betel chewing
Betel chewing is a part of many Asian and Pacific cultures and often takes place at ceremonies and gatherings, and preparation techniques vary from region to region. The nut is either slivered or grated, often flavoured with spices according to local tradition, and usually wrapped in a betel leaf (note that betel leaf comes from the betel pepper plant Piper betle, which is not botanically related to the Betel Palm), along with some lime (calcium oxide or calcium hydroxide) to better extract the alkaloids. Some people also chew tobacco with betel nut. After about 20 minutes of chewing, the fibrous residue which remains of the nut is spat on the street, where it remains visible due to its characteristic bright red pigment. Trails of bright red sputum lining the sidewalks are a sure indication of the popularity of betel chewing in an area. In Papua New Guinea and the Solomon Islands, fresh betel nut is sold on street corners, is chewed with a fresh leaf or 'fruit leaf' (daka in PNG) and mixed with lime. In these countries, dried or flavoured betel nut is not popular. Betel nut chewing has recently been introduced into Vanuatu where it is growing in popularity, especially in the northern islands of the country. In Guam, Betel nut (called Pugua'in the native Chamorro language) is a social pastime as a means to extend friendship, and can be found in many, if not most, large gatherings as part of the food display.
## Other uses
Powdered betel nut is used as a constituent in some tooth powders. Other medicinal uses include the removal of tapeworms and other intestinal parasites by swallowing a few teaspoons of powdered betel nut, or by taking tablets containing the extracted alkaloids.
# Availability
In South Asia, betel nuts are often chewed as an ingredient in a snack called Paan. Also popular in India is a concoction of ground (or thin sliced) betel nuts (supari), tobacco and flavourings known as gutka. The Shimoga District in Karnataka is the largest producer of betelnut in India.
In Taiwan, betel nuts are known as binlang. Bags of 20 to 40 betel nuts are purchased fresh daily by a large number of consumers. To meet the steady year-round demand, there exist two kinds of betel nut shops, each of which sells cigarettes and drinks including beer in addition to their primary purpose of supplying betel nuts. On one hand, there are small mom and pop shops that are often poorly maintained and often do not stand out from other stores nearby. On the other hand, the second provides a sight unique to Taiwan. Such a shop often consists of nothing more than a single free-standing room, or booth, elevated one meter above the street that measures less than 3 meters by 2 meters. Large picture windows comprise two or more of the walls, allowing those who pass by a complete view of the interior. The interior is often painted brightly. Within such a shop, a provocatively dressed young woman can be seen preparing betel nuts (see betel nut beauty). Shops are often identified by multicolored (commonly green) fluorescent tubes or neon lights that frame the windows or that are arranged radially above a store. Customers stop on the side of the road and wait for the girls to bring their betel nut to their vehicles.
In the United States, betel nut is not a controlled or specially taxed substance and may be found in some Asian grocery stores. However, importation of betel in a form other than whole or carved kernels of nuts can be stopped at the discretion of US Customs officers on the grounds of food, agricultural, or medicinal drug violations. Such actions by Customs are very rare.
In the United Kingdom the betel nut is readily available in Asian grocery stores.
# Active compounds
The active chemical compounds of betel nut are arecaine and arecoline, alkaloids which are comparable to nicotine in its stimulating, mildly intoxicating and appetite-suppressing effects on the mind. It also contains the alkaloids arecaidine, arecolidine, guracine (guacine), guvacoline and a number of others that have not yet been studied extensively.
# Effects on health
## Carcinogenicity
The International Agency for Research on Cancer (IARC) regards betel nut to be a known human carcinogen. In countries and communities where betel is consumed extensively, there are vastly higher levels of oral cancer , and in Asian countries where it is consumed, oral cancer forms up to 50% of malignant cancers. Betel nut chewers in Taiwan were found to have a twenty-eight times higher risk of acquiring oral cancer . In addition, the mixing with chewing tobacco provides the same dangerous properties as normal chewing tobacco. Although a substantial proportion of the cancers are caused by the tobacco rather than the betel nut and leaves in the quid, according to WHO, betel chewing without tobacco also leads to cancer of the mouth . A British study reported in 2004 has tried to establish that there is a genetic aspect to this. Betel-nut chewers with faulty gene have higher risk of mouth cancer .
## Teeth
Regular betel chewing causes the teeth and gums to be stained red. It is believed to reduce the incidence of cavities, and toothpastes were once produced containing betel extracts. However, the increase in mouth ulcers and gum deterioration (leading to total loss of teeth) caused by betel chewing outweigh any positive effects.
## Habit-forming
Betel chewing is addictive, and some practitioners consume vast quantities. There is some alarming news released from the BHP (Bureau of Health Promotion) which shows that the habit of betel nut chewing is entering younger age groups and spreading across different professions.
The government of Pakistan has ruled that packets of betel nut must carry health warnings similar to those on cigarette packs, reports Asiaweek magazine. The magazine notes that millions of people in southern Asia are addicted to pan masala, a mixture of betel nut and various oils and other ingredients wrapped in a betel leaf. This is meant to be chewed. India had already placed warnings on packets of betel nut because of a reported link with cancer of the mouth. Children have also been known to choke to death on betel nut. Pakistan’s new laws will forbid the selling of betel nut to children under five years of age. At one stage during the early 2000 period betel nut was being offered in nightclubs in S.E Australia at an alarming rate. Prices ranged from $1-2 per nut. Its street name is "hurry".
## Other harmful effects
According to Medline Plus, "Long-term use has been associated with oral submucous fibrosis (OSF), pre-cancerous oral lesions and squamous cell carcinoma. Acute effects of betel chewing include asthma exacerbation, hypertension, and tachycardia. There may be a higher risk of cancers of the liver, mouth, esophagus, stomach, prostate, cervix, and lung with regular betel use. Other effects can include a possible effect on blood sugar levels, possibly increasing the risk of type 2 diabetes.
When done regularly, betel chewing is considered likely to have harmful effects on health including cancers of the stomach and mouth and damage to gums. Whether this is due to, or exacerbated by, lime being used in betel preparations and the addition of tobacco (in the case of gutka) or other impurities is open to question. It is well known in betel consuming countries that various items, such as opiates and tobacco, can be added to betel preparations to increase the addictive properties, and thus to bolster sales.
Very few studies exist of the use of a "pure" paan preparation: betel nut, betel leaf, and lime, and fewer studies exist of betel nut alone.
Medical literature at this stage (even though highly anecdotal) seems to indicate that regular, addiction-driven use (for example, eight pinches a day) of betel nut in the preparations popular in India, Pakistan, New Guinea, and Taiwan can be harmful. Regarding the preparation methods used in Vietnam and Guam, and regarding occasional usage, there seems to be no strong indication one way or another.
Betal Nuts are known to be a high anti-thiamine factor.
## Positive effects
MedlinePlus indicates "poor-quality research" showing a possible beneficial effect for sufferers of anaemia during pregnancy. However, it counsels against betel nut chewing due a possible risk of spontaneous abortions. It also indicates "poor-quality studies" showing a possible beneficial effect on schizophrenia and for stroke recovery.
# Structure
According to the botanical classification, the betelnut tree belongs to the same family as oil palm and talipot palm, the Arecaceae, but their outer appearances are quite different. | Betel nut
# Overview
Betel nut (Bettlenut), also known as Paaku, Pinang, Areca nut or Cau in Vietnamese and Supari in Bengali language, is the seed of the Betel palm (Areca catechu). Betel nuts can be chewed for their effects as a mildly euphoric stimulant, attributed to the presence of relatively high levels of psychoactive alkaloids. Chewing it increases the capacity to work, also causes a hot sensation in the body; heightened alertness and sweating are an important and popular cultural activity in many Asian countries. It is also used as an offering in Hinduism. In East and Nort-east India, Betel nut is chewed with Paan (Betel leaf). Betel nut and betel leaves are different in chemical compositions. Betel nuts contain arecaidine and guacine whereas the betel leaf oil contains a number of terpeneols.
# Uses
## Modern day consumption
In India (the largest consumer of betel nut), the betel nut is cut into small pieces using a special instrument called sarota, and the husk is wrapped in a "betel leaf" along with lime and may include clove, cardamom, catechu (kattha), etc. for extra flavouring. Betel leaf has a fresh, peppery taste, but, depending on the variety of betel pepper from which it comes, it can be very bitter. Experienced chewers might mix the betel nut with tobacco (the drug effect of the nicotine in tobacco resembles that of betel nut). This preparation of betel leaf with or without betel nut is commonly referred to as paan in India and Pakistan, and is available everywhere.
Betel nut is also sold in ready-to-eat pouches called Pan Masala. It is a mixture of many spices whose primary base is betel nut crushed into very small pieces. Sometimes Pan Masala also includes a small quantity of tobacco; in this case, the product is called gutka.
Betel leaf is a different species of plant than the betel nut, and not in the areca family, but the Piper family (same as pepper and Kava).
## Tradition
Betel chewing is a tradition which dates back thousands of years. The bitter poultice is an acquired taste, and, although it is not clear why the people of the Pacific originally began to chew betelnut, the habit has been passed down through the generations and now provides a cultural link to their past.
The betel and betel juice play an important role in many countries including Myanmar (where it is called kunya), the Solomon Islands and Vietnam. The betel leaves and areca juices are used ceremonially in Vietnamese weddings. Betel leaves and areca juices start the talk between the groom's parents and the bride's parents about the young couple's marriage. The betel and areca are such important symbols of love and marriage that in Vietnamese the phrase "matters of betel and areca" (chuyện trầu cau) is synonymous with marriage. There is a folk tale explaining the origin of this Vietnamese tradition.[1]
In northeast India Betel leaves (pan) with a bit of lime and raw betel nut (called Tamul in Assamese, Sopari in Gujarati, and Kwai in Khasi) are consumed by a majority of the people. In Assam it is a tradition to offer Pan-tamul (Betel leaves and raw betel nut) to guests after tea or meals in a brass plate with stands called a Bota. In Assam betel nuts also have a variety of uses during religious and marriage ceremonies, where it takes on fertility symbolisms. It is also a tradition, especially in Upper Assam, to invite guests to wedding receptions by offering a few betel nuts with leaves. During Bihu, the husori players are offered betel nuts and leaves by each household and their blessings are solicited.
The city Guwahati (guwa betel nut; haat market-place in Assamese) in Assam is named after this nut.
- Chamorro: pugua (Areca catechu), papulu (Piper betel), åfok (lime)
## Betel chewing
Betel chewing is a part of many Asian and Pacific cultures and often takes place at ceremonies and gatherings, and preparation techniques vary from region to region. The nut is either slivered or grated, often flavoured with spices according to local tradition, and usually wrapped in a betel leaf (note that betel leaf comes from the betel pepper plant Piper betle, which is not botanically related to the Betel Palm), along with some lime (calcium oxide or calcium hydroxide) to better extract the alkaloids. Some people also chew tobacco with betel nut. After about 20 minutes of chewing, the fibrous residue which remains of the nut is spat on the street, where it remains visible due to its characteristic bright red pigment. Trails of bright red sputum lining the sidewalks are a sure indication of the popularity of betel chewing in an area. In Papua New Guinea and the Solomon Islands, fresh betel nut is sold on street corners, is chewed with a fresh leaf or 'fruit leaf' (daka in PNG) and mixed with lime. In these countries, dried or flavoured betel nut is not popular. Betel nut chewing has recently been introduced into Vanuatu where it is growing in popularity, especially in the northern islands of the country. In Guam, Betel nut (called Pugua'in the native Chamorro language) is a social pastime as a means to extend friendship, and can be found in many, if not most, large gatherings as part of the food display.
## Other uses
Powdered betel nut is used as a constituent in some tooth powders. Other medicinal uses include the removal of tapeworms and other intestinal parasites by swallowing a few teaspoons of powdered betel nut, or by taking tablets containing the extracted alkaloids.
# Availability
In South Asia, betel nuts are often chewed as an ingredient in a snack called Paan. Also popular in India is a concoction of ground (or thin sliced) betel nuts (supari), tobacco and flavourings known as gutka. The Shimoga District in Karnataka is the largest producer of betelnut in India.
In Taiwan, betel nuts are known as binlang. Bags of 20 to 40 betel nuts are purchased fresh daily by a large number of consumers. To meet the steady year-round demand, there exist two kinds of betel nut shops, each of which sells cigarettes and drinks including beer in addition to their primary purpose of supplying betel nuts. On one hand, there are small mom and pop shops that are often poorly maintained and often do not stand out from other stores nearby. On the other hand, the second provides a sight unique to Taiwan. Such a shop often consists of nothing more than a single free-standing room, or booth, elevated one meter above the street that measures less than 3 meters by 2 meters. Large picture windows comprise two or more of the walls, allowing those who pass by a complete view of the interior. The interior is often painted brightly. Within such a shop, a provocatively dressed young woman can be seen preparing betel nuts (see betel nut beauty). Shops are often identified by multicolored (commonly green) fluorescent tubes or neon lights that frame the windows or that are arranged radially above a store. Customers stop on the side of the road and wait for the girls to bring their betel nut to their vehicles.
In the United States, betel nut is not a controlled or specially taxed substance and may be found in some Asian grocery stores. However, importation of betel in a form other than whole or carved kernels of nuts can be stopped at the discretion of US Customs officers on the grounds of food, agricultural, or medicinal drug violations. Such actions by Customs are very rare.
In the United Kingdom the betel nut is readily available in Asian grocery stores.
# Active compounds
The active chemical compounds of betel nut are arecaine and arecoline, alkaloids which are comparable to nicotine in its stimulating, mildly intoxicating and appetite-suppressing effects on the mind. It also contains the alkaloids arecaidine, arecolidine, guracine (guacine), guvacoline and a number of others that have not yet been studied extensively.
# Effects on health
## Carcinogenicity
The International Agency for Research on Cancer (IARC) regards betel nut to be a known human carcinogen. In countries and communities where betel is consumed extensively, there are vastly higher levels of oral cancer [2], and in Asian countries where it is consumed, oral cancer forms up to 50% of malignant cancers. Betel nut chewers in Taiwan were found to have a twenty-eight times higher risk of acquiring oral cancer [3]. In addition, the mixing with chewing tobacco provides the same dangerous properties as normal chewing tobacco. Although a substantial proportion of the cancers are caused by the tobacco rather than the betel nut and leaves in the quid, according to WHO, betel chewing without tobacco also leads to cancer of the mouth [4]. A British study reported in 2004 has tried to establish that there is a genetic aspect to this. Betel-nut chewers with faulty gene have higher risk of mouth cancer .
## Teeth
Regular betel chewing causes the teeth and gums to be stained red. It is believed to reduce the incidence of cavities, and toothpastes were once produced containing betel extracts. However, the increase in mouth ulcers and gum deterioration (leading to total loss of teeth) caused by betel chewing outweigh any positive effects.
## Habit-forming
Betel chewing is addictive, and some practitioners consume vast quantities. There is some alarming news released from the BHP (Bureau of Health Promotion) which shows that the habit of betel nut chewing is entering younger age groups and spreading across different professions.
The government of Pakistan has ruled that packets of betel nut must carry health warnings similar to those on cigarette packs, reports Asiaweek magazine. The magazine notes that millions of people in southern Asia are addicted to pan masala, a mixture of betel nut and various oils and other ingredients wrapped in a betel leaf. This is meant to be chewed. India had already placed warnings on packets of betel nut because of a reported link with cancer of the mouth. Children have also been known to choke to death on betel nut. Pakistan’s new laws will forbid the selling of betel nut to children under five years of age.[citation needed] At one stage during the early 2000 period betel nut was being offered in nightclubs in S.E Australia at an alarming rate. Prices ranged from $1-2 per nut. Its street name is "hurry".
## Other harmful effects
According to Medline Plus, "Long-term use has been associated with oral submucous fibrosis (OSF), pre-cancerous oral lesions and squamous cell carcinoma. Acute effects of betel chewing include asthma exacerbation, hypertension, and tachycardia. There may be a higher risk of cancers of the liver, mouth, esophagus, stomach, prostate, cervix, and lung with regular betel use. Other effects can include a possible effect on blood sugar levels, possibly increasing the risk of type 2 diabetes.
When done regularly, betel chewing is considered likely to have harmful effects on health including cancers of the stomach and mouth and damage to gums. Whether this is due to, or exacerbated by, lime being used in betel preparations and the addition of tobacco (in the case of gutka) or other impurities is open to question. It is well known in betel consuming countries that various items, such as opiates and tobacco, can be added to betel preparations to increase the addictive properties, and thus to bolster sales.
Very few studies exist of the use of a "pure" paan preparation: betel nut, betel leaf, and lime, and fewer studies exist of betel nut alone.
Medical literature at this stage (even though highly anecdotal) seems to indicate that regular, addiction-driven use (for example, eight pinches a day) of betel nut in the preparations popular in India, Pakistan, New Guinea, and Taiwan can be harmful. Regarding the preparation methods used in Vietnam and Guam, and regarding occasional usage, there seems to be no strong indication one way or another.
Betal Nuts are known to be a high anti-thiamine factor.
## Positive effects
MedlinePlus indicates "poor-quality research" showing a possible beneficial effect for sufferers of anaemia during pregnancy.[citation needed] However, it counsels against betel nut chewing due a possible risk of spontaneous abortions. It also indicates "poor-quality studies" showing a possible beneficial effect on schizophrenia and for stroke recovery.
# Structure
According to the botanical classification, the betelnut tree belongs to the same family as oil palm and talipot palm, the Arecaceae, but their outer appearances are quite different. | https://www.wikidoc.org/index.php/Betel_nut | |
0c5f4f8bb1467fa0b4b936433e2c065aa6c3cf46 | wikidoc | Bevirimat | Bevirimat
Bevirimat is a anti-HIV drug derived from a betulinic acid-like compound, first isolated from Syzygium claviflorum, a Chinese herb. It is believed to inhibit HIV by a novel mechanism, so-called maturation inhibition. It is not currently FDA-approved, but is undergoing clinical trials conducted by the pharmaceutical company Panacos.
# Clinical trials
In December 2007, some results of the Phase IIb trial were released. Thomson Financial News reported that, "some patients respond 'very well' to the drug, while another population 'does not respond as well at current dose levels.'" Panacos said it intends to add a group to the study at a higher dosage.
# Pharmacokinetics
According to the only currently available study, "the mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour."
# Mechanism of action
Bevirimat targets the gag polyprotein precursor, the main structural protein responsible for assembly and budding of virion particles. By binding to the gag polyprotein, bevirimat prevents its cleavage by the protease enzyme into functional subunits. Unlike the protease inhibitors, bevirimat binds the gag protein, not the protease enzyme. The resulting virus particles are structurally defective and are incapable of spreading infection around the body. For unknown reasons, protease inhibitor-resistant HIV-1 was hypersensitive to bevirimat in vitro. | Bevirimat
Bevirimat is a anti-HIV drug derived from a betulinic acid-like compound, first isolated from Syzygium claviflorum, a Chinese herb. It is believed to inhibit HIV by a novel mechanism, so-called maturation inhibition. [1] It is not currently FDA-approved, but is undergoing clinical trials conducted by the pharmaceutical company Panacos.
# Clinical trials
In December 2007, some results of the Phase IIb trial were released. Thomson Financial News reported that, "some patients respond 'very well' to the drug, while another population 'does not respond as well at current dose levels.'" Panacos said it intends to add a group to the study at a higher dosage.[2]
# Pharmacokinetics
According to the only currently available study, "the mean terminal elimination half-life of bevirimat ranged from 56.3 to 69.5 hours, and the mean clearance ranged from 173.9 to 185.8 mL/hour." [3]
# Mechanism of action
Bevirimat targets the gag polyprotein precursor, the main structural protein responsible for assembly and budding of virion particles.[4] By binding to the gag polyprotein, bevirimat prevents its cleavage by the protease enzyme into functional subunits. Unlike the protease inhibitors, bevirimat binds the gag protein, not the protease enzyme. The resulting virus particles are structurally defective and are incapable of spreading infection around the body.[5] For unknown reasons, protease inhibitor-resistant HIV-1 was hypersensitive to bevirimat in vitro.[6]
# External links
- An animation illustrating Bevirimat's mechanism of action
- Overview and Publication Listing for Bevirimat from Panacos | https://www.wikidoc.org/index.php/Bevirimat | |
794fe1bacc1d32e6a455627b1ee05d70509ecb9f | wikidoc | Biguanide | Biguanide
Biguanides (ATC A10 BA) form a class of oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment.
# Examples
Examples of biguanides:
- metformin - widely used in treatment of diabetes mellitus type 2 combined with obesity
- phenformin - withdrawn from the market in most countries due to toxic effects
- buformin - withdrawn from the market due to toxic effects
Proguanil is a biguanide used not for diabetes, but rather as an antimalarial drug.
# History
Galega officinalis was used for diabetes treatment in traditional medicine for centuries. In the 1920s, guanidine compounds were discovered in Galega extracts. Animal studies showed that these compunds lowered blood glucose levels. Some less toxic derivatives, synthalin A and synthalin B, were used for diabetes treatment, but after the discovery of insulin they were forgotten for the next several decades. Biguanides were reintroduced into Type 2 diabetes treatment in the late 1950s. Initially phenformin was widely used, but its potential for sometimes fatal lactic acidosis resulted in its withdrawal from pharmacotherapy in most pharmacopeias (in the U.S. in 1977). Metformin has a much better safety profile, and it is the principal biguanide drug used in pharmacotherapy worldwide.
# Pharmacotherapy
Biguanides do not affect the output of insulin, unlike other hypoglycemic agents such as sulfonylureas and meglitinides. Therefore, they are not only effective in Type 2 diabetics, but they can also be effective in Type 1 patients in concert with insulin therapy.
# Mode of action
The exact mode of action of biguanides is not fully elucidated. However, in hyperinsulinemia, biguanides can lower fasting levels of insulin in plasma. Their therapeutic uses derive from their tendency to reduce gluconeogenesis in the liver, and as a result, reduces the level of glucose in the blood. Biguanides also tend to make the cells of the body more willing to absorb glucose already present in the blood stream, and there again reducing the level of glucose in the plasma.
# Side effects and toxicity
The most common side effect is diarrhea and dyspepsia, occurring in up to 30% of patients. The most important and serious side effect is lactic acidosis. Phenformin and buformin are more prone to cause acidosis than metformin therefore they have been practically replaced by it. However, when metformin is combined with other drugs (combination therapy), hypoglycemia and other side effects are possible. | Biguanide
Biguanides (ATC A10 BA) form a class of oral antihyperglycemic drugs used for diabetes mellitus or prediabetes treatment.
# Examples
Examples of biguanides:
- metformin - widely used in treatment of diabetes mellitus type 2 combined with obesity
- phenformin - withdrawn from the market in most countries due to toxic effects
- buformin - withdrawn from the market due to toxic effects
Proguanil is a biguanide used not for diabetes, but rather as an antimalarial drug.
# History
Galega officinalis was used for diabetes treatment in traditional medicine for centuries. In the 1920s, guanidine compounds were discovered in Galega extracts. Animal studies showed that these compunds lowered blood glucose levels. Some less toxic derivatives, synthalin A and synthalin B, were used for diabetes treatment, but after the discovery of insulin they were forgotten for the next several decades. Biguanides were reintroduced into Type 2 diabetes treatment in the late 1950s. Initially phenformin was widely used, but its potential for sometimes fatal lactic acidosis resulted in its withdrawal from pharmacotherapy in most pharmacopeias (in the U.S. in 1977). Metformin has a much better safety profile, and it is the principal biguanide drug used in pharmacotherapy worldwide.
# Pharmacotherapy
Biguanides do not affect the output of insulin, unlike other hypoglycemic agents such as sulfonylureas and meglitinides. Therefore, they are not only effective in Type 2 diabetics, but they can also be effective in Type 1 patients in concert with insulin therapy.
# Mode of action
The exact mode of action of biguanides is not fully elucidated. However, in hyperinsulinemia, biguanides can lower fasting levels of insulin in plasma. Their therapeutic uses derive from their tendency to reduce gluconeogenesis in the liver, and as a result, reduces the level of glucose in the blood. Biguanides also tend to make the cells of the body more willing to absorb glucose already present in the blood stream, and there again reducing the level of glucose in the plasma.
# Side effects and toxicity
The most common side effect is diarrhea and dyspepsia, occurring in up to 30% of patients. The most important and serious side effect is lactic acidosis. Phenformin and buformin are more prone to cause acidosis than metformin therefore they have been practically replaced by it. However, when metformin is combined with other drugs (combination therapy), hypoglycemia and other side effects are possible.
Template:Oral hypoglycemics
Template:Antimalarials
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Biguanide | |
6a26b25a9e053f1e00f9ac9bd5f57bd69351f2a4 | wikidoc | Bilastine | Bilastine
# Overview
Bilastine (trade name Bilaxten) is a second generation antihistamine drug for the treatment of allergic rhinoconjunctivitis and urticaria (hives).
It exerts its effect as a selective histamine H1 receptor antagonist, and has a effectiveness similar to cetirizine, fexofenadine and desloratadine. It was developed in Spain by FAES Farma.
Bilastine is approved in the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria, but it is not approved by the U.S. Food and Drug Administration for any use in the United States. Bilastine meets the current European Academy of Allergy and Clinical Immunology (EAACI) and Allergic Rhinitis and its Impact of Asthma (ARIA) criteria for medication used in the treatment of allergic rhinitis.
Bilastine has been effective in the treatment of ocular symptoms and diseases of allergies, including rhinoconjuctivitis. Additionally, bilastine has been shown to improve quality of life, and all nasal and ocular symptoms related to allergic rhinitis.
# Chemistry
Bilastine, or 2- piperidin-1-yl] ethyl] phenyl]-2-methylpropionic acid, is a novel molecule with a molecular weight of 463.6 daltons and a chemical structure similar to piperidinyl-benzimidazole. Bilastine can be therefore classified into the same chemical group as many of the new antihistamines on the market, although it is not structurally derived, nor is it a metabolite or enantiomer of any of them, but an original molecule designed with the intent of fulfiling all the requirements of a second-generation antihistamine.
# Dosage
A therapeutic dosage of bilastine is 20 mg once a day orally and shows a rapid onset of action (within 30–60 minutes). It should be taken only by children older than 12 years and adults.
# Pharmacodynamics
Bilastine binds to guinea-pig cerebellar histamine H1-receptors (Ki=44 nM) and to human recombinant histamine H1-receptors (Ki=64 nM) with an affinity comparable to that of astemizole and diphenhydramine, and superior than that of cetirizine by three-fold and fexofenadine by five-fold (Corcóstegui). In different murine models, bilastine by oral route, antagonizes the effects of histamine in a dose-dependent manner, with potency similar to that of cetirizine and between 5.5 and 10 times greater than that of fexofenadine.
Preclinical investigations demonstrate the affinity and specificity of bilastine for histamine H1-receptors compared with other histamine receptors subtypes and other 30 receptors from different amines. In vivo experimentation confirmed the antihistaminic and antiallergic activity, which was at least comparable to that of other second-generation H1-antihistamines such as cetirizine.
Clinical studies using different dosages were done on histamine-induced wheal and flare reaction over a 24-h period, compared with a single 10-mg oral dose of cetirizine. The results of this research indicated that bilastine was at least as efficient as cetirizine in reducing histamine-mediated effects in healthy volunteers. Remarkably, 20 and 50 mg of bilastine reduced the wheal and flare reaction significantly more quickly than cetirizine.
# Clinical Efficacy
The clinical efficacy of bilastine in allergic rhinitis (AR) and urticaria has been assessed in 10 clinical assays in which over 4,600 patients were involved. All of them compared bilastine with placebo and another second generation antihistamine with confirmed efficacy (active comparator). In a first study performed under controlled conditions of allergen exposure and time of exposure with sensitised volunteers (Vienna Challenge Chamber), bilastine 20 mg shows an efficacy similar to that of cetirizine 10 mg for the relief of symptomatic seasonal AR (SAR), with a rapid onset of action (1 h) and a duration of action of at least 24 h. The duration of the effect of both compounds is higher than that of fexofenadine at a dose of 120 mg.
The studies on SAR were double-blind, placebo-controlled, parallel-group involving male and female patients over 12 year of age with symptomatic disease at the beginning of the study. Nasal symptoms (sneezing, rhinorrhea, nasal itching and congestion) were assessed both before treatment and during treatment period on a daily basis. Non nasal symptoms (itchy eye, watery eye, itchy ear and palate) were also assessed according to a 0–3 scale, so that the Total Symptoms Score (TSS) and other related parameters could clearly reflect daily evolution of SAR in each patient and treatment group. Parameters such as quality of life and discomfort were also assessed, and in the same way the type and frequency of AE, tolerability and general safety of treatment were registered. In this SAR studies the daily oral administration during 14 days of bilastine 20 mg proves to have the same efficacy than the administration of cetirizine 10 mg or than the administration of desloratadine 5 mg. Likewise, bilastine 20 mg shows a safety and tolerability profile similar to placebo and significantly superior to that registered for cetirizine, the risk of somnolence and fatigue being respectively 4 and 20 times lower at 1.8% and 0.4%.
The studies in urticaria were double-blind, placebo-controlled, parallel-group involving male and female patients over 18 year of age with symptomatic disease (idiopathic chronic urticaria) at the beginning of the study. Itching intensity as well as number and maximum size of wheals were assessed according to a 0–3 scale so that the Total Symptom Score (TSS) and other related parameters could clearly reflect the daily evolution of urticaria in each patient and treatment group. Parameters such as quality of life and discomfort were also assessed, and in the same way the type and frequency of AE, tolerability and general safety of treatment were registered. In this urticaria studies the daily oral administration during 28 days of bilastine 20 mg proves to have the same efficacy – for the reduction of TSS and the quality of life parameters- than the administration of levocetirizine 5 mg. Likewise, Bilastine 20 mg shows a safety and tolerability profile similar to placebo.
Recently, twenty patients with cold contact urticaria (CCU) were included in a randomized, crossover, double-blind, placebo-controlled 12-week study. They received placebo, 20, 40 or 80 mg of bilastine daily each for 7 days with 14-day washout periods. The primary variable was change in critical temperature thresholds (CTT). Secondary variables were changes in pruritus, levels of histamine, IL-6, IL-8 and TNF-α collected by skin microdialysis and safety and tolerability of bilastine. At doses of 20 mg was highly effective (P < 0.0001) in reducing CTT. Up-dosing to 80 mg significantly (P < 0.04) increased its effectiveness. At this dose, 19 of 20 (95%) patients responded to treatment, with 12 of 20 (60%) becoming symptom free. Only one patient was refractory to treatment. Microdialysis levels of histamine, IL-6 and IL-8 assessed 1-3 h after cold challenge (4°C) were significantly (P < 0.05) decreased following up-dosing with 80 mg bilastine. Bilastine was effective in reducing the symptoms of patients with CCU. Increased efficacy of bilastine with fourfold up-dosing was without sedation and supports urticaria treatment guidelines.
# Pharmacokinetics
## Distribution
Bilastine distribution has an apparent volume of distribution of 1.29 L/kg, and has an elimination half-life of 14.5 h and plasma protein binding of 84–90%.
## Absorption and bioavailability
Bilastine is most quickly absorbed with the absence of food, and reaches a mean peak plasma concentration of 220 ng/mL approximately 1 h after both single and multiple dosing. Absorption is reduced by a high-fat breakfast or fruit juice, and the estimated global oral bioavailability is approximately 60%. Bilastine has linear pharmacokinetics in the 2.5–220 mg dose range in healthy adult subjects without evidence of accumulation after 14 days of treatment.
## Metabolism
Bilastine is not significantly metabolized in humans and is largely eliminated unchanged both in urine and feces – a third and two thirds of the administered dose, respectively, according to a Phase I mass-balance study with radiolabeled bilastine. Bilastine does not readily cross the blood brain barrier and is not metabolized by the liver. Ninety six percent of the administered dose is eliminated within 24 hours.
In relation to its antihistamine effect, oral doses of 20 mg daily of bilastine, measured as skin wheal-and-flare surface areas for 24 h, bilastine is capable of inhibiting 50% of the surface areas – throughout the whole administration interval.
## Drug interactions and food effects
Preclinical data suggest the possibility of interactions between bilastine and drugs or food that are inhibitors or inducers of the P-glycoproteins. Coadministration of bilastine and grapefruit juice (a known P-glycoprotein-mediated drug transport activator) significantly reduced bilastine systemic exposure. This interaction is due to the known effect of grapefruit flavonoids on intestinal transporter systems such as P-glycoproteins and organic anion transporting peptide (OATP).
# Safety and tolerability
Toxicity of bilastine investigated in preclinical toxicology studies in mice, rats and dogs after oral and intravenous administration showed no mortality observed after oral administration of massive doses. After intravenous administration, LD50 (lethal dose for 50% of animals) values were 33 and 45–75 mg/kg in mice and rats, respectively. No signs of toxicity were observed in any organ after bilastine massive overdosing, either orally (in mice, rats and dogs), or intravenously (in rats and dogs) during 4 weeks. No effects on fertility, no teratogenic or mutagenic effects, and no apparent carcinogenic potential were seen in the studies carried out in rats, mice and rabbits.
In clinical research, bilastine has proven to be well tolerated, with an adverse events profile similar to that of placebo in healthy volunteers, patients with AR and with chronic idiopathic urticaria. Although the tolerance profile of bilastine and levocetirizine or desloratadine were very similar, bilastine was markedly better tolerated than cetirizine in a clinical assay in SAR, with fewer adverse events in the bilastine group. No anticholinergic adverse events were observed in the clinical trials with bilastine. No serious adverse events were reported during the research and there were no clinically significant changes in vital signs, electrocardiography (ECG) or laboratory tests. Pharmacokinetic/pharmacodynamic profiles and studies in special populations indicate that bilastine as dose adjustment is not necessary in elderly patients, or in hepatic or renal insufficiency.
Recently a total of 12 healthy volunteers (males, 18 – 55 years) were included in a randomised, double-blind, cross-over clinical trial to assess occupation of brain histamine H1 receptors after administration of single doses of bilastine 20 mg, evaluated by positron emission tomography (PET) with -doxepin as radiolabeled drug. Hydroxyzine 25 mg (single dose) was used as positive control. For each subjects five brain regions-of-interest (ROI) were defined. This ROI were located on the cortical areas (frontal cortex, parietal cortex, occipital cortex, temporal cortex and insula) based on the known location of H1 receptors in the brain. The cerebellum was used as reference region to obtain the “binding potential” (BP) at baseline and after drug administration. Finally, H1 receptors occupancy (RO) as percentage was estimated as:
RO =100 - /BP placebo,
where “BP placebo” corresponds to the binding potential measured after administration of placebo and “BP antihistamine” corresponds to the binding potential measured after administration of the antihistamine (bilastine or hydroxyzine). The secondary objectives were to determine blood concentrations of bilastine at the time of PET. For each ROI, the BP parameter was calculated. The BP TOTAL was the mean value of 5 ROI studied. Results showed less BP mean values in all different brain ROI and in BP TOTAL with hydroxyzine 25 mg than with bilastine 20 mg, and also less BP with hydroxyzine than with placebo in all different ROI. These differences were statistically significant. BP TOTAL was 0.2561 ± 0.0809 for placebo, 0.2601 ± 0.0723 for bilastine 20 mg and 0.1299 ± 0.0671 for hydroxyzine 25 mg. For each ROI, the RO parameter was calculated according to formula before indicated. Lower RO in all ROI and in RO TOTAL was observed with bilastine 20 mg in comparison to hydroxyzine 25 mg. These differences were statistically significant (p0.05, no significant) were calculated.
## Cardiac safety
The clinical cardiac safety of bilastine has been assessed in all of the clinical trials performed so far (more than 3,500 patients treated with bilastine) and in a phase I study (Thorough QT/QTc study) designed according to the ICH E14 guidance and the most demanding requirements from the Food and Drug Administration (FDA). When electrocardiograms (ECG) data from all of the phase I studies are analysed, no significant alteration is appreciated in any of the parameters after administering bilastine at single doses (up to 11 times the therapeutic dose), nor at multiple doses (up to 10 times the therapeutic dose). Phase II and III studies on AR and urticaria (including the open-label extension phase of 12 months) do not reveal alterations in the ECG, nor significant prolongations of the QTc interval after administration of bilastine 20 mg.
The Thorough QT/QTc study was designed to assess the effect on the QT/QTc interval, both of the therapeutic dose (20 mg) and 100 mg of bilastine, but also the coadministration of the therapeutic dose with usual doses of ketoconazol (400 mg/day), a metabolism inhibitor and a P-gP dependent transport system. It was verified that bilastine 20 and 100 mg administered during 4 days, does not induce significant changes in the QT/QTc interval duration in any of the individuals. Likewise, coadministration of bilastine 20 mg and ketoconazol 400 mg does not produce any significant prolongation of the QT/QTc interval attributable to bilastine.
# Side effects
Bilastine has been shown to have no adverse cardiac side effects, and does not affect driving ability, cardiac conduction or alertness. Possible side effects include headache and drowsiness.
Uncommon side effects (affects 1 to 10 users in 1,000) include abnormal ECG heart tracing, blood tests which show changes in the way the liver is working, dizziness, stomach pain, tiredness, increased appetite, irregular heartbeat, increased weight, nausea (the feeling of being sick), anxiety, dry or uncomfortable nose, belly pain, diarrhea, gastritis (inflammation of the stomach wall), vertigo (a feeling of dizziness or spinning), feeling of weakness, thirst, dyspnoea (difficulty in breathing ), dry mouth, indigestion, itching, cold sores (oral herpes), fever, tinnitus (ringing in the ears), difficulty in sleeping, blood tests which show changes in the way kidney is working, and increased blood fats. | Bilastine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bilastine (trade name Bilaxten) is a second generation antihistamine drug for the treatment of allergic rhinoconjunctivitis and urticaria (hives).
It exerts its effect as a selective histamine H1 receptor antagonist,[1] and has a effectiveness similar to cetirizine, fexofenadine and desloratadine.[2] It was developed in Spain by FAES Farma.
Bilastine is approved in the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria,[3] but it is not approved by the U.S. Food and Drug Administration for any use in the United States.[4] Bilastine meets the current European Academy of Allergy and Clinical Immunology (EAACI) and Allergic Rhinitis and its Impact of Asthma (ARIA) criteria for medication used in the treatment of allergic rhinitis.[5]
Bilastine has been effective in the treatment of ocular symptoms and diseases of allergies, including rhinoconjuctivitis.[2] Additionally, bilastine has been shown to improve quality of life, and all nasal and ocular symptoms related to allergic rhinitis.[5]
# Chemistry
Bilastine, or 2-[4-[2-[4-[1-(2-ethoxyethyl) benzimidazol-2-yl] piperidin-1-yl] ethyl] phenyl]-2-methylpropionic acid, is a novel molecule with a molecular weight of 463.6 daltons and a chemical structure similar to piperidinyl-benzimidazole.[6] Bilastine can be therefore classified into the same chemical group as many of the new antihistamines on the market, although it is not structurally derived, nor is it a metabolite or enantiomer of any of them, but an original molecule designed with the intent of fulfiling all the requirements of a second-generation antihistamine.[6]
# Dosage
A therapeutic dosage of bilastine is 20 mg once a day orally [2] and shows a rapid onset of action (within 30–60 minutes).[2] It should be taken only by children older than 12 years and adults.[5]
# Pharmacodynamics
Bilastine binds to guinea-pig cerebellar histamine H1-receptors (Ki=44 nM) and to human recombinant histamine H1-receptors (Ki=64 nM) with an affinity comparable to that of astemizole and diphenhydramine, and superior than that of cetirizine by three-fold and fexofenadine by five-fold (Corcóstegui). In different murine models, bilastine by oral route, antagonizes the effects of histamine in a dose-dependent manner, with potency similar to that of cetirizine and between 5.5 and 10 times greater than that of fexofenadine.[7]
Preclinical investigations demonstrate the affinity and specificity of bilastine for histamine H1-receptors compared with other histamine receptors subtypes and other 30 receptors from different amines. In vivo experimentation confirmed the antihistaminic and antiallergic activity, which was at least comparable to that of other second-generation H1-antihistamines such as cetirizine.
Clinical studies using different dosages were done on histamine-induced wheal and flare reaction over a 24-h period, compared with a single 10-mg oral dose of cetirizine.[6] The results of this research indicated that bilastine was at least as efficient as cetirizine in reducing histamine-mediated effects in healthy volunteers. Remarkably, 20 and 50 mg of bilastine reduced the wheal and flare reaction significantly more quickly than cetirizine.[6]
# Clinical Efficacy
The clinical efficacy of bilastine in allergic rhinitis (AR) and urticaria has been assessed in 10 clinical assays in which over 4,600 patients were involved. All of them compared bilastine with placebo and another second generation antihistamine with confirmed efficacy (active comparator). In a first study performed under controlled conditions of allergen exposure and time of exposure with sensitised volunteers (Vienna Challenge Chamber), bilastine 20 mg shows an efficacy similar to that of cetirizine 10 mg for the relief of symptomatic seasonal AR (SAR), with a rapid onset of action (1 h) and a duration of action of at least 24 h.[8] The duration of the effect of both compounds is higher than that of fexofenadine at a dose of 120 mg.
The studies on SAR were double-blind, placebo-controlled, parallel-group involving male and female patients over 12 year of age with symptomatic disease at the beginning of the study. Nasal symptoms (sneezing, rhinorrhea, nasal itching and congestion) were assessed both before treatment and during treatment period on a daily basis. Non nasal symptoms (itchy eye, watery eye, itchy ear and palate) were also assessed according to a 0–3 scale, so that the Total Symptoms Score (TSS) and other related parameters could clearly reflect daily evolution of SAR in each patient and treatment group. Parameters such as quality of life and discomfort were also assessed, and in the same way the type and frequency of AE, tolerability and general safety of treatment were registered. In this SAR studies the daily oral administration during 14 days of bilastine 20 mg proves to have the same efficacy than the administration of cetirizine 10 mg or than the administration of desloratadine 5 mg.[9][10] Likewise, bilastine 20 mg shows a safety and tolerability profile similar to placebo and significantly superior to that registered for cetirizine, the risk of somnolence and fatigue being respectively 4 and 20 times lower at 1.8% and 0.4%.[10]
The studies in urticaria were double-blind, placebo-controlled, parallel-group involving male and female patients over 18 year of age with symptomatic disease (idiopathic chronic urticaria) at the beginning of the study. Itching intensity as well as number and maximum size of wheals were assessed according to a 0–3 scale so that the Total Symptom Score (TSS) and other related parameters could clearly reflect the daily evolution of urticaria in each patient and treatment group. Parameters such as quality of life and discomfort were also assessed, and in the same way the type and frequency of AE, tolerability and general safety of treatment were registered. In this urticaria studies the daily oral administration during 28 days of bilastine 20 mg proves to have the same efficacy – for the reduction of TSS and the quality of life parameters- than the administration of levocetirizine 5 mg.[11] Likewise, Bilastine 20 mg shows a safety and tolerability profile similar to placebo.
Recently, twenty patients with cold contact urticaria (CCU) were included in a randomized, crossover, double-blind, placebo-controlled 12-week study.[12] They received placebo, 20, 40 or 80 mg of bilastine daily each for 7 days with 14-day washout periods. The primary variable was change in critical temperature thresholds (CTT). Secondary variables were changes in pruritus, levels of histamine, IL-6, IL-8 and TNF-α collected by skin microdialysis and safety and tolerability of bilastine. At doses of 20 mg was highly effective (P < 0.0001) in reducing CTT. Up-dosing to 80 mg significantly (P < 0.04) increased its effectiveness. At this dose, 19 of 20 (95%) patients responded to treatment, with 12 of 20 (60%) becoming symptom free. Only one patient was refractory to treatment. Microdialysis levels of histamine, IL-6 and IL-8 assessed 1-3 h after cold challenge (4°C) were significantly (P < 0.05) decreased following up-dosing with 80 mg bilastine. Bilastine was effective in reducing the symptoms of patients with CCU. Increased efficacy of bilastine with fourfold up-dosing was without sedation and supports urticaria treatment guidelines.
# Pharmacokinetics
## Distribution
Bilastine distribution has an apparent volume of distribution of 1.29 L/kg, and has an elimination half-life of 14.5 h and plasma protein binding of 84–90%.[13]
## Absorption and bioavailability
Bilastine is most quickly absorbed with the absence of food, and reaches a mean peak plasma concentration of 220 ng/mL approximately 1 h after both single and multiple dosing.[6] Absorption is reduced by a high-fat breakfast or fruit juice, and the estimated global oral bioavailability is approximately 60%.[6] Bilastine has linear pharmacokinetics in the 2.5–220 mg dose range in healthy adult subjects without evidence of accumulation after 14 days of treatment.[6]
## Metabolism
Bilastine is not significantly metabolized in humans and is largely eliminated unchanged both in urine and feces – a third and two thirds of the administered dose, respectively, according to a Phase I mass-balance study with radiolabeled bilastine.[14] Bilastine does not readily cross the blood brain barrier and is not metabolized by the liver.[6] Ninety six percent of the administered dose is eliminated within 24 hours.[6]
In relation to its antihistamine effect, oral doses of 20 mg daily of bilastine, measured as skin wheal-and-flare surface areas for 24 h, bilastine is capable of inhibiting 50% of the surface areas – throughout the whole administration interval.[6]
## Drug interactions and food effects
Preclinical data suggest the possibility of interactions between bilastine and drugs or food that are inhibitors or inducers of the P-glycoproteins. Coadministration of bilastine and grapefruit juice (a known P-glycoprotein-mediated drug transport activator) significantly reduced bilastine systemic exposure.[15] This interaction is due to the known effect of grapefruit flavonoids on intestinal transporter systems such as P-glycoproteins and organic anion transporting peptide (OATP).[16]
# Safety and tolerability
Toxicity of bilastine investigated in preclinical toxicology studies in mice, rats and dogs after oral and intravenous administration showed no mortality observed after oral administration of massive doses. After intravenous administration, LD50 (lethal dose for 50% of animals) values were 33 and 45–75 mg/kg in mice and rats, respectively. No signs of toxicity were observed in any organ after bilastine massive overdosing, either orally (in mice, rats and dogs), or intravenously (in rats and dogs) during 4 weeks. No effects on fertility, no teratogenic or mutagenic effects, and no apparent carcinogenic potential were seen in the studies carried out in rats, mice and rabbits.[17]
In clinical research, bilastine has proven to be well tolerated, with an adverse events profile similar to that of placebo in healthy volunteers, patients with AR and with chronic idiopathic urticaria. Although the tolerance profile of bilastine and levocetirizine or desloratadine were very similar,[18] bilastine was markedly better tolerated than cetirizine in a clinical assay in SAR, with fewer adverse events in the bilastine group. No anticholinergic adverse events were observed in the clinical trials with bilastine. No serious adverse events were reported during the research and there were no clinically significant changes in vital signs, electrocardiography (ECG) or laboratory tests. Pharmacokinetic/pharmacodynamic profiles and studies in special populations indicate that bilastine as dose adjustment is not necessary in elderly patients, or in hepatic or renal insufficiency.
Recently a total of 12 healthy volunteers (males, 18 – 55 years) were included in a randomised, double-blind, cross-over clinical trial to assess occupation of brain histamine H1 receptors after administration of single doses of bilastine 20 mg, evaluated by positron emission tomography (PET) with [11C]-doxepin as radiolabeled drug. Hydroxyzine 25 mg (single dose) was used as positive control. For each subjects five brain regions-of-interest (ROI) were defined. This ROI were located on the cortical areas (frontal cortex, parietal cortex, occipital cortex, temporal cortex and insula) based on the known location of H1 receptors in the brain. The cerebellum was used as reference region to obtain the “binding potential” (BP) at baseline and after drug administration. Finally, H1 receptors occupancy (RO) as percentage was estimated as:
RO =100 • [BP placebo - BP antihistamine]/BP placebo,
where “BP placebo” corresponds to the binding potential measured after administration of placebo and “BP antihistamine” corresponds to the binding potential measured after administration of the antihistamine (bilastine or hydroxyzine). The secondary objectives were to determine blood concentrations of bilastine at the time of PET. For each ROI, the BP parameter was calculated. The BP TOTAL was the mean value of 5 ROI studied. Results showed less BP mean values in all different brain ROI and in BP TOTAL with hydroxyzine 25 mg than with bilastine 20 mg, and also less BP with hydroxyzine than with placebo in all different ROI. These differences were statistically significant. BP TOTAL was 0.2561 ± 0.0809 for placebo, 0.2601 ± 0.0723 for bilastine 20 mg and 0.1299 ± 0.0671 for hydroxyzine 25 mg. For each ROI, the RO parameter was calculated according to formula before indicated. Lower RO in all ROI and in RO TOTAL was observed with bilastine 20 mg in comparison to hydroxyzine 25 mg. These differences were statistically significant (p<0.01). RO (%) TOTAL was -3.92 ± 14.39% for bilastine 20 mg and 53.95 ± 14.13% for hydroxyzine 25 mg. For both antihistamines the TEMPORAL was the cortex region with higher RO values. There was no significant linear relationship between individual values of the AUC0-2.5h of bilastine plasma concentration and the mean BP TOTAL. A correlation coefficient (r2) of 0.0634 (p>0.05, no significant) were calculated.[19]
## Cardiac safety
The clinical cardiac safety of bilastine has been assessed in all of the clinical trials performed so far (more than 3,500 patients treated with bilastine) and in a phase I study (Thorough QT/QTc study) designed according to the ICH E14 guidance and the most demanding requirements from the Food and Drug Administration (FDA). When electrocardiograms (ECG) data from all of the phase I studies are analysed, no significant alteration is appreciated in any of the parameters after administering bilastine at single doses (up to 11 times the therapeutic dose), nor at multiple doses (up to 10 times the therapeutic dose). Phase II and III studies on AR and urticaria (including the open-label extension phase of 12 months) do not reveal alterations in the ECG, nor significant prolongations of the QTc interval after administration of bilastine 20 mg.
The Thorough QT/QTc study was designed to assess the effect on the QT/QTc interval, both of the therapeutic dose (20 mg) and 100 mg of bilastine, but also the coadministration of the therapeutic dose with usual doses of ketoconazol (400 mg/day), a metabolism inhibitor and a P-gP dependent transport system. It was verified that bilastine 20 and 100 mg administered during 4 days, does not induce significant changes in the QT/QTc interval duration in any of the individuals.[20][21] Likewise, coadministration of bilastine 20 mg and ketoconazol 400 mg does not produce any significant prolongation of the QT/QTc interval attributable to bilastine.
# Side effects
Bilastine has been shown to have no adverse cardiac side effects, and does not affect driving ability, cardiac conduction or alertness.[5] Possible side effects include headache and drowsiness.
Uncommon side effects (affects 1 to 10 users in 1,000) include abnormal ECG heart tracing, blood tests which show changes in the way the liver is working, dizziness, stomach pain, tiredness, increased appetite, irregular heartbeat, increased weight, nausea (the feeling of being sick), anxiety, dry or uncomfortable nose, belly pain, diarrhea, gastritis (inflammation of the stomach wall), vertigo (a feeling of dizziness or spinning), feeling of weakness, thirst, dyspnoea (difficulty in breathing ), dry mouth, indigestion, itching, cold sores (oral herpes), fever, tinnitus (ringing in the ears), difficulty in sleeping, blood tests which show changes in the way kidney is working, and increased blood fats.[22] | https://www.wikidoc.org/index.php/Bilastine | |
acbce02133ce8ac80d355a4d7e9c43dbeeb8da3b | wikidoc | Bile acid | Bile acid
# Overview
Bile acids are steroid acids found predominantly in the bile of mammals.
# Production and distribution
They are produced in the liver by the oxidation of cholesterol, conjugated (with either the amino acid taurine or glycine, or a sulfate, or a glucuronide) and are stored in the gallbladder. Upon eating a meal containing fat, the contents of the gallbladder are secreted into the intestine. In humans, the rate limiting step is the addition of a hydroxyl group on position 7 of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase.) Bile acids serve multiple functions, which include: elimination of cholesterol from the body, driving the flow of bile to eliminate catabolites from the liver, serving to emulsify lipids and fat soluble vitamins in the intestine, and (likely) to aid reducing the bacteria flora found in the small intestine and biliary tract.
Synthesis of bile acids is a major consumer of cholesterol in most species (other than humans). The body synthesizes about 800 mg of cholesterol per day and about half of that is used for bile acid synthesis. In total about 20-30 grams of bile acids are secreted into the intestine daily; about 90% of excreted bile acids are reabsorbed (by active transport in the ileum) and recycled. This is referred to as the enterohepatic circulation.
# Types
Bile salts constitute a large family of molecules, composed of a steroid structure with four rings, a five or eight carbon side-chain terminating in a carboxylic acid, and the presence and orientation of different numbers of hydroxyl groups. The four rings are labelled from left to right (as commonly drawn) A, B, C, and D, with the D-ring being smaller by one carbon than the other three. The hydroxyl groups have a choice of being in 2 positions, either up (or out) termed beta (often drawn by convention as a solid line), or down, termed alpha (seen as a dashed line in drawings). All bile acids have a hydroxyl group on position 3, which was derived from the parent molecule, cholesterol. In cholesterol, the 4 steroid rings are flat and the position of the 3-hydroxyl is beta. In many species, the initial step in the formation of a bile acid is the addition of a 7-alpha hydroxyl group. Subsequently, in the conversion from cholesterol to a bile acid, the junction between the first two steroid rings (A and B) is altered, making the molecule bent, and in this process, the 3-hydroxyl is converted to the alpha orientation. Thus, the default simplest bile acid (of 24 carbons) has two hydroxyl groups at positions 3-alpha and 7-alpha. The chemical name for this compound is 3-alpha,7-alpha-dihydroxy-5-beta-cholan-24-oic acid, or as it is commonly known, chenodeoxycholic acid. This bile acid was first isolated from the domestic goose, from which the "cheno" portion of the name was derived. Another bile acid, cholic acid (with 3 hydroxyl groups) had already been described, so the discovery of chenodeoxcholic acid (with 2 hydroxyl groups) made the new bile acid a "deoxycholic acid" in that it had one less hydroxyl group than cholic acid. The 5-beta portion of the name denotes the orientation of the junction between rings A and B of the steroid nucleus (in this case, they are bent). The term "cholan" denotes a particular steroid structure of 24 carbons, and the "24-oic acid" indicates that the carboxylic acid is found at position 24, which happens to be at the end of the side-chain. Chenodeoxycholic acid is made by many species, and is quite a functional bile acid. Its chief drawback lies in the ability of intestinal bacteria to remove the 7-alpha hydroxyl group, a process termed dehydroxylation. The resulting bile acid has only a 3-alpha hydroxyl group and is termed lithocholic acid (litho = stone). It is poorly water-soluble and rather toxic to cells. Bile acids formed by synthesis in the liver are termed "primary" bile acids, and those made by bacteria are termed "secondary" bile acids. As a result, chenodeoxycholic acid is a primary bile acid, and lithocholic acid is a secondary bile acid. To avoid the problems associated with the production of lithocholic acid, most species add a third hydroxyl group to chenodeoxycholic acid. In this manner, the subsequent removal of the 7-alpha hydroxyl group by intestinal bacteria will result in a less toxic, still functional dihydroxy bile acid. Over the course of vertebrate evolution, a number of positions have been chosen for placement of the third hydroxyl group. Initially, the 16-alpha position was favored, particularly in birds. Later, this position was superseded by a large number of species selecting position 12-alpha. Primates (including humans) utilize 12-alpha for their third hydroxyl group position. The resulting primary bile acid in humans is 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholan-24-oic acid, or as it is commonly called, cholic acid. In the intestine, cholic acid is dehydroxylated to form the dihydroxy bile acid deoxycholic acid. In many vertebrate orders still subject to speciation, new species are discarding 12-alpha hydroxylation in favor of a hydroxy group on position 23 of the side-chain. It should be noted that vertebrate families and species exist that have experimented with and utilize just about every position imaginable on the steroid nucleus and side-chain.
The principal bile acids are:
- Cholic acid
- Chenodeoxycholic acid
- Glycocholic acid
- Taurocholic acid
- Deoxycholic acid
In humans, the most important bile acids are cholic acid, deoxycholic acid, and chenodeoxycholic acid, Prior to secretion by the liver, they are conjugated with either the amino acid glycine or taurine. Conjugation increases their water solubility, preventing passive re-absorption once secreted into the small intestine. As a result, the concentration of bile acids in the small intestine can stay high enough to form micelles and solubilize lipids. The term "critical micellar concentration" refers to both an intrinsic property of the bile acid itself and amount of bile acid necessary to function in the spontaneous and dynamic formation of micelles.
# Regulation
As surfactants or detergents, bile acids are potentially toxic to cells and their levels are tightly regulated. They function directly as signaling molecules in the liver and the intestines by activating a nuclear hormone receptor known as FXR also known by its gene name NR1H4. This results in inhibition of bile acid synthesis in the liver when bile acid levels are too high. Emerging evidence associates FXR activation with alterations in triglyceride metabolism, glucose metabolism and liver growth.
# Clinical significance
Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted as a way to lower cholesterol. This is the mechanism of action behind bile acid sequestrants. Bile acid sequestrants bind bile acids in the gut, preventing their reabsorption. The sequestered bile acids are then excreted in the feces. | Bile acid
# Overview
Bile acids are steroid acids found predominantly in the bile of mammals.
# Production and distribution
They are produced in the liver by the oxidation of cholesterol, conjugated (with either the amino acid taurine or glycine, or a sulfate, or a glucuronide) and are stored in the gallbladder. Upon eating a meal containing fat, the contents of the gallbladder are secreted into the intestine. In humans, the rate limiting step is the addition of a hydroxyl group on position 7 of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase.) Bile acids serve multiple functions, which include: elimination of cholesterol from the body, driving the flow of bile to eliminate catabolites from the liver, serving to emulsify lipids and fat soluble vitamins in the intestine, and (likely) to aid reducing the bacteria flora found in the small intestine and biliary tract.
Synthesis of bile acids is a major consumer of cholesterol in most species (other than humans). The body synthesizes about 800 mg of cholesterol per day and about half of that is used for bile acid synthesis. In total about 20-30 grams of bile acids are secreted into the intestine daily; about 90% of excreted bile acids are reabsorbed (by active transport in the ileum) and recycled. This is referred to as the enterohepatic circulation.
# Types
Bile salts constitute a large family of molecules, composed of a steroid structure with four rings, a five or eight carbon side-chain terminating in a carboxylic acid, and the presence and orientation of different numbers of hydroxyl groups. The four rings are labelled from left to right (as commonly drawn) A, B, C, and D, with the D-ring being smaller by one carbon than the other three. The hydroxyl groups have a choice of being in 2 positions, either up (or out) termed beta (often drawn by convention as a solid line), or down, termed alpha (seen as a dashed line in drawings). All bile acids have a hydroxyl group on position 3, which was derived from the parent molecule, cholesterol. In cholesterol, the 4 steroid rings are flat and the position of the 3-hydroxyl is beta. In many species, the initial step in the formation of a bile acid is the addition of a 7-alpha hydroxyl group. Subsequently, in the conversion from cholesterol to a bile acid, the junction between the first two steroid rings (A and B) is altered, making the molecule bent, and in this process, the 3-hydroxyl is converted to the alpha orientation. Thus, the default simplest bile acid (of 24 carbons) has two hydroxyl groups at positions 3-alpha and 7-alpha. The chemical name for this compound is 3-alpha,7-alpha-dihydroxy-5-beta-cholan-24-oic acid, or as it is commonly known, chenodeoxycholic acid. This bile acid was first isolated from the domestic goose, from which the "cheno" portion of the name was derived. Another bile acid, cholic acid (with 3 hydroxyl groups) had already been described, so the discovery of chenodeoxcholic acid (with 2 hydroxyl groups) made the new bile acid a "deoxycholic acid" in that it had one less hydroxyl group than cholic acid. The 5-beta portion of the name denotes the orientation of the junction between rings A and B of the steroid nucleus (in this case, they are bent). The term "cholan" denotes a particular steroid structure of 24 carbons, and the "24-oic acid" indicates that the carboxylic acid is found at position 24, which happens to be at the end of the side-chain. Chenodeoxycholic acid is made by many species, and is quite a functional bile acid. Its chief drawback lies in the ability of intestinal bacteria to remove the 7-alpha hydroxyl group, a process termed dehydroxylation. The resulting bile acid has only a 3-alpha hydroxyl group and is termed lithocholic acid (litho = stone). It is poorly water-soluble and rather toxic to cells. Bile acids formed by synthesis in the liver are termed "primary" bile acids, and those made by bacteria are termed "secondary" bile acids. As a result, chenodeoxycholic acid is a primary bile acid, and lithocholic acid is a secondary bile acid. To avoid the problems associated with the production of lithocholic acid, most species add a third hydroxyl group to chenodeoxycholic acid. In this manner, the subsequent removal of the 7-alpha hydroxyl group by intestinal bacteria will result in a less toxic, still functional dihydroxy bile acid. Over the course of vertebrate evolution, a number of positions have been chosen for placement of the third hydroxyl group. Initially, the 16-alpha position was favored, particularly in birds. Later, this position was superseded by a large number of species selecting position 12-alpha. Primates (including humans) utilize 12-alpha for their third hydroxyl group position. The resulting primary bile acid in humans is 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholan-24-oic acid, or as it is commonly called, cholic acid. In the intestine, cholic acid is dehydroxylated to form the dihydroxy bile acid deoxycholic acid. In many vertebrate orders still subject to speciation, new species are discarding 12-alpha hydroxylation in favor of a hydroxy group on position 23 of the side-chain. It should be noted that vertebrate families and species exist that have experimented with and utilize just about every position imaginable on the steroid nucleus and side-chain.
The principal bile acids are:
- Cholic acid
- Chenodeoxycholic acid
- Glycocholic acid
- Taurocholic acid
- Deoxycholic acid
In humans, the most important bile acids are cholic acid, deoxycholic acid, and chenodeoxycholic acid, Prior to secretion by the liver, they are conjugated with either the amino acid glycine or taurine. Conjugation increases their water solubility, preventing passive re-absorption once secreted into the small intestine. As a result, the concentration of bile acids in the small intestine can stay high enough to form micelles and solubilize lipids. The term "critical micellar concentration" refers to both an intrinsic property of the bile acid itself and amount of bile acid necessary to function in the spontaneous and dynamic formation of micelles.
# Regulation
As surfactants or detergents, bile acids are potentially toxic to cells and their levels are tightly regulated. They function directly as signaling molecules in the liver and the intestines by activating a nuclear hormone receptor known as FXR also known by its gene name NR1H4. This results in inhibition of bile acid synthesis in the liver when bile acid levels are too high. Emerging evidence associates FXR activation with alterations in triglyceride metabolism, glucose metabolism and liver growth.
# Clinical significance
Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted as a way to lower cholesterol. This is the mechanism of action behind bile acid sequestrants. Bile acid sequestrants bind bile acids in the gut, preventing their reabsorption. The sequestered bile acids are then excreted in the feces.
# External links
- Bile+Acids+and+Salts at the US National Library of Medicine Medical Subject Headings (MeSH)
de:Gallensäuren
sv:Gallsyror
Template:WS | https://www.wikidoc.org/index.php/Bile_acid | |
deaf90a105243e7c83e971d3ba710dbd437458dd | wikidoc | Bile bear | Bile bear
A bile bear or battery bear is the term used for Asiatic black bears kept in captivity in Vietnam and China so that bile may be extracted from them for sale as a traditional Chinese medicine (TCM). The bears are also known as moon bears because of the cream-colored crescent moon shape on their chest. The Asiatic black bear, the one most commonly used on bear farms, is an endangered species.
# Living conditions
The bears live in extraction cages, also known as crush cages, which are little bigger than themselves for ease of "milking." Bears may live as long as twenty-five years in these cages with the confinement causing mental stress as well as severe muscle atrophy. Their bile is extracted through a bile fistula, a tube that is surgically inserted through the abdominal wall and into the gall bladder, where bile is stored after being secreted by the liver via the hepatic duct. This bile fistula is connected to a collection system. Between 10 and 20 ml of bile is tapped from each bear twice daily. The WSPA reports that, during milking, investigators saw bears moaning, banging their heads against their cages, and chewing their own paws. The mortality rate is between 50 and 60 percent. Bears in bile farms suffer from a variety of physical problems which include loss of hair, malnutrition, stunted growth, muscle mass loss and often have teeth and claws extracted. When the bears stop producing bile after a few years, they are usually killed for their meat, fur, paws and gall bladders. Bear paws are considered a delicacy.
# Numbers
There are estimated to be around 4,000 bile bears in Vietnam, where their bile can sell for 100,000 dong (~ US$6.25) a millilitre (with 37,500 dong a week regarded as the poverty line for an urban resident), and around 9,000 bile bears in China. The World Society for the Protection of Animals (WSPA) conducted a study in 1999 and 2000, and estimates that there are 247 bile-bear farms in China, holding 7,002 bears,
though the Chinese government has called the figures "pure speculation."
In July 2000, Animals Asia Foundation, a Hong-Kong based charity set up by Jill Robinson MBE, signed an agreement with the Chinese government to rescue 500 suffering and endangered Moon Bears from the worst bile farms in Sichuan province, and work towards ending the practice. Today, the China Bear Rescue has seen freedom for 219 previously farmed Moon Bears at a Sanctuary in Chengdu, and is helping to advance the concept of animal welfare in China.
The Chinese consider bear farms a way to reduce the demand on the wild bear population. Officially 7,600 captive bears are farmed in China. According to Chinese officials, 10,000 wild bears would need to be killed each year to produce as much bile. The government sees farming as a reasonable answer to the loss of wild bears from poaching, and at the same time claim insouciance regarding the cruelty issues that concern Western animal rights activists. However, the government's agreement with Animals Asia Foundation to allow the rescue of 500 bears from farms may represent a softening of the government's tough stance on bear suffering.
# Bile trade
The monetary value of the bile comes from the traditional prescription of bear bile by doctors practising traditional Chinese medicine. Bear bile contains ursodeoxycholic acid (UDCA), which is believed to reduce fever, protect the liver, improve eyesight, break down gallstones, and act as an anti-inflammatory. The high demand for the bile has led to the introduction of intensive farming of bears. Because only minute amounts are used in traditional Chinese medicine, a total of 500 kg of bear bile is used by practitioners every year, but according to WSPA more than 7,000 kg is being produced, most of it being used in wines, eyedrops, and general tonics.
In January 2006, the Chinese State Council Information Office held a press conference in Beijing, during which the government said that it was enforcing a "Technical Code of Practice for Raising Black Bears," which "requires hygienic, painless practice for gall extraction and make strict regulations on the techniques and conditions for nursing, exercise and propagation." However, a 2007 Veterinary Report published by the Animals Asia Foundation stated that the Technical Code was not being enforced and that many bears were still spending their entire lives in small extraction cages without free access to food or water. AAF also noted that the free-dripping technique promoted in the Technical Code was unsanitary as the fistula created to access the gall bladder allowed for an open portal through which bacteria could infiltrate the abdomen. The AAF Vet Report also stated that surgeries to create free-dripping fistulas caused bears great suffering as they were performed without appropriate antibiotics or pain management and the bears were repeatedly exposed to this process as the fistulas often healed over. The free-dripping method still requires the bears to be prodded with a metal rod when the wound heals over and, under veterinary examination, some bears with free-dripping fistulas were actually found to have clear perspex catheters permanently implanted into their gall bladders. In addition to the suffering caused by infection and pain at the incision site, 28% of fistulated bears also experience abdominal hernias and more than a third eventually succumb to liver cancer, believed to be associated with the bile-extraction process.
# Pharmacology
The active therapeutic substance in bear bile--and in the bile of all mammals--is ursodeoxycholic acid (UDCA). This acid has been recognized by both Asian and Western physicians for at least 40 years to have benefits for patients with diseases of the liver and biliary system. Before the manufacture of UDCA by pharmaceutical companies, bear bile was prescribed by practitioners of traditional Chinese medicine because it contained a higher percentage of UDCA than the bile of other mammals. However, modern chemistry has made this fact irrelevant. Today, pharmaceutical-grade UDCA is now collected from slaughter houses, then purified and packaged under trade names such as Ursofalk, Actigall, and UrsoForte. These products are approved by the Federal Drug Administration (FDA). Substances in mammalian bile other than UDCA, such as cholesterol, have never been demonstrated to have any healing effect in humans. Despite this observation and the availability of affordable pharmaceutical-grade UDCA, some practitioners of traditional Chinese medicine continue to prescribe whole bear bile for their patients and reject any sort of modern substitute. These individuals drive the market demand for bear bile and pressure the Chinese government to continue the practice of bear farming.
# Notes
- ↑ Asiatic black bear
- ↑ U.S. Embassy of China: "Bile Bear Report."
- ↑ Morality rate
- ↑ Parry-Jones, Rob & Vincent, Amanda. "Can we tame wild medicine?", New Scientist, vol 157 issue 2115, January 3, 1998, page 26. | Bile bear
A bile bear or battery bear is the term used for Asiatic black bears kept in captivity in Vietnam and China so that bile may be extracted from them for sale as a traditional Chinese medicine (TCM). The bears are also known as moon bears because of the cream-colored crescent moon shape on their chest.[1] The Asiatic black bear, the one most commonly used on bear farms, is an endangered species.
# Living conditions
The bears live in extraction cages, also known as crush cages, which are little bigger than themselves for ease of "milking." Bears may live as long as twenty-five years in these cages with the confinement causing mental stress as well as severe muscle atrophy.[2] Their bile is extracted through a bile fistula, a tube that is surgically inserted through the abdominal wall and into the gall bladder, where bile is stored after being secreted by the liver via the hepatic duct. This bile fistula is connected to a collection system. Between 10 and 20 ml of bile is tapped from each bear twice daily. The WSPA reports that, during milking, investigators saw bears moaning, banging their heads against their cages, and chewing their own paws. The mortality rate is between 50 and 60 percent. Bears in bile farms suffer from a variety of physical problems which include loss of hair, malnutrition, stunted growth, muscle mass loss and often have teeth and claws extracted.[3] When the bears stop producing bile after a few years, they are usually killed for their meat, fur, paws and gall bladders. Bear paws are considered a delicacy.
# Numbers
Template:Alib
There are estimated to be around 4,000 bile bears in Vietnam, where their bile can sell for 100,000 dong (~ US$6.25) a millilitre (with 37,500 dong a week regarded as the poverty line for an urban resident), and around 9,000 bile bears in China. The World Society for the Protection of Animals (WSPA) conducted a study in 1999 and 2000, and estimates that there are 247 bile-bear farms in China, holding 7,002 bears,
[2] though the Chinese government has called the figures "pure speculation." [3]
In July 2000, Animals Asia Foundation, a Hong-Kong based charity set up by Jill Robinson MBE, signed an agreement with the Chinese government to rescue 500 suffering and endangered Moon Bears from the worst bile farms in Sichuan province, and work towards ending the practice. Today, the China Bear Rescue has seen freedom for 219 previously farmed Moon Bears at a Sanctuary in Chengdu, and is helping to advance the concept of animal welfare in China.[4]
The Chinese consider bear farms a way to reduce the demand on the wild bear population. Officially 7,600 captive bears are farmed in China. According to Chinese officials, 10,000 wild bears would need to be killed each year to produce as much bile.[4] The government sees farming as a reasonable answer to the loss of wild bears from poaching, and at the same time claim insouciance regarding the cruelty issues that concern Western animal rights activists. However, the government's agreement with Animals Asia Foundation to allow the rescue of 500 bears from farms may represent a softening of the government's tough stance on bear suffering. [5]
# Bile trade
The monetary value of the bile comes from the traditional prescription of bear bile by doctors practising traditional Chinese medicine. Bear bile contains ursodeoxycholic acid (UDCA), which is believed to reduce fever, protect the liver, improve eyesight, break down gallstones, and act as an anti-inflammatory. The high demand for the bile has led to the introduction of intensive farming of bears. Because only minute amounts are used in traditional Chinese medicine, a total of 500 kg of bear bile is used by practitioners every year, but according to WSPA more than 7,000 kg is being produced, most of it being used in wines, eyedrops, and general tonics.
In January 2006, the Chinese State Council Information Office held a press conference in Beijing, during which the government said that it was enforcing a "Technical Code of Practice for Raising Black Bears," which "requires hygienic, painless practice for gall extraction and make strict regulations on the techniques and conditions for nursing, exercise and propagation." [6] However, a 2007 Veterinary Report published by the Animals Asia Foundation stated that the Technical Code was not being enforced and that many bears were still spending their entire lives in small extraction cages without free access to food or water. AAF also noted that the free-dripping technique promoted in the Technical Code was unsanitary as the fistula created to access the gall bladder allowed for an open portal through which bacteria could infiltrate the abdomen. The AAF Vet Report also stated that surgeries to create free-dripping fistulas caused bears great suffering as they were performed without appropriate antibiotics or pain management and the bears were repeatedly exposed to this process as the fistulas often healed over. The free-dripping method still requires the bears to be prodded with a metal rod when the wound heals over and, under veterinary examination, some bears with free-dripping fistulas were actually found to have clear perspex catheters permanently implanted into their gall bladders. In addition to the suffering caused by infection and pain at the incision site, 28% of fistulated bears also experience abdominal hernias and more than a third eventually succumb to liver cancer, believed to be associated with the bile-extraction process.[7]
# Pharmacology
The active therapeutic substance in bear bile--and in the bile of all mammals--is ursodeoxycholic acid (UDCA). This acid has been recognized by both Asian and Western physicians for at least 40 years to have benefits for patients with diseases of the liver and biliary system. Before the manufacture of UDCA by pharmaceutical companies, bear bile was prescribed by practitioners of traditional Chinese medicine because it contained a higher percentage of UDCA than the bile of other mammals. However, modern chemistry has made this fact irrelevant. Today, pharmaceutical-grade UDCA is now collected from slaughter houses, then purified and packaged under trade names such as Ursofalk, Actigall, and UrsoForte. These products are approved by the Federal Drug Administration (FDA). Substances in mammalian bile other than UDCA, such as cholesterol, have never been demonstrated to have any healing effect in humans. Despite this observation and the availability of affordable pharmaceutical-grade UDCA, some practitioners of traditional Chinese medicine continue to prescribe whole bear bile for their patients and reject any sort of modern substitute.[8] These individuals drive the market demand for bear bile and pressure the Chinese government to continue the practice of bear farming.
# Notes
- ↑ Asiatic black bear
- ↑ U.S. Embassy of China: "Bile Bear Report."
- ↑ Morality rate
- ↑ Parry-Jones, Rob & Vincent, Amanda. "Can we tame wild medicine?", New Scientist, vol 157 issue 2115, January 3, 1998, page 26. | https://www.wikidoc.org/index.php/Bile_bear | |
b93a82e45868ef6eee8df4ca4601fef5079c5a2a | wikidoc | Bile duct | Bile duct
# Overview
A bile duct is any of a number of long tube-like structures that carry bile.
Bile, required for the digestion of food, is excreted by the liver into passages that carry bile toward the hepatic duct, which joins with the cystic duct (carrying bile to and from the gallbladder) to form the common bile duct, which opens into the intestine.
The biliary tree (see below) is the whole network of various sized ducts branching through the liver.
The path is as follows: Bile canaliculi → Canals of Hering → interlobular bile ducts → intrahepatic bile ducts → left and right hepatic ducts merge to form → common hepatic duct exits liver and joins → cystic duct (from gall bladder) forming → common bile duct → joins with pancreatic duct → forming ampulla of Vater → enters duodenum
# Common bile duct
The top half of the common bile duct is associated with the liver, while the bottom half of the common bile duct is associated with the pancreas, through which it passes on its way to the intestine. It opens in the part of the intestine called the duodenum into a structure called the ampulla of Vater.
# Pathology
Blockage of the bile duct by a cancer, gallstones, or scarring from injury prevents the bile from being transported to the intestine and the active ingredient in the bile (bilirubin) instead accumulates in the blood. This condition is called jaundice and the skin and eyes become yellow from the bilirubin in the blood. This condition also causes severe itchiness from the bilirubin deposited in the tissues. In certain types of jaundice, the urine will be noticeably darker, and the stools will be much paler than usual. This is caused by the bilirubin all going to the bloodstream and being filtered into the urine by the kidneys, instead of some being lost in the stools through the ampulla of Vater.
Jaundice is commonly caused by conditions such as pancreatic cancer, which causes blockage of the bile duct passing through the cancerous portion of the pancreas; cholangiocarcinoma, cancer of the bile ducts; blockage by a stone in patients with gallstones; and from scarring after injury to the bile duct during gallbladder removal.
# Additional images
- Section across portal canal of pig. X 250. | Bile duct
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A bile duct is any of a number of long tube-like structures that carry bile.
Bile, required for the digestion of food, is excreted by the liver into passages that carry bile toward the hepatic duct, which joins with the cystic duct (carrying bile to and from the gallbladder) to form the common bile duct, which opens into the intestine.
The biliary tree (see below) is the whole network of various sized ducts branching through the liver.
The path is as follows: Bile canaliculi → Canals of Hering → interlobular bile ducts → intrahepatic bile ducts → left and right hepatic ducts merge to form → common hepatic duct exits liver and joins → cystic duct (from gall bladder) forming → common bile duct → joins with pancreatic duct → forming ampulla of Vater → enters duodenum
# Common bile duct
The top half of the common bile duct is associated with the liver, while the bottom half of the common bile duct is associated with the pancreas, through which it passes on its way to the intestine. It opens in the part of the intestine called the duodenum into a structure called the ampulla of Vater.
# Pathology
Blockage of the bile duct by a cancer, gallstones, or scarring from injury prevents the bile from being transported to the intestine and the active ingredient in the bile (bilirubin) instead accumulates in the blood. This condition is called jaundice and the skin and eyes become yellow from the bilirubin in the blood. This condition also causes severe itchiness from the bilirubin deposited in the tissues. In certain types of jaundice, the urine will be noticeably darker, and the stools will be much paler than usual. This is caused by the bilirubin all going to the bloodstream and being filtered into the urine by the kidneys, instead of some being lost in the stools through the ampulla of Vater.
Jaundice is commonly caused by conditions such as pancreatic cancer, which causes blockage of the bile duct passing through the cancerous portion of the pancreas; cholangiocarcinoma, cancer of the bile ducts; blockage by a stone in patients with gallstones; and from scarring after injury to the bile duct during gallbladder removal.
# Additional images
- Section across portal canal of pig. X 250.
# External links
- The Cholangiocarcinoma Foundation
- The Johns Hopkins Gall Bladder & Bile Duct Cancer Web page
- Template:EMedicineDictionary
- Bile+Ducts at the US National Library of Medicine Medical Subject Headings (MeSH)
Template:Digestive glands
cs:Žlučovod
id:Saluran empedu
is:Gallrás
it:Dotti biliari
pag:Apgo
fi:Sappitiehyt
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Bile_duct | |
104ad9b75fa4f15206af62e7b9a7ecc24143fbb9 | wikidoc | Bilirubin | Bilirubin
Bilirubin is a yellow breakdown product of normal heme catabolism. Its levels are elevated in certain diseases and it is responsible for the yellow colour of bruises and the brown colour of feces. Bilirubin reduction in the gut leads to a product called urobilinogen, which is excreted in urine.
# Chemistry
Bilirubin consists of an open chain of four pyrrole-like rings (tetrapyrrole). In heme, by contrast, these four rings are connected into a larger ring, called a porphyrin.
Bilirubin is very similar to the pigment phycobilin used by certain algae to capture light energy, and to the pigment phytochrome used by plants to sense light. All of these contain an open chain of four pyrrolic rings.
Like these other pigments, bilirubin changes its conformation when exposed to light. This is used in the phototherapy of jaundiced newborns: the illuminated version of bilirubin is more soluble than the unilluminated version.
Several textbooks and research articles show incorrect chemical structures for the two isoforms of bilirubin.
# Function
Bilirubin is created by the activity of biliverdin reductase on biliverdin. Bilirubin, when oxidized, reverts to become biliverdin once again. This cycle, in addition to the demonstration of the potent antioxidant activity of bilirubin, has led to the hypothesis that bilirubin's main physiologic role is as a cellular antioxidant.
# Metabolism
Erythrocytes (red blood cells) generated in the bone marrow are destroyed in the spleen when they get old or damaged. This releases hemoglobin, which is broken down to heme, as the globin parts are turned into amino acids. The heme is then turned into unconjugated bilirubin in the macrophages of the spleen. It is then bound to albumin and sent to the liver.
In the liver it is conjugated with glucuronic acid, making it water soluble. Much of it goes into the bile and thus out into the small intestine. Some of the conjugated bilirubin remains in the large intestine and is metabolised by colonic bacteria to stercobilinogen and then oxidised to stercobilin.
Some is reabsorbed, and excreted in the urine as urobilinogen and the oxidised form, urobilin. If the liver’s function is impaired, or biliary drainage blocked, some of the conjugated bilirubin appears in the urine, turning it dark amber.
# Bilirubin toxicity
Unconjugated hyperbilirubinaemia in the neonate can lead to accumulation of bilirubin in certain brain regions, a phenomenon known as kernicterus, with consequent irreversible damage to these areas manifesting as various neurological deficits, seizures, abnormal reflexes and eye movements. Aside from specific chronic medical conditions that may lead to hyperbilirubinaemia, neonates in general are at increased risk since they lack the intestinal bacteria that facilitate the breakdown and excretion of conjugated bilirubin in the feces (this is largely why the feces of a neonate are paler than those of an adult). Instead the conjugated bilirubin is converted back into the unconjugated form by the enzyme b-glucoronidase and a large proportion is reabsorbed through the enterohepatic circulation.
# Bilirubin benefits
Reasonable levels of bilirubin can be beneficial to the organism. Evidence is accumulating that suggests bilirubin can protect tissues against oxidative damage caused by free radicals and other reactive oxygen species.
Statistical analysis of people with high normal or slightly elevated bilirubin levels in blood shows that they have a lower risk of developing cardiovascular diseases.
# Bilirubin blood tests
Bilirubin is in one of two forms:
Total bilirubin measures both BU and BC. Total and direct bilirubin levels can be measured from the blood, but indirect bilirubin is calculated from the total and direct bilirubin.
To further elucidate the causes of jaundice or increased bilirubin, it is usually simpler to look at other liver function tests (especially the enzymes ALT, AST, GGT, Alk Phos), blood film examination (hemolysis, etc.) or evidence of infective hepatitis (e.g., Hepatitis A, B, C, delta E, etc).
Bilirubin is an excretion product, and the body does not control levels. Bilirubin levels reflect the balance between production and excretion. Thus, there is no "normal" level of bilirubin.
Bilirubin is broken down by light, and therefore blood collection tubes (especially serum tubes) should be protected from such exposure.
# Interpretation
Different sources provide reference ranges which are similar but not identical. Some examples for adults are provided below (different reference ranges are often used for newborns):
Mild rises in bilirubin may be caused by
- Hemolysis or increased breakdown of red blood cells.
- Gilbert's syndrome - a genetic disorder of bilirubin metabolism which can result in mild jaundice, found in about 5% of the population.
- Drugs: Cladribine
Moderate rise in bilirubin may be caused by
- Drugs (especially anti-psychotic, some sex hormones, and a wide range of other drugs such as Vedolizumab).
- Hepatitis (levels may be moderate or high).
- Biliary stricture (benign or malignant)
Very high levels of bilirubin may be caused by
- Neonatal hyperbilirubinaemia, where the newborn's liver is not able to properly conjugate the bilirubin (see jaundice).
- Unusually large bile duct obstruction, eg stone in common bile duct, tumour obstructing common bile duct etc.
- Severe liver failure with cirrhosis.
- Severe hepatitis.
- Crigler-Najjar syndrome
- Dubin-Johnson syndrome
- Choledocholithiasis (chronic or acute)
Cirrhosis may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis
Indirect bilirubin is fat soluble and direct bilirubin is water soluble.
# Jaundice
Jaundice may be noticeable in the sclera (white) of the eyes at levels of about 30-50 μmol/l, and in the skin at higher levels. Jaundice is classified depending upon whether the bilirubin is free or conjugated to glucuronic acid into:
- Conjugated jaundice
- Unconjugated jaundice
# Cultural references
- (1988) Bilirubin was used as a wordplay in the novel The Silence of the Lambs. The incarcerated psychopathic psychiatrist Hannibal Lecter assists the FBI in capturing a killer. Lecter gives the name of the killer as "Billy Rubin". After Lecter escapes from custody, they find a piece of paper in his cell on which he had written his warden's name (Chilton) and, from the C,H,N,O in the name, given the formula for bilirubin.
- (1990) In Juan Luis Guerra's song, "Me sube la bilirrubina" on the album Bachata Rosa, the protagonist's bilirubin levels increase as a result of unrequited love.
- (2001) German industrial band Einstürzende Neubauten have a song called "Bili Rubin", on Strategies Against Architecture III. | Bilirubin
Template:NatOrganicBox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Bilirubin is a yellow breakdown product of normal heme catabolism. Its levels are elevated in certain diseases and it is responsible for the yellow colour of bruises and the brown colour of feces. Bilirubin reduction in the gut leads to a product called urobilinogen, which is excreted in urine.
# Chemistry
Bilirubin consists of an open chain of four pyrrole-like rings (tetrapyrrole). In heme, by contrast, these four rings are connected into a larger ring, called a porphyrin.
Bilirubin is very similar to the pigment phycobilin used by certain algae to capture light energy, and to the pigment phytochrome used by plants to sense light. All of these contain an open chain of four pyrrolic rings.
Like these other pigments, bilirubin changes its conformation when exposed to light. This is used in the phototherapy of jaundiced newborns: the illuminated version of bilirubin is more soluble than the unilluminated version.
Several textbooks and research articles show incorrect chemical structures for the two isoforms of bilirubin. [1]
# Function
Bilirubin is created by the activity of biliverdin reductase on biliverdin. Bilirubin, when oxidized, reverts to become biliverdin once again. This cycle, in addition to the demonstration of the potent antioxidant activity of bilirubin, has led to the hypothesis that bilirubin's main physiologic role is as a cellular antioxidant.[2]
# Metabolism
Erythrocytes (red blood cells) generated in the bone marrow are destroyed in the spleen when they get old or damaged. This releases hemoglobin, which is broken down to heme, as the globin parts are turned into amino acids. The heme is then turned into unconjugated bilirubin in the macrophages of the spleen. It is then bound to albumin and sent to the liver.
In the liver it is conjugated with glucuronic acid, making it water soluble. Much of it goes into the bile and thus out into the small intestine. Some of the conjugated bilirubin remains in the large intestine and is metabolised by colonic bacteria to stercobilinogen and then oxidised to stercobilin.
Some is reabsorbed, and excreted in the urine as urobilinogen and the oxidised form, urobilin. If the liver’s function is impaired, or biliary drainage blocked, some of the conjugated bilirubin appears in the urine, turning it dark amber.
# Bilirubin toxicity
Unconjugated hyperbilirubinaemia in the neonate can lead to accumulation of bilirubin in certain brain regions, a phenomenon known as kernicterus, with consequent irreversible damage to these areas manifesting as various neurological deficits, seizures, abnormal reflexes and eye movements. Aside from specific chronic medical conditions that may lead to hyperbilirubinaemia, neonates in general are at increased risk since they lack the intestinal bacteria that facilitate the breakdown and excretion of conjugated bilirubin in the feces (this is largely why the feces of a neonate are paler than those of an adult). Instead the conjugated bilirubin is converted back into the unconjugated form by the enzyme b-glucoronidase and a large proportion is reabsorbed through the enterohepatic circulation.
# Bilirubin benefits
Reasonable levels of bilirubin can be beneficial to the organism. Evidence is accumulating that suggests bilirubin can protect tissues against oxidative damage caused by free radicals and other reactive oxygen species.
Statistical analysis of people with high normal or slightly elevated bilirubin levels in blood shows that they have a lower risk of developing cardiovascular diseases.
# Bilirubin blood tests
Bilirubin is in one of two forms:
Total bilirubin measures both BU and BC. Total and direct bilirubin levels can be measured from the blood, but indirect bilirubin is calculated from the total and direct bilirubin.
To further elucidate the causes of jaundice or increased bilirubin, it is usually simpler to look at other liver function tests (especially the enzymes ALT, AST, GGT, Alk Phos), blood film examination (hemolysis, etc.) or evidence of infective hepatitis (e.g., Hepatitis A, B, C, delta E, etc).
Bilirubin is an excretion product, and the body does not control levels. Bilirubin levels reflect the balance between production and excretion. Thus, there is no "normal" level of bilirubin.
Bilirubin is broken down by light, and therefore blood collection tubes (especially serum tubes) should be protected from such exposure.
# Interpretation
Different sources provide reference ranges which are similar but not identical. Some examples for adults are provided below (different reference ranges are often used for newborns):
Mild rises in bilirubin may be caused by
- Hemolysis or increased breakdown of red blood cells.
- Gilbert's syndrome - a genetic disorder of bilirubin metabolism which can result in mild jaundice, found in about 5% of the population.
- Drugs: Cladribine
Moderate rise in bilirubin may be caused by
- Drugs (especially anti-psychotic, some sex hormones, and a wide range of other drugs such as Vedolizumab).
- Hepatitis (levels may be moderate or high).
- Biliary stricture (benign or malignant)
Very high levels of bilirubin may be caused by
- Neonatal hyperbilirubinaemia, where the newborn's liver is not able to properly conjugate the bilirubin (see jaundice).
- Unusually large bile duct obstruction, eg stone in common bile duct, tumour obstructing common bile duct etc.
- Severe liver failure with cirrhosis.
- Severe hepatitis.
- Crigler-Najjar syndrome
- Dubin-Johnson syndrome
- Choledocholithiasis (chronic or acute)
Cirrhosis may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis
Indirect bilirubin is fat soluble and direct bilirubin is water soluble.
# Jaundice
Jaundice may be noticeable in the sclera (white) of the eyes at levels of about 30-50 μmol/l, and in the skin at higher levels. Jaundice is classified depending upon whether the bilirubin is free or conjugated to glucuronic acid into:
- Conjugated jaundice
- Unconjugated jaundice
# Cultural references
- (1988) Bilirubin was used as a wordplay in the novel The Silence of the Lambs. The incarcerated psychopathic psychiatrist Hannibal Lecter assists the FBI in capturing a killer. Lecter gives the name of the killer as "Billy Rubin". After Lecter escapes from custody, they find a piece of paper in his cell on which he had written his warden's name (Chilton) and, from the C,H,N,O in the name, given the formula for bilirubin.
- (1990) In Juan Luis Guerra's song, "Me sube la bilirrubina" on the album Bachata Rosa, the protagonist's bilirubin levels increase as a result of unrequited love.
- (2001) German industrial band Einstürzende Neubauten have a song called "Bili Rubin", on Strategies Against Architecture III. | https://www.wikidoc.org/index.php/Bilirubin | |
10868a2d905bfcbe9617f1ad169839accc9c0e4b | wikidoc | Biodiesel | Biodiesel
# Overview
Biodiesel refers to a non-petroleum-based diesel fuel consisting of short chain alkyl (methyl or ethyl) esters, made by transesterification of vegetable oils or animal fats, which can be used (alone, or blended with conventional petrodiesel) in unmodified diesel-engine vehicles. Biodiesel is distinguished from the straight vegetable oil (SVO) (aka "waste vegetable oil", "WVO", "unwashed biodiesel", "pure plant oil", "PPO") used (alone, or blended) as fuels in some converted diesel vehicles. "Biodiesel" is standardized as mono-alkyl ester and other kinds of diesel-grade fuels of biological origin are not included.
# Blends
Blends of biodiesel and conventional hydrocarbon-based diesel are products most commonly distributed for use in the retail diesel fuel marketplace. Much of the world uses a system known as the "B" factor to state the amount of biodiesel in any fuel mix: fuel containing 20% biodiesel is labeled B20, while pure biodiesel is referred to as B100. It is common to see B99, since 1% petrodiesel is sufficiently toxic to retard mold. Blends of 20 percent biodiesel with 80 percent petroleum diesel (B20) can generally be used in unmodified diesel engines. Biodiesel can also be used in its pure form (B100), but may require certain engine modifications to avoid maintenance and performance problems. Blending B100 with petro diesel may be accomplished by:
- Mixing in tanks at manufacturing point prior to delivery to tanker truck
- Splash mixing in the tanker truck (adding specific percentages of Biodiesel and Petro Diesel)
- In-line mixing, two components arrive at tanker truck simultaneously.
# Origin
On August 31, 1937, G. Chavanne of the University of Brussels (Belgium) was granted a patent for a 'Procedure for the transformation of vegetable oils for their uses as fuels' (fr. 'Procédé de Transformation d’Huiles Végétales en Vue de Leur Utilisation comme Carburants') Belgian Patent 422,877. This patent described the alcoholysis (often referred to as transesterification) of vegetable oils using ethanol (and mentions methanol) in order to separate the fatty acids from the glycerol by replacing the glycerol with short linear alcohols. This appears to be the first account of the production of what is known as 'biodiesel' today.
# Applications
Biodiesel can be used in pure form (B100) or may be blended with petroleum diesel at any concentration in most modern diesel engines. Biodiesel has different solvent properties than petrodiesel, and will degrade natural rubber gaskets and hoses in vehicles (mostly found in vehicles manufactured before 1992), although these tend to wear out naturally and most likely will have already been replaced with FKM, which is nonreactive to biodiesel. Biodiesel has been known to break down deposits of residue in the fuel lines where petrodiesel has been used. As a result, fuel filters may become clogged with particulates if a quick transition to pure biodiesel is made. Therefore, it is recommended to change the fuel filters on engines and heaters shortly after first switching to a biodiesel blend.
## Distribution
Biodiesel use and production are increasing rapidly. Fueling stations make biodiesel readily available to consumers across Europe, and increasingly in the USA and Canada. A growing number of transport fleets use it as an additive in their fuel. Biodiesel is often more expensive to purchase than petroleum diesel but this is expected to diminish due to economies of scale and agricultural subsidies versus the rising cost of petroleum as reserves are depleted.
## Vehicular use and manufacturer acceptance
In 2005, DaimlerChrysler released Jeep Liberty CRD diesels from the factory into the American market with 5% biodiesel blends, indicating at least partial acceptance of biodiesel as an acceptable diesel fuel additive. In 2007, DiamlerChrysler indicated intention to increase warranty coverage to 20% biodiesel blends if biofuel quality in the United States can be standardized.
## Railroad use
The British businessman Richard Branson's Virgin Voyager train, number 220007 Thames Voyager , billed as the world's first "biodiesel train" was converted to run on 80% petrodiesel and only 20% biodiesel, and it is claimed it will save 14% on direct emissions.
## Aircraft use
Aircraft manufacturers are understandably even more cautious, but a test flight has been performed by an ex Soviet Aircraft (completely powered on biofuel); testing has been announced by Rolls Royce plc, Air New Zealand and Boeing (one engine out of four on a Boeing 747); and commercial passenger jet testing has also been announced by Virgin Atlantic's Richard Branson.
The world's first biofuel-powered commercial aircraft took off from London's Heathrow Airport on February 24 2008 and touched down in Amsterdam on a demonstration flight hailed as a first step towards "cleaner" flying. The "BioJet" fuel for this flight was produced by Seattle based Imperium Renewables, Inc.
## As a heating oil
Biodiesel can also be used as a heating fuel in domestic and commercial boilers, sometimes known as bioheat. Older furnaces may contain rubber parts that would be affected by biodiesel's solvent properties, but can otherwise burn biodiesel without any conversion required. Care must be taken at first, however, given that varnishes left behind by petrodiesel will be released and can clog pipes- fuel filtering and prompt filter replacement is required. Another approach is to start using biodiesel as blend, and decreasing the petroleum proportion over time can allow the varnishes to come off more gradually and be less likely to clog. Thanks to its strong solvent properties, however, the furnace is cleaned out and generally becomes more efficient. A technical research paper describes laboratory research and field trials project using pure biodiesel and biodiesel blends as a heating fuel in oil fired boilers.
During the Biodiesel Expo 2006 in the UK, Andrew J. Robertson presented his biodiesel heating oil research from his technical paper and suggested that B20 biodiesel could reduce UK household CO2 emissions by 1.5 million tonnes per year
# Historical background
Transesterification of a vegetable oil was conducted as early as 1853 by scientists E. Duffy and J. Patrick, many years before the first diesel engine became functional. Rudolf Diesel's prime model, a single 10 ft (3 m) iron cylinder with a flywheel at its base, ran on its own power for the first time in Augsburg, Germany, on August 10, 1893. In remembrance of this event, August 10 has been declared "International Biodiesel Day".
Rudolf Diesel demonstrated a Diesel engine running on peanut oil (at the request of the French government) built by the French Otto Company at the World Fair in Paris, France in 1900, where it received the Grand Prix (highest prize).
This engine stood as an example of Diesel's vision because it was powered by peanut oil — a biofuel, though not biodiesel, since it was not transesterified. He believed that the utilization of biomass fuel was the real future of his engine. In a 1912 speech Diesel said, "the use of vegetable oils for engine fuels may seem insignificant today but such oils may become, in the course of time, as important as petroleum and the coal-tar products of the present time."
During the 1920's, diesel engine manufacturers altered their engines to utilize the lower viscosity of petrodiesel (a fossil fuel), rather than vegetable oil (a biomass fuel). The petroleum industries were able to make inroads in fuel markets because their fuel was much cheaper to produce than the biomass alternatives. The result, for many years, was a near elimination of the biomass fuel production infrastructure. Only recently, have environmental impact concerns and a decreasing price differential made biomass fuels such as biodiesel a growing alternative.
Despite the widespread use of fossil petroleum-derived diesel fuels, interest in vegetable oils as fuels in internal combustion engines is reported in several countries during the 1920's and 1930's and later during World War II. Belgium, France, Italy, the United Kingdom, Portugal, Germany, Brazil, Argentina, Japan and China have been reported to have tested and used vegetable oils as diesel fuels during this time. Some operational problems were reported due to the high viscosity of vegetable oils compared to petroleum diesel fuel, which result in poor atomization of the fuel in the fuel spray and often leads to deposits and coking of the injectors, combustion chamber and valves. Attempts to overcome these problems included heating of the vegetable oil, blending it with petroleum-derived diesel fuel or ethanol, pyrolysis and cracking of the oils.
On August 31, 1937, G. Chavanne of the University of Brussels (Belgium) was granted a patent for a "Procedure for the transformation of vegetable oils for their uses as fuels" (fr. 'Procédé de Transformation d’Huiles Végétales en Vue de Leur Utilisation comme Carburants') Belgian Patent 422,877. This patent described the alcoholysis (often referred to as transesterification) of vegetable oils using methanol and ethanol in order to separate the fatty acids from the glycerol by replacing the glycerol by short linear alcohols. This appears to be the first account of the production of what is known as "biodiesel" today.
More recently, in 1977, Brazilian scientist Expedito Parente produced biodiesel using transesterification with ethanol, and again filed a patent for the same process. This process is classified as biodiesel by international norms, conferring a "standardized identity and quality. No other proposed biofuel has been validated by the motor industry." Currently, Parente's company Tecbio is working with Boeing and NASA to certify bioquerosene (bio-kerosene), another product produced and patented by the Brazilian scientist.
Research into the use of transesterified sunflower oil, and refining it to diesel fuel standards, was initiated in South Africa in 1979. By 1983, the process for producing fuel-quality, engine-tested biodiesel was completed and published internationally. An Austrian company, Gaskoks, obtained the technology from the South African Agricultural Engineers; the company erected the first biodiesel pilot plant in November 1987, and the first industrial-scale plant in April 1989 (with a capacity of 30,000 tons of rapeseed per annum).
Throughout the 1990s, plants were opened in many European countries, including the Czech Republic, Germany and Sweden. France launched local production of biodiesel fuel (referred to as diester) from rapeseed oil, which is mixed into regular diesel fuel at a level of 5%, and into the diesel fuel used by some captive fleets (e.g. public transportation) at a level of 30%. Renault, Peugeot and other manufacturers have certified truck engines for use with up to that level of partial biodiesel; experiments with 50% biodiesel are underway. During the same period, nations in other parts of the world also saw local production of biodiesel starting up: by 1998, the Austrian Biofuels Institute had identified 21 countries with commercial biodiesel projects. 100% Biodiesel is now available at many normal service stations across Europe.
In September 2005 Minnesota became the first U.S. state to mandate that all diesel fuel sold in the state contain part biodiesel, requiring a content of at least 2% biodiesel.
# Properties
Biodiesel has better lubricity than that of today's diesel fuels. During the manufacture of these, to comply with low SO2 engine emission limits set in modern standards, severe hydrotreatment is included. Biodiesel addition reduces wear increasing the life of the fuel injection equipment that relies on the fuel for its lubrication, such as high pressure injection pumps, pump injectors (also called unit injectors) and fuel injectors.
The volumetric energy density of biodiesel is about 33 MJ/L. This is 9 % lower than regular Number 2 petrodiesel. Variations in biodiesel energy density is more dependent on the feedstock used than the production process. Still these variations are less than for petrodiesel. It has been claimed biodiesel gives better lubricity and more complete combustion thus increasing the engine energy output and partially compensating for the higher energy density of petrodiesel.
Biodiesel is a liquid which varies in color — between golden and dark brown — depending on the production feedstock. It is immiscible with water, has a high boiling point and low vapor pressure. *The flash point of biodiesel (>130 °C, >266 °F) is significantly higher than that of petroleum diesel (64 °C, 147 °F) or gasoline (−45 °C, -52 °F). Biodiesel has a density of ~ 0.88 g/cm³, less than that of water.
Biodiesel has a viscosity similar to petrodiesel, the current industry term for diesel produced from petroleum. Biodiesel has high lubricity and virtually no sulfur content, and it is often used as an additive to Ultra-Low Sulfur Diesel (ULSD) fuel.
# Technical standards
The European standard for biodiesel is EN 14214, which is translated into the respective national standards for each country that forms the CEN (European Committee for Standardization) area e.g., for the United Kingdom, BS EN 14214 and for Germany DIN EN 14214. It may be used outside the CEN area as well.
There are other national specifications. ASTM D6751 is the most common standard referenced in the United States and Canada.There are also DIN standards for three different varieties of biodiesel, which are made of different oils:
- RME (rapeseed methyl ester, according to DIN E 51606)
- PME (vegetable methyl ester, purely vegetable products, according to DIN E 51606)
- FME (fat methyl ester, vegetable and animal products, according to DIN V 51606)
The standards ensure that the following important factors in the fuel production process are satisfied:
- Acid value
- Complete reaction.
- Removal of glycerin.
- Removal of catalyst.
- Removal of alcohol.
- Absence of free fatty acids.
- Low sulfur content.
- Cold Filter Plugging point
- Cloud Point
Basic industrial tests to determine whether the products conform to the standards typically include gas chromatography, a test that verifies only the more important of the variables above. Tests that are more complete are more expensive. Fuel meeting the quality standards is very non-toxic, with a toxicity rating (LD50) of greater than 50 mL/kg.
# Gelling
The cloud point, or temperature at which pure (B100) biodiesel starts to gel, varies significantly and depends upon the mix of esters and therefore the feedstock oil used to produce the biodiesel. For example, biodiesel produced from low erucic acid varieties of canola seed (RME) starts to gel at approximately −10 °C (14 °F). Biodiesel produced from tallow tends to gel at around +16 °C (61 °F). As of 2006, there are a very limited number of products that will significantly lower the gel point of straight biodiesel. A study carried out by Assiniboine Community College in Manitoba Canada managed to produce B100 biodiesel that was a clear flowing liquid at -38° by using a commercially available additive, Wintron XC30, in addition to low temperature filtration. A number of studies have shown that winter operation is possible with biodiesel blended with other fuel oils including #2 low sulfur diesel fuel and #1 diesel / kerosene. The exact blend depends on the operating environment: successful operations have run using a 65% LS #2, 30% K #1, and 5% bio blend. Other areas have run a 70% Low Sulfur #2, 20% Kerosene #1, and 10% bio blend or an 80% K#1, and 20% biodiesel blend. According to the National Biodiesel Board (NBB), B20 (20% biodiesel, 80% petrodiesel) does not need any treatment in addition to what is already taken with petrodiesel.
To permit the use of biodiesel without mixing and without the possibility of gelling at low temperatures, some people modify their vehicles with a second fuel tank for biodiesel in addition to the standard fuel tank. Alternately, a vehicle with two tanks is chosen. The second fuel tank is insulated and a heating coil using engine coolant is run through the tank. When a temperature sensor indicates that the fuel is warm enough to burn, the driver switches from the petrodiesel tank to the biodiesel tank. This is similar to the method used for running straight vegetable oil.
# Contamination by water
Biodiesel may contain small but problematic quantities of water. Although it is hydrophobic (non-miscible with water molecules), it is said to be, at the same time, hygroscopic to the point of attracting water molecules from atmospheric moisture; one of the reasons biodiesel can absorb water is the persistence of mono and diglycerides left over from an incomplete reaction. These molecules can act as an emulsifier, allowing water to mix with the biodiesel. In addition, there may be water that is residual to processing or resulting from storage tank condensation. The presence of water is a problem because:
- Water reduces the heat of combustion of the bulk fuel. This means more smoke, harder starting, less power.
- Water causes corrosion of vital fuel system components: fuel pumps, injector pumps, fuel lines, etc.
- Water & microbes cause the paper element filters in the system to fail ( rot), which in turn results in premature failure of the fuel pump due to ingestion of large particles.
- Water freezes to form ice crystals near 0 °C (32 °F). These crystals provide sites for nucleation and accelerate the gelling of the residual fuel.
- Water accelerates the growth of microbe colonies, which can plug up a fuel system. Biodiesel users who have heated fuel tanks therefore face a year-round microbe problem.
- Additionally, water can cause pitting in the pistons on a diesel engine.
Previously, the amount of water contaminating biodiesel has been difficult to measure by taking samples, since water and oil separate. However, it is now possible to measure the water content using water-in-oil sensors.
# Availability and prices
Global biodiesel production reached 3.8 million tons in 2005. Approximately 85% of biodiesel production came from the European Union.
In the United States, average retail (at the pump) prices, including Federal and state motor taxes, of B2/B5 are lower than petroleum diesel by about 12 cents, and B20 blends are the same as petrodiesel. B99 and B100 generally cost more than petrodiesel except where local governments provide a subsidy.
# Production
Biodiesel is commonly produced by the transesterification of the vegetable oil or animal fat feedstock. There are several methods for carrying out this transesterification reaction including the common batch process, supercritical processes, ultrasonic methods, and even microwave methods.
Chemically, transesterified biodiesel comprises a mix of mono-alkyl esters of long chain fatty acids. The most common form uses methanol (converted to sodium methoxide) to produce methyl esters as it is the cheapest alcohol available, though ethanol can be used to produce an ethyl ester biodiesel and higher alcohols such as isopropanol and butanol have also been used. Using alcohols of higher molecular weights improves the cold flow properties of the resulting ester, at the cost of a less efficient transesterification reaction. A lipid transesterification production process is used to convert the base oil to the desired esters. Any Free fatty acids (FFAs) in the base oil are either converted to soap and removed from the process, or they are esterified (yielding more biodiesel) using an acidic catalyst. After this processing, unlike straight vegetable oil, biodiesel has combustion properties very similar to those of petroleum diesel, and can replace it in most current uses.
A byproduct of the transesterification process is the production of glycerol. For every 1 tonne of biodiesel that is manufactured, 100 kg of glycerol are produced. Originally, there was a valuable market for the glycerol, which assisted the economics of the process as a whole. However, with the increase in global biodiesel production, the market price for this crude glycerol (containing 20% water and catalyst residues) has crashed. Research is being conducted globally to use this glycerol as a chemical building block. One initiative in the UK is The Glycerol Challenge.
Usually this crude glycerol has to be purified, typically by performing vacuum distillation. This is rather energy intensive. The refined glycerol (98%+ purity) can then be utilised directly, or converted into other products. The following announcements were made in 2007: A joint venture of Ashland Inc. and Cargill announced plans to make propylene glycol in Europe from glycerol and Dow Chemical announced similar plans for North America. Dow also plans to build a plant in China to make epichlorhydrin from glycerol. Epichlorhydrin is a raw material for epoxy resins.
## Production levels
Biodiesel production capacity is growing rapidly, with an average annual growth rate from 2002-2006 of over 40% . For the year 2006, the latest for which actual production figures could be obtained, total world biodiesel production was about 5-6 million tonnes, with 4.9 million tonnes processed in Europe (of which 2.7 million tonnes was from Germany) and most of the rest from the USA.
The capacity for 2007 in Europe totalled 10.3 million tonnes. This compares with a total demand for diesel in the US and Europe of approximately 490 million tonnes (147 billion gallons). Total world production of vegetable oil for all purposes in 2005/06 was about 110 million tonnes, with about 34 million tonnes each of palm oil and soybean oil.
## Biodiesel feedstocks
A variety of oils can be used to produce biodiesel. These include:
- Virgin oil feedstock; rapeseed and soybean oils are most commonly used, soybean oil alone accounting for about ninety percent of all fuel stocks in the US. It also can be obtained from field pennycress and Jatropha other crops such as mustard, flax, sunflower, palm oil, hemp (see List of vegetable oils for a more complete list);
- Waste vegetable oil (WVO);
- Animal fats including tallow, lard, yellow grease, chicken fat, and the by-products of the production of Omega-3 fatty acids from fish oil.
- Algae, which can be grown using waste materials such as sewage and without displacing land currently used for food production.
Many advocates suggest that waste vegetable oil is the best source of oil to produce biodiesel, but since the available supply is drastically less than the amount of petroleum-based fuel that is burned for transportation and home heating in the world, this local solution does not scale well.
Animal fats are similarly limited in supply, and it would not be efficient to raise animals simply for their fat. However, producing biodiesel with animal fat that would have otherwise been discarded could replace a small percentage of petroleum diesel usage. Currently, a 5-million dollar plant is being built in the USA, with the intent of producing 11.4 million litres (3 million gallons) biodiesel from some of the estimated 1 billion kg (2.3 billion pounds) of chicken fat produced annually the local Tyson poultry plant.
### Quantity of feedstocks required
Worldwide production of vegetable oil and animal fat is not yet sufficient to replace liquid fossil fuel use. Furthermore, some object to the vast amount of farming and the resulting fertilization, pesticide use, and land use conversion that would be needed to produce the additional vegetable oil. The estimated transportation diesel fuel and home heating oil used in the United States is about 160 million tonnes (350 billion pounds) according to the Energy Information Administration, US Department of Energy - . In the United States, estimated production of vegetable oil for all uses is about 11 million tonnes (24 billion pounds) and estimated production of animal fat is 5.3 million tonnes (12 billion pounds).
If the entire arable land area of the USA (470 million acres, or 1.9 million square kilometers) were devoted to biodiesel production from soy, this would just about provide the 160 million tonnes required (assuming an optimistic 98 gpa of biodiesel). This land area could in principle be reduced significantly using algae, if the obstacles can be overcome. The US DOE estimates that if algae fuel replaced all the petroleum fuel in the United States, it would require 15,000 square miles (38,849 square kilometers), which is a few thousand square miles larger than Maryland, or 1.3 Belgiums, assuming a yield of 15000 gpa. The advantages of algae are that it can be grown on non-arable land such as deserts or in marine environments, and the potential oil yields are much higher than from plants.
## Yield
Feedstock yield efficiency per acre affects the feasibility of ramping up production to the huge industrial levels required to power a significant percentage of national or world vehicles. Some typical yields in US gallons of biodiesel per acre are:
- Algae: 1800 gpa or more (est.- see soy figures and DOE quote below)
- Palm oil: 508 gpa
- Coconut: 230 gpa
- Rapeseed: 102 gpa
- Soy: 59.2-98.6 gpa in Indiana (Soy is used in 80% of USA biodiesel)
- Peanut: 90 gpa
- Sunflower: 82 gpa
Algae fuel yields have not yet been accurately determined, but DOE is reported as saying that algae yield 30 times more energy per acre than land crops such as soybeans., and some estimate even higher yields up to 15000 gpa .
The Jatropha plant has been cited as a high-yield source of biodiesel but such claims have also been exaggerated. The more realistic estimates put the yield at about 200 gpa (1.5-2 tonnes per hectare). It is grown in the Philippines, Mali and India, is drought-resistant, and can share space with other cash crops such as coffee, sugar, fruits and vegetables.
## Efficiency and economic arguments
According to a study written by Drs. Van Dyne and Raymer for the Tennessee Valley Authority, the average US farm consumes fuel at the rate of 82 litres per hectare (8.75 US gallons per acre) of land to produce one crop. However, average crops of rapeseed produce oil at an average rate of 1,029 L/ha (110 US gal/acre), and high-yield rapeseed fields produce about 1,356 L/ha (145 US gal/acre). The ratio of input to output in these cases is roughly 1:12.5 and 1:16.5. Photosynthesis is known to have an efficiency rate of about 3-6% of total solar radiation
and if the entire mass of a crop is utilized for energy production, the overall efficiency of this chain is currently about 1% While this may compare unfavorably to solar cells combined with an electric drive train, biodiesel is less costly to deploy (solar cells cost approximately US$1,000 per square meter) and transport (electric vehicles require batteries which currently have a much lower energy density than liquid fuels).
However, these statistics by themselves are not enough to show whether such a change makes economic sense.
Additional factors must be taken into account, such as: the fuel equivalent of the energy required for processing, the yield of fuel from raw oil, the return on cultivating food, the effect biodiesel will have of food prices and the relative cost of biodiesel versus petrodiesel.
The debate over the energy balance of biodiesel is ongoing. Transitioning fully to biofuels could require immense tracts of land if traditional food crops are used (although non food crops can be utilized). The problem would be especially severe for nations with large economies, since energy consumption scales with economic output.
If using only traditional food plants, most such nations do not have sufficient arable land to produce biofuel for the nation's vehicles. Nations with smaller economies (hence less energy consumption) and more arable land may be in better situations, although many regions cannot afford to divert land away from food production.
For third world countries, biodiesel sources that use marginal land could make more sense, e.g. honge oil nuts
grown along roads or jatropha grown along rail lines.
In tropical regions, such as Malaysia and Indonesia, oil palm is being planted at a rapid pace to supply growing biodiesel demand in Europe and other markets. It has been estimated in Germany that palm oil biodiesel has less than 1/3 the production costs of rapeseed biodiesel. The direct source of the energy content of biodiesel is solar energy captured by plants during photosynthesis. Regarding the positive energy balance of biodiesel:
Biodiesel is becoming of interest to companies interested in commercial scale production as well as the more usual home brew biodiesel user and the user of straight vegetable oil or waste vegetable oil in diesel engines. Homemade biodiesel processors are many and varied.
# Energy security
One of the main drivers for adoption of biodiesel is energy security. This means that a nations dependence on oil is reduced, and substituted with use of locally available sources, such as coal, gas or other renewable sources. Thus significant benefits can accrue to a country from adoption of biofuels, even without a reduction in greenhouse gas emissions. Whilst the total energy balance is debated, it is clear that the dependence on oil is reduced. One example is the energy used to manufacture fertilizers, which could come from a variety of sources other than petroleum. The the US NREL says that energy security is the number one driving force behind the US biofuels programme. and the White House "Energy Security for the 21st Century" makes clear that energy security is a major reason for promoting biodiesel. The EU commission president, Jose Manuel Barroso, speaking at a recent EU biofuels conference, stressed that properly managed biofuels have the potential to reinforce the EU's security of supply through diversification of energy sources.
# Environmental effects
## Greenhouse gas emissions
An often mentioned incentive for using biofuel is its capacity to lower greenhouse gas emissions compared to those of fossil fuels. If this is true or not depends on many factors. Especially the effects from land use change have potential to cause even more emissions than what would be caused by using fossil fuels alone.
Carbon dioxide is one of the major greenhouse gases. Although the burning of biodiesel produce carbon dioxide emissions similar to those from ordinary fossil fuels, the plant feedstock used in the production absorbs carbon dioxide from the atmosphere when it grows. Plants absorb carbon dioxide through a process known as photosynthesis which allows it to store energy from sunlight in the form of oil. After the oil is converted into biodiesel and burnt as fuel the energy and carbon is released again. Some of that energy can be used to power an engine while the carbon dioxide is released back into the atmosphere.
When considering the total amount of greenhouse gas emissions it is therefore important to consider the whole production process and what indirect effects such production might cause. The effect on carbon dioxide emissions is highly dependent on production methods and the type of feedstock used. Calculating the carbon intensity of biofuels is a complex and inexact process, and is highly dependent on the assumptions made in the calculation. A calculation usually includes:
- Emissions from growing the feedstock (e.g. Petrochemicals used in fertilizers)
- Emissions from transporting the feedstock to the factory
- Emissions from processing the feedstock into biodiesel
Other factors can be very significant but are sometimes not considered. These include:
- Emissions from the change in land use of the area where the fuel feedstock is grown.
- Emissions from transportation of the biodiesel from the factory to its point of use
- The efficiency of the biodiesel compared with standard diesel
- The amount of Carbon Dioxide produced at the tail pipe. (Biodiesel can produce 4.7% more)
- The benefits due to the production of useful bi-products, such as cattle feed or glycerine
If land use change is not considered and assuming todays production methods, biodiesel from rapeseed and sunflower oil produce 45%-65% lower greenhouse gas emissions than petrodiesel. However, there is ongoing research to improve the efficiency of the production process. Biodiesel produced from used cooking oil or other waste fat could reduce CO2 emissions by as much as 85%. As long as the feedstock is grown on existing cropland, land use change has little or no effect on greenhouse gas emissions. However, there is concern that increased feedstock production directly affect the rate of deforestation. Such clearcutting cause carbon stored in the forest, soil and peat layers to be released. The amount of greenhouse gas emissions from deforestation is so large that the benefits from lower emissions (caused by biodiesel use alone) would be negligible for hundreds of years. Biofuel produced from feedstocks such as palm oil could therefore cause much higher carbon dioxide emissions than ordinary fossil fuels.
## Deforestation
If deforestation, and monoculture farming techniques were used to grow biofuel crops, biodiesel is predicted to become a serious threat to the environment:
- Increasing the emission of climate change gases rather than helping curb them
- Damaging ecosystems and biodiversity
- Exacerbating social conflict
The demand for cheap oil from the tropical regions is of rising concern. In order to increase production, the amount of arable land is being expanded at the cost of tropical rainforest. Feedstock oils produced in Asia, South America and Africa are currently less expensive than those produced in Europe and North America suggesting that imports to these wealthier nations are likely to increase in the future.
In the Philippines and Indonesia forest clearing is already underway for the production of palm oil. Indigenous people are forced to move and their livelihood is destroyed when forest is cleared to make room for oil palm plantations. In some areas the use of pesticides for biofuel crops are disrupting clean water supplies, and the loss of habitat caused by deforestation is threatening many species of unique plants and animals. One example is the already-shrinking populations of orangutans on the Indonesian islands of Borneo and Sumatra, which face extinction if deforestation continue at it's projected rate.
## Pollution
In the United States, biodiesel is the only alternative fuel to have successfully completed the Health Effects Testing requirements (Tier I and Tier II) of the Clean Air Act (1990).
Biodiesel can reduce the direct tailpipe-emission of particulates, small particles of solid combustion products, on vehicles with particulate filters by as much as 20 percent compared with low-sulfur (< 50 ppm) diesel. Particulate emissions as the result of production are reduced by around 50 percent compared with fossil-sourced diesel. (Beer et al, 2004).
Biodiesel has a higher cetane rating than petrodiesel, which can improve performance and clean up emissions compared to crude petro-diesel (with cetane lower than 40). Biodiesel contains fewer aromatic hydrocarbons: benzofluoranthene: 56% reduction; Benzopyrenes: 71% reduction.
If burned without additives, Biodiesel (B100) is estimated to produce about 10% more nitrogen oxide NOx tailpipe-emissions than petrodiesel. As biodiesel has a low sulfur content, NOx emissions can be reduced through the use of catalytic converters to less than the NOx emissions from conventional diesel engines. However, modern diesel engines already use exhaust aftertreatment and EGR to reduce NOx emissions. These systems add complexity, increase costs, and reduce fuel economy (leading to higher CO2 emissions). As a transportation fuel, biodiesel is in its infancy in terms of additives which are capable of improving energy density, resistance to gelling, and NOx emissions. Debate continues over NOx, particulates, smog, and greenhouse gas emissions from biodiesel and all other new transportation fuels, biofuels in particular. Ultimately, greater clarity on the fundamental distinctions between smog and other local pollution issues vs. greenhouse gas emissions will be essential for both well founded public policy as well as well informed consumer choices.
## Biodegradable
A University of Idaho study compared biodegradation rates of biodiesel, neat vegetable oils, biodiesel and petroleum diesel blends, and neat 2-D diesel fuel. Using low concentrations of the product to be degraded (10 ppm) in nutrient and sewage sludge amended solutions, they demonstrated that biodiesel degraded at the same rate as a dextrose control and 5 times as quickly as petroleum diesel over a period of 28 days, and that biodiesel blends doubled the rate of petroleum diesel degradation through co-metabolism. The same study examined soil degradation using 10 000 ppm of biodiesel and petroleum diesel, and found biodiesel degraded at twice the rate of petroleum diesel in soil. In all cases, it was determined biodiesel also degraded more completely than petroleum diesel, which produced poorly degradable undetermined intermediates. Toxicity studies for the same project demonstrated no mortalities and few toxic effects on rats and rabbits with up to 5000 mg/kg of biodiesel. Petroleum diesel showed no mortalities at the same concentration either, however toxic effects such as hair loss and urinary discoloring were noted with concentrations of greater than 2000 mg/l in rabbits.
# Food vs fuel
Food quality vegetable oil has become so expensive there is no longer a profit viability for its use. Food grade vegetable oil pricing is on a similar upward ramp as food in general. Accessing food stuffs in poor countries has always been problematic for the inhabitants. Non food grade vegetable feed stocks are under use or consideration for use to make biodiesel and have been so during the entire history of biodiesel.
In some poor countries the rising price of vegetable oil is causing problems. There are those that say using a food crop for fuel sets up competition between food in poor countries and fuel in rich countries. Some propose that fuel only be made from non-edible vegetable oils like jatropha oil. Others argue that the problem is more fundamental. Farmers can switch from producing food crops to producing biofuel crops to make more money, even if the new crops are not edible. The law of supply and demand predicts that if fewer farmers are producing food the price of food will rise. It may take some time, as farmers can take some time to change which things they are growing, but increasing demand for biofuels is likely to result in price increases for many kinds of food. Some have pointed out that there are poor farmers and poor countries making more money because of the higher price of vegetable oil.
# Current research
There is ongoing research into finding more suitable crops and improving oil yield. Using the current yields, vast amounts of land and fresh water would be needed to produce enough oil to completely replace fossil fuel usage. It would require twice the land area of the US to be devoted to soybean production, or two-thirds to be devoted to rapeseed production, to meet current US heating and transportation needs.
Specially bred mustard varieties can produce reasonably high oil yields, and have the added benefit that the meal leftover after the oil has been pressed out can act as an effective and biodegradable pesticide.
## Algaculture
From 1978 to 1996, the U.S. National Renewable Energy Laboratory experimented with using algae as a biodiesel source in the "Aquatic Species Program".
A self-published article by Michael Briggs, at the UNH Biodiesel Group, offers estimates for the realistic replacement of all vehicular fuel with biodiesel by utilizing algae that have a natural oil content greater than 50%, which Briggs suggests can be grown on algae ponds at wastewater treatment plants. This oil-rich algae can then be extracted from the system and processed into biodiesel, with the dried remainder further reprocessed to create ethanol.
The production of algae to harvest oil for biodiesel has not yet been undertaken on a commercial scale, but feasibility studies have been conducted to arrive at the above yield estimate. In addition to its projected high yield, algaculture — unlike crop-based biofuels — does not entail a decrease in food production, since it requires neither farmland nor fresh water. Some companies are pursuing algae bio-reactors for various purposes, including biodiesel production.
On May 11, 2006 the Aquaflow Bionomic Corporation in Marlborough, New Zealand announced that it had produced its first sample of bio-diesel fuel made from algae found in sewage ponds.
Unlike previous attempts, the algae was naturally grown in pond discharge from the Marlborough District Council's sewage treatment works.
The Department of Environmental Science at Ateneo de Manila University in the Philippines, is working on producing biofuel from algae, using a local species of algae. | Biodiesel
# Overview
Biodiesel refers to a non-petroleum-based diesel fuel consisting of short chain alkyl (methyl or ethyl) esters, made by transesterification of vegetable oils or animal fats, which can be used (alone, or blended with conventional petrodiesel) in unmodified diesel-engine vehicles. Biodiesel is distinguished from the straight vegetable oil (SVO) (aka "waste vegetable oil", "WVO", "unwashed biodiesel", "pure plant oil", "PPO") used (alone, or blended) as fuels in some converted diesel vehicles. "Biodiesel" is standardized as mono-alkyl ester and other kinds of diesel-grade fuels of biological origin are not included.[1]
# Blends
Blends of biodiesel and conventional hydrocarbon-based diesel are products most commonly distributed for use in the retail diesel fuel marketplace. Much of the world uses a system known as the "B" factor to state the amount of biodiesel in any fuel mix: fuel containing 20% biodiesel is labeled B20, while pure biodiesel is referred to as B100. It is common to see B99, since 1% petrodiesel is sufficiently toxic to retard mold. Blends of 20 percent biodiesel with 80 percent petroleum diesel (B20) can generally be used in unmodified diesel engines. Biodiesel can also be used in its pure form (B100), but may require certain engine modifications to avoid maintenance and performance problems. Blending B100 with petro diesel may be accomplished by:
- Mixing in tanks at manufacturing point prior to delivery to tanker truck
- Splash mixing in the tanker truck (adding specific percentages of Biodiesel and Petro Diesel)
- In-line mixing, two components arrive at tanker truck simultaneously.
# Origin
On August 31, 1937, G. Chavanne of the University of Brussels (Belgium) was granted a patent for a 'Procedure for the transformation of vegetable oils for their uses as fuels' (fr. 'Procédé de Transformation d’Huiles Végétales en Vue de Leur Utilisation comme Carburants') Belgian Patent 422,877. This patent described the alcoholysis (often referred to as transesterification) of vegetable oils using ethanol (and mentions methanol) in order to separate the fatty acids from the glycerol by replacing the glycerol with short linear alcohols. This appears to be the first account of the production of what is known as 'biodiesel' today.[2]
# Applications
Biodiesel can be used in pure form (B100) or may be blended with petroleum diesel at any concentration in most modern diesel engines. Biodiesel has different solvent properties than petrodiesel, and will degrade natural rubber gaskets and hoses in vehicles (mostly found in vehicles manufactured before 1992), although these tend to wear out naturally and most likely will have already been replaced with FKM, which is nonreactive to biodiesel. Biodiesel has been known to break down deposits of residue in the fuel lines where petrodiesel has been used.[3] As a result, fuel filters may become clogged with particulates if a quick transition to pure biodiesel is made. Therefore, it is recommended to change the fuel filters on engines and heaters shortly after first switching to a biodiesel blend.[citation needed]
## Distribution
Biodiesel use and production are increasing rapidly. Fueling stations make biodiesel readily available to consumers across Europe, and increasingly in the USA and Canada. A growing number of transport fleets use it as an additive in their fuel. Biodiesel is often more expensive to purchase than petroleum diesel but this is expected to diminish due to economies of scale and agricultural subsidies versus the rising cost of petroleum as reserves are depleted.
## Vehicular use and manufacturer acceptance
In 2005, DaimlerChrysler released Jeep Liberty CRD diesels from the factory into the American market with 5% biodiesel blends, indicating at least partial acceptance of biodiesel as an acceptable diesel fuel additive.[4] In 2007, DiamlerChrysler indicated intention to increase warranty coverage to 20% biodiesel blends if biofuel quality in the United States can be standardized.[5]
## Railroad use
The British businessman Richard Branson's Virgin Voyager train, number 220007 Thames Voyager [6], billed as the world's first "biodiesel train" was converted to run on 80% petrodiesel and only 20% biodiesel, and it is claimed it will save 14% on direct emissions.
## Aircraft use
Aircraft manufacturers are understandably even more cautious, but a test flight has been performed by an ex Soviet Aircraft (completely powered on biofuel);[7] testing has been announced by Rolls Royce plc, Air New Zealand and Boeing (one engine out of four on a Boeing 747);[8] and commercial passenger jet testing has also been announced[9] by Virgin Atlantic's Richard Branson.
The world's first biofuel-powered commercial aircraft took off from London's Heathrow Airport on February 24 2008 and touched down in Amsterdam on a demonstration flight hailed as a first step towards "cleaner" flying. The "BioJet" fuel for this flight was produced by Seattle based Imperium Renewables, Inc.[10]
## As a heating oil
Biodiesel can also be used as a heating fuel in domestic and commercial boilers, sometimes known as bioheat. Older furnaces may contain rubber parts that would be affected by biodiesel's solvent properties, but can otherwise burn biodiesel without any conversion required. Care must be taken at first, however, given that varnishes left behind by petrodiesel will be released and can clog pipes- fuel filtering and prompt filter replacement is required. Another approach is to start using biodiesel as blend, and decreasing the petroleum proportion over time can allow the varnishes to come off more gradually and be less likely to clog. Thanks to its strong solvent properties, however, the furnace is cleaned out and generally becomes more efficient. A technical research paper [11] describes laboratory research and field trials project using pure biodiesel and biodiesel blends as a heating fuel in oil fired boilers.
During the Biodiesel Expo 2006 in the UK, Andrew J. Robertson presented his biodiesel heating oil research from his technical paper and suggested that B20 biodiesel could reduce UK household CO2 emissions by 1.5 million tonnes per year
# Historical background
Transesterification of a vegetable oil was conducted as early as 1853 by scientists E. Duffy and J. Patrick, many years before the first diesel engine became functional. Rudolf Diesel's prime model, a single 10 ft (3 m) iron cylinder with a flywheel at its base, ran on its own power for the first time in Augsburg, Germany, on August 10, 1893. In remembrance of this event, August 10 has been declared "International Biodiesel Day".
Rudolf Diesel demonstrated a Diesel engine running on peanut oil (at the request of the French government) built by the French Otto Company at the World Fair in Paris, France in 1900, where it received the Grand Prix (highest prize).
[12]
This engine stood as an example of Diesel's vision because it was powered by peanut oil — a biofuel, though not biodiesel, since it was not transesterified. He believed that the utilization of biomass fuel was the real future of his engine. In a 1912 speech Diesel said, "the use of vegetable oils for engine fuels may seem insignificant today but such oils may become, in the course of time, as important as petroleum and the coal-tar products of the present time."
During the 1920's, diesel engine manufacturers altered their engines to utilize the lower viscosity of petrodiesel (a fossil fuel), rather than vegetable oil (a biomass fuel). The petroleum industries were able to make inroads in fuel markets because their fuel was much cheaper to produce than the biomass alternatives. The result, for many years, was a near elimination of the biomass fuel production infrastructure. Only recently, have environmental impact concerns and a decreasing price differential made biomass fuels such as biodiesel a growing alternative.
Despite the widespread use of fossil petroleum-derived diesel fuels, interest in vegetable oils as fuels in internal combustion engines is reported in several countries during the 1920's and 1930's and later during World War II. Belgium, France, Italy, the United Kingdom, Portugal, Germany, Brazil, Argentina, Japan and China have been reported to have tested and used vegetable oils as diesel fuels during this time. Some operational problems were reported due to the high viscosity of vegetable oils compared to petroleum diesel fuel, which result in poor atomization of the fuel in the fuel spray and often leads to deposits and coking of the injectors, combustion chamber and valves. Attempts to overcome these problems included heating of the vegetable oil, blending it with petroleum-derived diesel fuel or ethanol, pyrolysis and cracking of the oils.
On August 31, 1937, G. Chavanne of the University of Brussels (Belgium) was granted a patent for a "Procedure for the transformation of vegetable oils for their uses as fuels" (fr. 'Procédé de Transformation d’Huiles Végétales en Vue de Leur Utilisation comme Carburants') Belgian Patent 422,877. This patent described the alcoholysis (often referred to as transesterification) of vegetable oils using methanol and ethanol in order to separate the fatty acids from the glycerol by replacing the glycerol by short linear alcohols. This appears to be the first account of the production of what is known as "biodiesel" today.
More recently, in 1977, Brazilian scientist Expedito Parente produced biodiesel using transesterification with ethanol, and again filed a patent for the same process. This process is classified as biodiesel by international norms, conferring a "standardized identity and quality. No other proposed biofuel has been validated by the motor industry."[13] Currently, Parente's company Tecbio is working with Boeing and NASA to certify bioquerosene (bio-kerosene), another product produced and patented by the Brazilian scientist.[14]
Research into the use of transesterified sunflower oil, and refining it to diesel fuel standards, was initiated in South Africa in 1979. By 1983, the process for producing fuel-quality, engine-tested biodiesel was completed and published internationally.[15] An Austrian company, Gaskoks, obtained the technology from the South African Agricultural Engineers; the company erected the first biodiesel pilot plant in November 1987, and the first industrial-scale plant in April 1989 (with a capacity of 30,000 tons of rapeseed per annum).
Throughout the 1990s, plants were opened in many European countries, including the Czech Republic, Germany and Sweden. France launched local production of biodiesel fuel (referred to as diester) from rapeseed oil, which is mixed into regular diesel fuel at a level of 5%, and into the diesel fuel used by some captive fleets (e.g. public transportation) at a level of 30%. Renault, Peugeot and other manufacturers have certified truck engines for use with up to that level of partial biodiesel; experiments with 50% biodiesel are underway. During the same period, nations in other parts of the world also saw local production of biodiesel starting up: by 1998, the Austrian Biofuels Institute had identified 21 countries with commercial biodiesel projects. 100% Biodiesel is now available at many normal service stations across Europe.
In September 2005 Minnesota became the first U.S. state to mandate that all diesel fuel sold in the state contain part biodiesel, requiring a content of at least 2% biodiesel.[16]
# Properties
Biodiesel has better lubricity than that of today's diesel fuels. During the manufacture of these, to comply with low SO2 engine emission limits set in modern standards, severe hydrotreatment is included. Biodiesel addition reduces wear[17] increasing the life of the fuel injection equipment that relies on the fuel for its lubrication, such as high pressure injection pumps, pump injectors (also called unit injectors) and fuel injectors.
The volumetric energy density of biodiesel is about 33 MJ/L. This is 9 % lower than regular Number 2 petrodiesel. Variations in biodiesel energy density is more dependent on the feedstock used than the production process. Still these variations are less than for petrodiesel.[18] It has been claimed biodiesel gives better lubricity and more complete combustion thus increasing the engine energy output and partially compensating for the higher energy density of petrodiesel.[19]
Biodiesel is a liquid which varies in color — between golden and dark brown — depending on the production feedstock. It is immiscible with water, has a high boiling point and low vapor pressure. *The flash point of biodiesel (>130 °C, >266 °F)[20] is significantly higher than that of petroleum diesel (64 °C, 147 °F) or gasoline (−45 °C, -52 °F). Biodiesel has a density of ~ 0.88 g/cm³, less than that of water.
Biodiesel has a viscosity similar to petrodiesel, the current industry term for diesel produced from petroleum. Biodiesel has high lubricity and virtually no sulfur content, and it is often used as an additive to Ultra-Low Sulfur Diesel (ULSD) fuel.
# Technical standards
The European standard for biodiesel is EN 14214, which is translated into the respective national standards for each country that forms the CEN (European Committee for Standardization) area e.g., for the United Kingdom, BS EN 14214 and for Germany DIN EN 14214. It may be used outside the CEN area as well.
There are other national specifications. ASTM D6751 is the most common standard referenced in the United States and Canada.There are also DIN standards for three different varieties of biodiesel, which are made of different oils:
- RME (rapeseed methyl ester, according to DIN E 51606)
- PME (vegetable methyl ester, purely vegetable products, according to DIN E 51606)
- FME (fat methyl ester, vegetable and animal products, according to DIN V 51606)
The standards ensure that the following important factors in the fuel production process are satisfied:
- Acid value
- Complete reaction.
- Removal of glycerin.
- Removal of catalyst.
- Removal of alcohol.
- Absence of free fatty acids.
- Low sulfur content.
- Cold Filter Plugging point
- Cloud Point
Basic industrial tests to determine whether the products conform to the standards typically include gas chromatography, a test that verifies only the more important of the variables above. Tests that are more complete are more expensive. Fuel meeting the quality standards is very non-toxic, with a toxicity rating (LD50) of greater than 50 mL/kg.
# Gelling
The cloud point, or temperature at which pure (B100) biodiesel starts to gel, varies significantly and depends upon the mix of esters and therefore the feedstock oil used to produce the biodiesel. For example, biodiesel produced from low erucic acid varieties of canola seed (RME) starts to gel at approximately −10 °C (14 °F). Biodiesel produced from tallow tends to gel at around +16 °C (61 °F). As of 2006, there are a very limited number of products that will significantly lower the gel point of straight biodiesel. A study carried out by Assiniboine Community College in Manitoba Canada managed to produce B100 biodiesel that was a clear flowing liquid at -38° by using a commercially available additive, Wintron XC30, in addition to low temperature filtration.[citation needed] A number of studies have shown that winter operation is possible with biodiesel blended with other fuel oils including #2 low sulfur diesel fuel and #1 diesel / kerosene. The exact blend depends on the operating environment: successful operations have run using a 65% LS #2, 30% K #1, and 5% bio blend. Other areas have run a 70% Low Sulfur #2, 20% Kerosene #1, and 10% bio blend or an 80% K#1, and 20% biodiesel blend. According to the National Biodiesel Board (NBB), B20 (20% biodiesel, 80% petrodiesel) does not need any treatment in addition to what is already taken with petrodiesel.
To permit the use of biodiesel without mixing and without the possibility of gelling at low temperatures, some people modify their vehicles with a second fuel tank for biodiesel in addition to the standard fuel tank. Alternately, a vehicle with two tanks is chosen. The second fuel tank is insulated and a heating coil using engine coolant is run through the tank. When a temperature sensor indicates that the fuel is warm enough to burn, the driver switches from the petrodiesel tank to the biodiesel tank. This is similar to the method used for running straight vegetable oil.
# Contamination by water
Biodiesel may contain small but problematic quantities of water. Although it is hydrophobic (non-miscible with water molecules), it is said to be, at the same time, hygroscopic to the point of attracting water molecules from atmospheric moisture[21]; one of the reasons biodiesel can absorb water is the persistence of mono and diglycerides left over from an incomplete reaction. These molecules can act as an emulsifier, allowing water to mix with the biodiesel.[citation needed] In addition, there may be water that is residual to processing or resulting from storage tank condensation. The presence of water is a problem because:
- Water reduces the heat of combustion of the bulk fuel. This means more smoke, harder starting, less power.
- Water causes corrosion of vital fuel system components: fuel pumps, injector pumps, fuel lines, etc.
- Water & microbes cause the paper element filters in the system to fail ( rot), which in turn results in premature failure of the fuel pump due to ingestion of large particles.
- Water freezes to form ice crystals near 0 °C (32 °F). These crystals provide sites for nucleation and accelerate the gelling of the residual fuel.
- Water accelerates the growth of microbe colonies, which can plug up a fuel system. Biodiesel users who have heated fuel tanks therefore face a year-round microbe problem.
- Additionally, water can cause pitting in the pistons on a diesel engine.
Previously, the amount of water contaminating biodiesel has been difficult to measure by taking samples, since water and oil separate. However, it is now possible to measure the water content using water-in-oil sensors.[citation needed]
# Availability and prices
Template:See details
Global biodiesel production reached 3.8 million tons in 2005. Approximately 85% of biodiesel production came from the European Union.
In the United States, average retail (at the pump) prices, including Federal and state motor taxes, of B2/B5 are lower than petroleum diesel by about 12 cents, and B20 blends are the same as petrodiesel.[22] B99 and B100 generally cost more than petrodiesel except where local governments provide a subsidy.
# Production
Template:See details
Biodiesel is commonly produced by the transesterification of the vegetable oil or animal fat feedstock. There are several methods for carrying out this transesterification reaction including the common batch process, supercritical processes, ultrasonic methods, and even microwave methods.
Chemically, transesterified biodiesel comprises a mix of mono-alkyl esters of long chain fatty acids. The most common form uses methanol (converted to sodium methoxide) to produce methyl esters as it is the cheapest alcohol available, though ethanol can be used to produce an ethyl ester biodiesel and higher alcohols such as isopropanol and butanol have also been used. Using alcohols of higher molecular weights improves the cold flow properties of the resulting ester, at the cost of a less efficient transesterification reaction. A lipid transesterification production process is used to convert the base oil to the desired esters. Any Free fatty acids (FFAs) in the base oil are either converted to soap and removed from the process, or they are esterified (yielding more biodiesel) using an acidic catalyst. After this processing, unlike straight vegetable oil, biodiesel has combustion properties very similar to those of petroleum diesel, and can replace it in most current uses.
A byproduct of the transesterification process is the production of glycerol. For every 1 tonne of biodiesel that is manufactured, 100 kg of glycerol are produced. Originally, there was a valuable market for the glycerol, which assisted the economics of the process as a whole. However, with the increase in global biodiesel production, the market price for this crude glycerol (containing 20% water and catalyst residues) has crashed. Research is being conducted globally to use this glycerol as a chemical building block. One initiative in the UK is The Glycerol Challenge.
Usually this crude glycerol has to be purified, typically by performing vacuum distillation. This is rather energy intensive. The refined glycerol (98%+ purity) can then be utilised directly, or converted into other products. The following announcements were made in 2007: A joint venture of Ashland Inc. and Cargill announced plans to make propylene glycol in Europe from glycerol[23] and Dow Chemical announced similar plans for North America.[24] Dow also plans to build a plant in China to make epichlorhydrin from glycerol.[25] Epichlorhydrin is a raw material for epoxy resins.
## Production levels
Biodiesel production capacity is growing rapidly, with an average annual growth rate from 2002-2006 of over 40% [26]. For the year 2006, the latest for which actual production figures could be obtained, total world biodiesel production was about 5-6 million tonnes, with 4.9 million tonnes processed in Europe [27] (of which 2.7 million tonnes was from Germany) and most of the rest from the USA. [28]
The capacity for 2007 in Europe totalled 10.3 million tonnes. This compares with a total demand for diesel in the US and Europe of approximately 490 million tonnes (147 billion gallons).[29] Total world production of vegetable oil for all purposes in 2005/06 was about 110 million tonnes, with about 34 million tonnes each of palm oil and soybean oil. [30]
## Biodiesel feedstocks
Template:Vegetable oils
A variety of oils can be used to produce biodiesel. These include:
- Virgin oil feedstock; rapeseed and soybean oils are most commonly used, soybean oil alone accounting for about ninety percent of all fuel stocks in the US. It also can be obtained from field pennycress and Jatropha other crops such as mustard, flax, sunflower, palm oil, hemp (see List of vegetable oils for a more complete list);
- Waste vegetable oil (WVO);
- Animal fats including tallow, lard, yellow grease, chicken fat, [31] and the by-products of the production of Omega-3 fatty acids from fish oil.
- Algae, which can be grown using waste materials such as sewage[32] and without displacing land currently used for food production.
Many advocates suggest that waste vegetable oil is the best source of oil to produce biodiesel, but since the available supply is drastically less than the amount of petroleum-based fuel that is burned for transportation and home heating in the world, this local solution does not scale well.
Animal fats are similarly limited in supply, and it would not be efficient to raise animals simply for their fat. However, producing biodiesel with animal fat that would have otherwise been discarded could replace a small percentage of petroleum diesel usage. Currently, a 5-million dollar plant is being built in the USA, with the intent of producing 11.4 million litres (3 million gallons) biodiesel from some of the estimated 1 billion kg (2.3 billion pounds) of chicken fat[33] produced annually the local Tyson poultry plant. [31]
### Quantity of feedstocks required
Worldwide production of vegetable oil and animal fat is not yet sufficient to replace liquid fossil fuel use. Furthermore, some object to the vast amount of farming and the resulting fertilization, pesticide use, and land use conversion that would be needed to produce the additional vegetable oil. The estimated transportation diesel fuel and home heating oil used in the United States is about 160 million tonnes (350 billion pounds) according to the Energy Information Administration, US Department of Energy - [34]. In the United States, estimated production of vegetable oil for all uses is about 11 million tonnes (24 billion pounds) and estimated production of animal fat is 5.3 million tonnes (12 billion pounds).[35]
If the entire arable land area of the USA (470 million acres, or 1.9 million square kilometers) were devoted to biodiesel production from soy, this would just about provide the 160 million tonnes required (assuming an optimistic 98 gpa of biodiesel). This land area could in principle be reduced significantly using algae, if the obstacles can be overcome. The US DOE estimates that if algae fuel replaced all the petroleum fuel in the United States, it would require 15,000 square miles (38,849 square kilometers), which is a few thousand square miles larger than Maryland, or 1.3 Belgiums, [36] [37]assuming a yield of 15000 gpa. The advantages of algae are that it can be grown on non-arable land such as deserts or in marine environments, and the potential oil yields are much higher than from plants.
## Yield
Feedstock yield efficiency per acre affects the feasibility of ramping up production to the huge industrial levels required to power a significant percentage of national or world vehicles. Some typical yields in US gallons of biodiesel per acre are:
- Algae: 1800 gpa or more (est.- see soy figures and DOE quote below)
- Palm oil: 508 gpa[38]
- Coconut: 230 gpa[38]
- Rapeseed: 102 gpa[38]
- Soy: 59.2-98.6 gpa in Indiana[39] (Soy is used in 80% of USA biodiesel[40])
- Peanut: 90 gpa[38]
- Sunflower: 82 gpa[38]
Algae fuel yields have not yet been accurately determined, but DOE is reported as saying that algae yield 30 times more energy per acre than land crops such as soybeans.[41], and some estimate even higher yields up to 15000 gpa .[42]
The Jatropha plant has been cited as a high-yield source of biodiesel but such claims have also been exaggerated. The more realistic estimates put the yield at about 200 gpa (1.5-2 tonnes per hectare).[43] It is grown in the Philippines, Mali and India, is drought-resistant, and can share space with other cash crops such as coffee, sugar, fruits and vegetables.[44]
## Efficiency and economic arguments
According to a study written by Drs. Van Dyne and Raymer for the Tennessee Valley Authority, the average US farm consumes fuel at the rate of 82 litres per hectare (8.75 US gallons per acre) of land to produce one crop. However, average crops of rapeseed produce oil at an average rate of 1,029 L/ha (110 US gal/acre), and high-yield rapeseed fields produce about 1,356 L/ha (145 US gal/acre). The ratio of input to output in these cases is roughly 1:12.5 and 1:16.5. Photosynthesis is known to have an efficiency rate of about 3-6% of total solar radiation[45]
and if the entire mass of a crop is utilized for energy production, the overall efficiency of this chain is currently about 1%[46] While this may compare unfavorably to solar cells combined with an electric drive train, biodiesel is less costly to deploy (solar cells cost approximately US$1,000 per square meter) and transport (electric vehicles require batteries which currently have a much lower energy density than liquid fuels).
However, these statistics by themselves are not enough to show whether such a change makes economic sense.
Additional factors must be taken into account, such as: the fuel equivalent of the energy required for processing, the yield of fuel from raw oil, the return on cultivating food, the effect biodiesel will have of food prices and the relative cost of biodiesel versus petrodiesel.
The debate over the energy balance of biodiesel is ongoing. Transitioning fully to biofuels could require immense tracts of land if traditional food crops are used (although non food crops can be utilized). The problem would be especially severe for nations with large economies, since energy consumption scales with economic output.[47]
If using only traditional food plants, most such nations do not have sufficient arable land to produce biofuel for the nation's vehicles. Nations with smaller economies (hence less energy consumption) and more arable land may be in better situations, although many regions cannot afford to divert land away from food production.
For third world countries, biodiesel sources that use marginal land could make more sense, e.g. honge oil nuts[48]
grown along roads or jatropha grown along rail lines.
In tropical regions, such as Malaysia and Indonesia, oil palm is being planted at a rapid pace to supply growing biodiesel demand in Europe and other markets. It has been estimated in Germany that palm oil biodiesel has less than 1/3 the production costs of rapeseed biodiesel.[49] The direct source of the energy content of biodiesel is solar energy captured by plants during photosynthesis. Regarding the positive energy balance of biodiesel[citation needed]:
Biodiesel is becoming of interest to companies interested in commercial scale production as well as the more usual home brew biodiesel user and the user of straight vegetable oil or waste vegetable oil in diesel engines. Homemade biodiesel processors are many and varied.
# Energy security
One of the main drivers for adoption of biodiesel is energy security. This means that a nations dependence on oil is reduced, and substituted with use of locally available sources, such as coal, gas or other renewable sources. Thus significant benefits can accrue to a country from adoption of biofuels, even without a reduction in greenhouse gas emissions. Whilst the total energy balance is debated, it is clear that the dependence on oil is reduced. One example is the energy used to manufacture fertilizers, which could come from a variety of sources other than petroleum. The the US NREL says that energy security is the number one driving force behind the US biofuels programme. [50]and the White House "Energy Security for the 21st Century" makes clear that energy security is a major reason for promoting biodiesel.[51] The EU commission president, Jose Manuel Barroso, speaking at a recent EU biofuels conference, stressed that properly managed biofuels have the potential to reinforce the EU's security of supply through diversification of energy sources. [52]
# Environmental effects
## Greenhouse gas emissions
An often mentioned incentive for using biofuel is its capacity to lower greenhouse gas emissions compared to those of fossil fuels. If this is true or not depends on many factors. Especially the effects from land use change have potential to cause even more emissions than what would be caused by using fossil fuels alone.[55]
Carbon dioxide is one of the major greenhouse gases. Although the burning of biodiesel produce carbon dioxide emissions similar to those from ordinary fossil fuels, the plant feedstock used in the production absorbs carbon dioxide from the atmosphere when it grows. Plants absorb carbon dioxide through a process known as photosynthesis which allows it to store energy from sunlight in the form of oil. After the oil is converted into biodiesel and burnt as fuel the energy and carbon is released again. Some of that energy can be used to power an engine while the carbon dioxide is released back into the atmosphere.
When considering the total amount of greenhouse gas emissions it is therefore important to consider the whole production process and what indirect effects such production might cause. The effect on carbon dioxide emissions is highly dependent on production methods and the type of feedstock used. Calculating the carbon intensity of biofuels is a complex and inexact process, and is highly dependent on the assumptions made in the calculation. A calculation usually includes:
- Emissions from growing the feedstock (e.g. Petrochemicals used in fertilizers)
- Emissions from transporting the feedstock to the factory
- Emissions from processing the feedstock into biodiesel
Other factors can be very significant but are sometimes not considered. These include:
- Emissions from the change in land use of the area where the fuel feedstock is grown.
- Emissions from transportation of the biodiesel from the factory to its point of use
- The efficiency of the biodiesel compared with standard diesel
- The amount of Carbon Dioxide produced at the tail pipe. (Biodiesel can produce 4.7% more)
- The benefits due to the production of useful bi-products, such as cattle feed or glycerine
If land use change is not considered and assuming todays production methods, biodiesel from rapeseed and sunflower oil produce 45%-65% lower greenhouse gas emissions than petrodiesel.[56][57][58][59] However, there is ongoing research to improve the efficiency of the production process.[56][58] Biodiesel produced from used cooking oil or other waste fat could reduce CO2 emissions by as much as 85%.[53] As long as the feedstock is grown on existing cropland, land use change has little or no effect on greenhouse gas emissions. However, there is concern that increased feedstock production directly affect the rate of deforestation. Such clearcutting cause carbon stored in the forest, soil and peat layers to be released. The amount of greenhouse gas emissions from deforestation is so large that the benefits from lower emissions (caused by biodiesel use alone) would be negligible for hundreds of years.[55][53] Biofuel produced from feedstocks such as palm oil could therefore cause much higher carbon dioxide emissions than ordinary fossil fuels.[60]
## Deforestation
If deforestation, and monoculture farming techniques were used to grow biofuel crops, biodiesel is predicted to become a serious threat to the environment:[61][62]
- Increasing the emission of climate change gases rather than helping curb them[55]
- Damaging ecosystems and biodiversity[63]
- Exacerbating social conflict[64]
The demand for cheap oil from the tropical regions is of rising concern. In order to increase production, the amount of arable land is being expanded at the cost of tropical rainforest.[60][65] Feedstock oils produced in Asia, South America and Africa are currently less expensive than those produced in Europe and North America suggesting that imports to these wealthier nations are likely to increase in the future.[60][65][63]
In the Philippines and Indonesia forest clearing is already underway for the production of palm oil.[60] Indigenous people are forced to move and their livelihood is destroyed when forest is cleared to make room for oil palm plantations.[64] In some areas the use of pesticides for biofuel crops are disrupting clean water supplies,[66] and the loss of habitat caused by deforestation is threatening many species of unique plants and animals. One example is the already-shrinking populations of orangutans on the Indonesian islands of Borneo and Sumatra, which face extinction if deforestation continue at it's projected rate.[63][67][68][69]
## Pollution
In the United States, biodiesel is the only alternative fuel to have successfully completed the Health Effects Testing requirements (Tier I and Tier II) of the Clean Air Act (1990).
Biodiesel can reduce the direct tailpipe-emission of particulates, small particles of solid combustion products, on vehicles with particulate filters by as much as 20 percent compared with low-sulfur (< 50 ppm) diesel. Particulate emissions as the result of production are reduced by around 50 percent compared with fossil-sourced diesel. (Beer et al, 2004).
Biodiesel has a higher cetane rating than petrodiesel, which can improve performance and clean up emissions compared to crude petro-diesel (with cetane lower than 40). Biodiesel contains fewer aromatic hydrocarbons: benzofluoranthene: 56% reduction; Benzopyrenes: 71% reduction.[citation needed]
If burned without additives, Biodiesel (B100) is estimated to produce about 10% more nitrogen oxide NOx tailpipe-emissions than petrodiesel. As biodiesel has a low sulfur content, NOx emissions can be reduced through the use of catalytic converters to less than the NOx emissions from conventional diesel engines. However, modern diesel engines already use exhaust aftertreatment and EGR to reduce NOx emissions. These systems add complexity, increase costs, and reduce fuel economy (leading to higher CO2 emissions). As a transportation fuel, biodiesel is in its infancy in terms of additives which are capable of improving energy density, resistance to gelling, and NOx emissions. Debate continues over NOx, particulates, smog, and greenhouse gas emissions from biodiesel and all other new transportation fuels, biofuels in particular. Ultimately, greater clarity on the fundamental distinctions between smog and other local pollution issues vs. greenhouse gas emissions will be essential for both well founded public policy as well as well informed consumer choices.
## Biodegradable
A University of Idaho study compared biodegradation rates of biodiesel, neat vegetable oils, biodiesel and petroleum diesel blends, and neat 2-D diesel fuel. Using low concentrations of the product to be degraded (10 ppm) in nutrient and sewage sludge amended solutions, they demonstrated that biodiesel degraded at the same rate as a dextrose control and 5 times as quickly as petroleum diesel over a period of 28 days, and that biodiesel blends doubled the rate of petroleum diesel degradation through co-metabolism.[70] The same study examined soil degradation using 10 000 ppm of biodiesel and petroleum diesel, and found biodiesel degraded at twice the rate of petroleum diesel in soil. In all cases, it was determined biodiesel also degraded more completely than petroleum diesel, which produced poorly degradable undetermined intermediates. Toxicity studies for the same project demonstrated no mortalities and few toxic effects on rats and rabbits with up to 5000 mg/kg of biodiesel. Petroleum diesel showed no mortalities at the same concentration either, however toxic effects such as hair loss and urinary discoloring were noted with concentrations of greater than 2000 mg/l in rabbits.
# Food vs fuel
Food quality vegetable oil has become so expensive there is no longer a profit viability for its use. Food grade vegetable oil pricing is on a similar upward ramp as food in general. Accessing food stuffs in poor countries has always been problematic for the inhabitants. Non food grade vegetable feed stocks are under use or consideration for use to make biodiesel and have been so during the entire history of biodiesel.
In some poor countries the rising price of vegetable oil is causing problems.[71][72] There are those that say using a food crop for fuel sets up competition between food in poor countries and fuel in rich countries. Some propose that fuel only be made from non-edible vegetable oils like jatropha oil. Others argue that the problem is more fundamental. Farmers can switch from producing food crops to producing biofuel crops to make more money, even if the new crops are not edible.[73][74] The law of supply and demand predicts that if fewer farmers are producing food the price of food will rise. It may take some time, as farmers can take some time to change which things they are growing, but increasing demand for biofuels is likely to result in price increases for many kinds of food. Some have pointed out that there are poor farmers and poor countries making more money because of the higher price of vegetable oil.[75]
# Current research
There is ongoing research into finding more suitable crops and improving oil yield. Using the current yields, vast amounts of land and fresh water would be needed to produce enough oil to completely replace fossil fuel usage. It would require twice the land area of the US to be devoted to soybean production, or two-thirds to be devoted to rapeseed production, to meet current US heating and transportation needs.[citation needed]
Specially bred mustard varieties can produce reasonably high oil yields, and have the added benefit that the meal leftover after the oil has been pressed out can act as an effective and biodegradable pesticide.[citation needed]
## Algaculture
From 1978 to 1996, the U.S. National Renewable Energy Laboratory experimented with using algae as a biodiesel source in the "Aquatic Species Program".[50]
A self-published article by Michael Briggs, at the UNH Biodiesel Group, offers estimates for the realistic replacement of all vehicular fuel with biodiesel by utilizing algae that have a natural oil content greater than 50%, which Briggs suggests can be grown on algae ponds at wastewater treatment plants.[37] This oil-rich algae can then be extracted from the system and processed into biodiesel, with the dried remainder further reprocessed to create ethanol.
The production of algae to harvest oil for biodiesel has not yet been undertaken on a commercial scale, but feasibility studies have been conducted to arrive at the above yield estimate. In addition to its projected high yield, algaculture — unlike crop-based biofuels — does not entail a decrease in food production, since it requires neither farmland nor fresh water. Some companies[4][5] are pursuing algae bio-reactors for various purposes, including biodiesel production.
On May 11, 2006 the Aquaflow Bionomic Corporation in Marlborough, New Zealand announced that it had produced its first sample of bio-diesel fuel made from algae found in sewage ponds.[32]
Unlike previous attempts, the algae was naturally grown in pond discharge from the Marlborough District Council's sewage treatment works.
The Department of Environmental Science at Ateneo de Manila University in the Philippines, is working on producing biofuel from algae, using a local species of algae.[76] | https://www.wikidoc.org/index.php/Biodiesel | |
73217cbe6f2447dff3698734369b0d8f0625576b | wikidoc | Bioethics | Bioethics
Bioethics is the ethics of biological science and medicine. Bioethicists are concerned with the ethical questions that arise in the relationships among life sciences, biotechnology, medicine, politics, law, philosophy, and theology.
# Scope
Scientific research has produced substantial social benefits. It has also posed some troubling ethical questions. Public attention was drawn to these questions by abuses of human subjects in biomedical experiments, especially during the Second World War. During the Nuremberg War Crime Trials, the Nuremberg code was drafted as a set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp prisoners. This code is often credited with jump starting the interdisciplinary field now called bioethics.
On July 12, 1974, the National Research Act (Pub. L. 93-348) was signed into law in the United States, thereby creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. One of the commission's charges was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects, as well as to develop guidelines. After nearly five years of discussion and collaboration, these guidelines were published. In 1979, a statement of basic ethical principles and guidelines to assist decision-makers in resolving the ethical problems that surround the conduct of research with human subjects appeared in the Federal Register. This became known as the Belmont Report. The report centered around the following three important principles, or general prescriptive judgments:
1. Respect for Persons
2. Beneficence
3. Justice
To apply the general principles to the conduct of research involving humans, the Belmont Report suggested that the following requirements be considered: informed consent, risk/benefit assessment, and the just and fair selection of subjects of research. The Belmont Report remains a touchstone for many bioethicists.
With new challenges in public health and health policy, and with advances in bio-technology, today bioethics is a fast-growing academic and professional area of inquiry. Since the early 1980s, the field has generated at least a dozen English-language journals. In addition, many academic medical centers and some schools of law, engineering and the liberal arts offer degree programs with a specialization in bioethics. Such programs train physicians and nurses, attorneys, philosophers, theologians, health services researchers and even bench scientists.
As a field of inquiry, bioethics received another boost when President Clinton created an Advisory Committee on Human Radiation Experiments, chaired by Ruth Faden of the Johns Hopkins Berman Institute of Bioethics. The committee sought to analyze the following questions:
What is the federal government's responsibility for wrongs and harms to human subjects as a result of experiments with ionizing radiation? What remedies are appropriate for those wronged or harmed? And what lessons learned from studying research standards and practices in the past and present can be applied to the future?
President Clinton directed the Advisory Committee to uncover the U.S. history of human radiation experiments during the period 1944 through 1974. It was in 1944 that the first known human radiation experiment of interest was planned, and in 1974 that the U.S. Department of Health, Education and Welfare adopted regulations governing the conduct of human research, a watershed event in the history of federal protections for human subjects. In addition, the Advisory Committee examined cases in which the government had intentionally released radiation into the environment for research purposes. The Advisory Committee also identified ethical and scientific standards for evaluating these events, and made recommendations to help ensure that wrongdoing could not be repeated.
Today, the field of bioethics struggles with its proper scope. Should it concern itself with the ethical evaluation of all questions involving biology and medicine? Some bioethicists would narrow ethical evaluation only to the morality of medical treatments or technological innovations, and the timing of medical treatment of humans. Others would broaden the scope of ethical evaluation to include the morality of all actions that might help or harm organisms capable of feeling fear and pain, and include within bioethics all such actions if they bear a relation to medicine and biology. The 1989 funding of the U.S. Human Genome Project, today known as the NHGRI, is credited with helping to create a more rigorous social science approach to the field.
# Why bioethics?
The issues raised by bioethics as a distinct area of academic inquiry (why must it exist apart from philosophy? isn't everyone an 'ethicist'?) are largely answered by the needs of institutions. Bioethicists today are not hired or engaged in conversation (and thus "named") because of their opinions or because they have special skills of reasoning, but because they know and can put to work the enormous body of research and history of discussions about bioethics in a fair, honest and intelligent way, using tools from the different disciplines that "feed" the field. Training programs in bioethics differ in skill sets of faculty and size of program, but across the US, and increasingly globally, they do seem to share a commitment to that goal with few exceptions.
As a result, bioethics has been distinctively created, by institutions, specifically the multi-million dollar commitment of major and minor medical centers to the study of medical ethics as part of the development of curriculum and research efforts. Today it is all but impossible to create a major medical research effort without ethicists to assist. First in the regulatory review of research, the responsibility of the IRB, which can be staffed by persons not trained in ethics in any rigorous way, or trained specifically in the ethical and regulatory aspects of research with human subjects, rather than more comprehensively in bioethics. The second form of assistance is by those who can think in advance of the onset of research about its social, ethical and economic implications. A shrinking number of those who would say that they "work in bioethics" are actually employed in other academic disciplines, because so many such disciplines reject as credible or important the work of bioethics in journals that are outside the methods of the traditional discipline within which such a person would work. A publication in JAMA would be meaningless to a tenure committee in most philosophy departments. A publication in the Journal of Philosophy would be meaningless to the same committee in a medical school. Seven articles would be sufficient for promotion in many philosophy departments, where 37 might be closer to the typical number of peer-reviewed publications for bioethicists, but of much shorter length, and philosophers would contest the possibility of rigor at that level of productivity. A book is a primary credential in the liberal arts and law. A book is virtually meaningless in medicine. So, as institutions employing bioethics change, the jobs change, and thus the training changes.
Nonetheless, many claim to work in bioethics, and indeed can feel free to do so, in just the same way that self-help book authors claim to work in philosophy. However, those not working in and trained in bioethics in the now fairly well established range of ways typical of bioethicists, demonstrated by, e.g., publishing in AJOB, Hastings Center Report, Journal of Medical Ethics, etc., will be perceived as amateurs by those in the field per se, again for the same reason that while Einstein did fabulous work as a patent clerk, he would not have been properly considered a physicist (and was not) until he joined the academic community, because without such standards universities and their growth in terms of new disciplines would spiral out of control.
# Ideology and methodology
Bioethicists often focus on using philosophy to help analyze issues, and philosophical ethicists such as Peter Singer tend to treat the field as a branch of moral or ethical philosophy. However, this approach is sometimes challenged, and bioethics is becoming increasingly interdisciplinary. Many bioethicists come from backgrounds outside of academic philosophy, and some even claim that the methods of analytic philosophy have had a negative effect on the field's development. The percentage of bioethicists with professional backgrounds in health care, especially physicians, has been steadily increasing over time. In fact, the last two Presidents of the primary academic society for bioethicists in the U.S. (the American Society for Bioethics and Humanities) have been physicians. Some bioethicists, especially those who perform ethics consultation in clinical settings, emphasize the practical aspects of bioethics, and view the field as more closely related to clinical practice or public health than philosophy.
Religious bioethicists have developed rules and guidelines on how to deal with these issues from within the viewpoint of their respective faiths. Many religious bioethicists are Jewish, and Christian scholars. Since the Indian traditions of Hinduism, Buddhism, and Jainism considers the sanctity of all life, there is much literature related to the philosophy and ethics related to life in each of these traditions. A growing number of religious scholars from Islam have also become involved in this field. There has been some criticism by liberal Muslims that only the more religiously conservative voices in Islam are being heard on this issue.
Although there are a number of eminently qualified philosophers who approach bioethics from a religious perspective, some Western secular bioethicists are critical of the fact that religious bioethicists are often religious scholars without an academic degree or training in disciplines that pertain to the issues, such as philosophy (wherein the formal study of ethics is usually found), biology or medicine. From the standpoint of bioethicists whose work is secular, the central cause for caution as regards religious bioethics work is that tools and methods should be brought to bear on problems, rather than starting with conclusions, and then looking for justifications. Of course, this criticism does not apply solely, of even to all, forms of religious bioethical work.
In the case of most non-Western cultures a strict separation of religion from philosophy does not exist. In many Asian cultures, there is a lively (and often less dogmatic, but more pragmatic) discussion on bioethical issues. The discussion often refers to common demographic policies which are criticised, as in the case of China. Buddhist bioethics, in general, is characterised by a naturalistic outlook that leads to a rationalistic, pragmatic approach. Buddhist bioethicists include Damien Keown. In India, Vandana Shiva is the leading bioethicist whose speaks from the Hindu tradition. In Africa, and partly also in Latin America, the debate on bioethics frequently focus on its practical relevance in the context of underdevelopment and (national or global) power relations.
# Issues
Areas of health sciences that are the subject of published, peer-reviewed bioethical analysis include:
- Abortion
- Animal rights
- Artificial insemination
- Artificial life
- Artificial womb
- Assisted suicide
- Biopiracy
- Blood/blood plasma (trade)
- Body modification
- Brain-computer interface
- Chimeras
- Circumcision
- Cloning
- Confidentiality (medical records)
- Consent
- Contraception
- Cryonics
- Eugenics
- Euthanasia (human, non-human animal)
- Feeding tube
- Gene therapy
- Genetically modified food
- Genomics
- Great Ape Project
- Human cloning
- Human enhancement
- Human genetic engineering
- Iatrogenesis
- Infertility (treatments)
- Life extension
- Life support
- Lobotomy
- Medical malpractice
- Medical research
- Medical torture
- Moral obligation
- Nanomedicine
- Organ donation (fair allocation, class and race biases)
- Pain management
- Parthenogenesis
- Patients' Bill of Rights
- Placebo
- Population control
- Prescription drugs (prices in the US)
- Procreative beneficence
- Procreative liberty
- Professional ethics
- Psychosurgery
- Recreational drug use
- Reproductive rights
- Reprogenetics
- Sperm and eggs (donation)
- Spiritual drug use
- Stem cell research
- Suicide
- Surrogacy
- Transexuality
- Transhumanism
- Transplant trade
# List of notable bioethicists
- Jacob M. Appel
- John D. Arras
- Tom L. Beauchamp
- J. David Bleich
- sarah V. Brakman
- Baruch Brody
- Howard Brody
- Arthur Caplan
- Ronald A. Carson
- Eric J. Cassell
- R. Alto Charo
- James F. Childress
- Elliot Dorff
- H. Tristram Engelhardt, Jr.
- Ruth Faden
- Joseph Fins
- Joseph Fletcher
- Norm Fost
- Robert P. George
- Walter Glannon
- Mordechai Halperin
- James Hughes
- Immanuel Jakobovits
- Albert R. Jonsen
- Leon Kass
- Sir Ian Kennedy
- Ken Kirkwood
- Mark Kuczewski
- John Lantos
- Robert Levine
- Bernard Lo
- Alex John London
- William F. May
- Van McCrary
- Glenn McGee
- Gilbert Meilaender
- Jonathan Moreno
- Thomas Murray
- E. Haavi Morreim
- Lawrence J. Nelson
- Bernard Nathanson
- Onora O'Neill
- Edmund Pellegrino
- Gregory E. Pence
- Thomas Percival
- Stephen G. Post
- James Rachels
- John A. Robertson
- Fred Rosner
- Judith Wilson Ross
- Hans-Martin Sass
- Julian Savulescu
- Harold Shapiro
- Mark Siegler
- Daniel Sinclair
- Peter Singer
- Wesley J. Smith
- Moshe David Tendler
- Etienne Vermeersch
- Eliezer Waldenberg
- William J. Winslade
- Matthew K. Wynia
- Stuart J. Youngner
- Laurie Zoloth | Bioethics
Template:Ethics
Bioethics is the ethics of biological science and medicine. Bioethicists are concerned with the ethical questions that arise in the relationships among life sciences, biotechnology, medicine, politics, law, philosophy, and theology.
# Scope
Scientific research has produced substantial social benefits. It has also posed some troubling ethical questions. Public attention was drawn to these questions by abuses of human subjects in biomedical experiments, especially during the Second World War. During the Nuremberg War Crime Trials, the Nuremberg code was drafted as a set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp prisoners. This code is often credited with jump starting the interdisciplinary field now called bioethics.
On July 12, 1974, the National Research Act (Pub. L. 93-348) was signed into law in the United States, thereby creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. One of the commission's charges was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects, as well as to develop guidelines. After nearly five years of discussion and collaboration, these guidelines were published. In 1979, a statement of basic ethical principles and guidelines to assist decision-makers in resolving the ethical problems that surround the conduct of research with human subjects appeared in the Federal Register. This became known as the Belmont Report. The report centered around the following three important principles, or general prescriptive judgments:
1. Respect for Persons
2. Beneficence
3. Justice
To apply the general principles to the conduct of research involving humans, the Belmont Report suggested that the following requirements be considered: informed consent, risk/benefit assessment, and the just and fair selection of subjects of research. The Belmont Report remains a touchstone for many bioethicists.
With new challenges in public health and health policy, and with advances in bio-technology, today bioethics is a fast-growing academic and professional area of inquiry. Since the early 1980s, the field has generated at least a dozen English-language journals. In addition, many academic medical centers and some schools of law, engineering and the liberal arts offer degree programs with a specialization in bioethics. Such programs train physicians and nurses, attorneys, philosophers, theologians, health services researchers and even bench scientists.
As a field of inquiry, bioethics received another boost when President Clinton created an Advisory Committee on Human Radiation Experiments, chaired by Ruth Faden of the Johns Hopkins Berman Institute of Bioethics. The committee sought to analyze the following questions:
What is the federal government's responsibility for wrongs and harms to human subjects as a result of experiments with ionizing radiation? What remedies are appropriate for those wronged or harmed? And what lessons learned from studying research standards and practices in the past and present can be applied to the future?
President Clinton directed the Advisory Committee to uncover the U.S. history of human radiation experiments during the period 1944 through 1974. It was in 1944 that the first known human radiation experiment of interest was planned, and in 1974 that the U.S. Department of Health, Education and Welfare adopted regulations governing the conduct of human research, a watershed event in the history of federal protections for human subjects. In addition, the Advisory Committee examined cases in which the government had intentionally released radiation into the environment for research purposes. The Advisory Committee also identified ethical and scientific standards for evaluating these events, and made recommendations to help ensure that wrongdoing could not be repeated.
Today, the field of bioethics struggles with its proper scope. Should it concern itself with the ethical evaluation of all questions involving biology and medicine? Some bioethicists would narrow ethical evaluation only to the morality of medical treatments or technological innovations, and the timing of medical treatment of humans. Others would broaden the scope of ethical evaluation to include the morality of all actions that might help or harm organisms capable of feeling fear and pain, and include within bioethics all such actions if they bear a relation to medicine and biology. The 1989 funding of the U.S. Human Genome Project, today known as the NHGRI, is credited with helping to create a more rigorous social science approach to the field.[citation needed]
# Why bioethics?
Template:Essay-entry
The issues raised by bioethics as a distinct area of academic inquiry (why must it exist apart from philosophy? isn't everyone an 'ethicist'?) are largely answered by the needs of institutions. Bioethicists today are not hired or engaged in conversation (and thus "named") because of their opinions or because they have special skills of reasoning, but because they know and can put to work the enormous body of research and history of discussions about bioethics in a fair, honest and intelligent way, using tools from the different disciplines that "feed" the field. Training programs in bioethics differ in skill sets of faculty and size of program, but across the US, and increasingly globally, they do seem to share a commitment to that goal with few exceptions.
As a result, bioethics has been distinctively created, by institutions, specifically the multi-million dollar commitment of major and minor medical centers to the study of medical ethics as part of the development of curriculum and research efforts. Today it is all but impossible to create a major medical research effort without ethicists to assist. First in the regulatory review of research, the responsibility of the IRB, which can be staffed by persons not trained in ethics in any rigorous way, or trained specifically in the ethical and regulatory aspects of research with human subjects, rather than more comprehensively in bioethics. The second form of assistance is by those who can think in advance of the onset of research about its social, ethical and economic implications. A shrinking number of those who would say that they "work in bioethics" are actually employed in other academic disciplines, because so many such disciplines reject as credible or important the work of bioethics in journals that are outside the methods of the traditional discipline within which such a person would work. A publication in JAMA would be meaningless to a tenure committee in most philosophy departments. A publication in the Journal of Philosophy would be meaningless to the same committee in a medical school. Seven articles would be sufficient for promotion in many philosophy departments, where 37 might be closer to the typical number of peer-reviewed publications for bioethicists, but of much shorter length, and philosophers would contest the possibility of rigor at that level of productivity. A book is a primary credential in the liberal arts and law. A book is virtually meaningless in medicine. So, as institutions employing bioethics change, the jobs change, and thus the training changes.
Nonetheless, many claim to work in bioethics, and indeed can feel free to do so, in just the same way that self-help book authors claim to work in philosophy. However, those not working in and trained in bioethics in the now fairly well established range of ways typical of bioethicists, demonstrated by, e.g., publishing in AJOB, Hastings Center Report, Journal of Medical Ethics, etc., will be perceived as amateurs by those in the field per se, again for the same reason that while Einstein did fabulous work as a patent clerk, he would not have been properly considered a physicist (and was not) until he joined the academic community, because without such standards universities and their growth in terms of new disciplines would spiral out of control.
# Ideology and methodology
Bioethicists often focus on using philosophy to help analyze issues, and philosophical ethicists such as Peter Singer tend to treat the field as a branch of moral or ethical philosophy. However, this approach is sometimes challenged, and bioethics is becoming increasingly interdisciplinary. Many bioethicists come from backgrounds outside of academic philosophy, and some even claim that the methods of analytic philosophy have had a negative effect on the field's development. The percentage of bioethicists with professional backgrounds in health care, especially physicians, has been steadily increasing over time. In fact, the last two Presidents of the primary academic society for bioethicists in the U.S. (the American Society for Bioethics and Humanities) have been physicians. Some bioethicists, especially those who perform ethics consultation in clinical settings, emphasize the practical aspects of bioethics, and view the field as more closely related to clinical practice or public health than philosophy.
Religious bioethicists have developed rules and guidelines on how to deal with these issues from within the viewpoint of their respective faiths. Many religious bioethicists are Jewish, and Christian scholars. Since the Indian traditions of Hinduism, Buddhism, and Jainism considers the sanctity of all life, there is much literature related to the philosophy and ethics related to life in each of these traditions. A growing number of religious scholars from Islam have also become involved in this field. There has been some criticism by liberal Muslims that only the more religiously conservative voices in Islam are being heard on this issue.
Although there are a number of eminently qualified philosophers who approach bioethics from a religious perspective, some Western secular bioethicists are critical of the fact that religious bioethicists are often religious scholars without an academic degree or training in disciplines that pertain to the issues, such as philosophy (wherein the formal study of ethics is usually found), biology or medicine. From the standpoint of bioethicists whose work is secular, the central cause for caution as regards religious bioethics work is that tools and methods should be brought to bear on problems, rather than starting with conclusions, and then looking for justifications. Of course, this criticism does not apply solely, of even to all, forms of religious bioethical work.
In the case of most non-Western cultures a strict separation of religion from philosophy does not exist. In many Asian cultures, there is a lively (and often less dogmatic, but more pragmatic) discussion on bioethical issues. The discussion often refers to common demographic policies which are criticised, as in the case of China. Buddhist bioethics, in general, is characterised by a naturalistic outlook that leads to a rationalistic, pragmatic approach. Buddhist bioethicists include Damien Keown. In India, Vandana Shiva is the leading bioethicist whose speaks from the Hindu tradition. In Africa, and partly also in Latin America, the debate on bioethics frequently focus on its practical relevance in the context of underdevelopment and (national or global) power relations.
# Issues
Areas of health sciences that are the subject of published, peer-reviewed bioethical analysis include:
- Abortion
- Animal rights
- Artificial insemination
- Artificial life
- Artificial womb
- Assisted suicide
- Biopiracy
- Blood/blood plasma (trade)
- Body modification
- Brain-computer interface
- Chimeras
- Circumcision
- Cloning
- Confidentiality (medical records)
- Consent
- Contraception
- Cryonics
- Eugenics
- Euthanasia (human, non-human animal)
- Feeding tube
- Gene therapy
- Genetically modified food
- Genomics
- Great Ape Project
- Human cloning
- Human enhancement
- Human genetic engineering
- Iatrogenesis
- Infertility (treatments)
- Life extension
- Life support
- Lobotomy
- Medical malpractice
- Medical research
- Medical torture
- Moral obligation
- Nanomedicine
- Organ donation (fair allocation, class and race biases)
- Pain management
- Parthenogenesis
- Patients' Bill of Rights
- Placebo
- Population control
- Prescription drugs (prices in the US)
- Procreative beneficence
- Procreative liberty
- Professional ethics
- Psychosurgery
- Recreational drug use
- Reproductive rights
- Reprogenetics
- Sperm and eggs (donation)
- Spiritual drug use
- Stem cell research
- Suicide
- Surrogacy
- Transexuality
- Transhumanism
- Transplant trade
# List of notable bioethicists
- Jacob M. Appel
- John D. Arras
- Tom L. Beauchamp
- J. David Bleich
- sarah V. Brakman
- Baruch Brody
- Howard Brody
- Arthur Caplan
- Ronald A. Carson
- Eric J. Cassell
- R. Alto Charo
- James F. Childress
- Elliot Dorff
- H. Tristram Engelhardt, Jr.
- Ruth Faden
- Joseph Fins
- Joseph Fletcher
- Norm Fost
- Robert P. George
- Walter Glannon
- Mordechai Halperin
- James Hughes
- Immanuel Jakobovits
- Albert R. Jonsen
- Leon Kass
- Sir Ian Kennedy
- Ken Kirkwood
- Mark Kuczewski
- John Lantos
- Robert Levine
- Bernard Lo
- Alex John London
- William F. May
- Van McCrary
- Glenn McGee
- Gilbert Meilaender
- Jonathan Moreno
- Thomas Murray
- E. Haavi Morreim
- Lawrence J. Nelson
- Bernard Nathanson
- Onora O'Neill
- Edmund Pellegrino
- Gregory E. Pence
- Thomas Percival
- Stephen G. Post
- James Rachels
- John A. Robertson
- Fred Rosner
- Judith Wilson Ross
- Hans-Martin Sass
- Julian Savulescu
- Harold Shapiro
- Mark Siegler
- Daniel Sinclair
- Peter Singer
- Wesley J. Smith
- Moshe David Tendler
- Etienne Vermeersch
- Eliezer Waldenberg
- William J. Winslade
- Matthew K. Wynia
- Stuart J. Youngner
- Laurie Zoloth | https://www.wikidoc.org/index.php/Bioethicist | |
1ad5f4ceb434fc7e3c9f981c9d1519463b342c0f | wikidoc | Flavonoid | Flavonoid
# Overview
The term flavonoid refers to a class of plant secondary metabolites. According to the IUPAC nomenclature, they can be classified into:
- flavonoids, derived from 2-phenylchromen-4-one (2-phenyl-1,4-benzopyrone) structure
- isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure
- neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) structure.
Flavonoids are most commonly known for their antioxidant activity. However, it is now known that the health benefits they provide against cancer and heart disease are the result of other mechanisms. Flavonoids are also commonly referred to as bioflavonoids in the media – the terms are equivalent and interchangeable, for flavonoids are biological in origin.
# Biosynthesis
Flavonoids are synthesized by the phenylpropanoid metabolic pathway in which the amino acid phenylalanine is used to produce 4-coumaroyl-CoA. This can be combined with malonyl-CoA to yield the true backbone of flavonoids, a group of compounds called chalcones which contain two phenyl rings (see polyphenols). Conjugate ring-closure of chalcones results in the familiar form of flavonoids, the three-ringed structure of a flavone. The metabolic pathway continues through a series of enzymatic modifications to yield flavanones → dihydroflavonols → anthocyanins. Along this pathway many products can be formed, including the flavonols, flavan-3-ols, proanthocyanidins (tannins) and a host of other polyphenolics.
# Biological effects
Flavonoids are widely distributed in plants fulfilling many functions including producing yellow or red/blue pigmentation in flowers and protection from attack by microbes and insects. The widespread distribution of flavonoids, their variety and their relatively low toxicity compared to other active plant compounds (for instance alkaloids) mean that many animals, including humans, ingest significant quantities in their diet. Flavonoids have been referred to as "nature's biological response modifiers" because of strong experimental evidence of their inherent ability to modify the body's reaction to allergens, viruses, and carcinogens. They show anti-allergic, anti-inflammatory
, anti-microbial and anti-cancer activity.
Consumers and food manufacturers have become interested in flavonoids for their medicinal properties, especially their potential role in the prevention of cancers and cardiovascular disease. The beneficial effects of fruit, vegetables, and tea or even red wine have been attributed to flavonoid compounds rather than to known nutrients and vitamins.
## Health benefit not due to direct antioxidant value
In 2007, research conducted at the Linus Pauling Institute and published in Free Radical Biology and Medicine indicates that inside the human body, flavonoids themselves are of little or no direct antioxidant value. Unlike in the controlled conditions of a test tube, flavonoids are poorly absorbed by the human body (less than 5%), and most of what is absorbed is quickly metabolized and excreted from the body.
The huge increase in antioxidant capacity of blood seen after the consumption of flavonoid-rich foods is not caused directly by the flavonoids themselves, but most likely is due to increased uric acid levels that result from expelling flavonoids from the body. According to Frei, "we can now follow the activity of flavonoids in the body, and one thing that is clear is that the body sees them as foreign compounds and is trying to get rid of them. But this process of gearing up to get rid of unwanted compounds is inducing so-called Phase II enzymes that also help eliminate mutagens and carcinogens, and therefore may be of value in cancer prevention... Flavonoids could also induce mechanisms that help kill cancer cells and inhibit tumor invasion."
Their research also indicated that only small amounts of flavonoids are necessary to see these medical benefits. Taking large dietary supplements provides no extra benefit and may pose some risks.
### Diarrhea
A study done at Children's Hospital & Research Center Oakland, in collaboration with scientists at Heinrich Heine University in Germany, has shown that epicatechin, quercetin and luteolin can inhibit the development of fluids that result in diarrhea by targeting the intestinal cystic fibrosis transmembrane conductance regulator Cl– transport inhibiting cAMP-stimulated Cl– secretion in the intestine.
# Important flavonoids
## Quercetin
Quercetin is a flavonoid and more specifically a flavonol (see below), that constitutes the aglycone of the glycoside rutin. In studies, quercetin is found to be the most active of the flavonoids, and many medicinal plants owe much of their activity to their high quercetin content. Quercetin has demonstrated significant anti-inflammatory activity because of direct inhibition of several initial processes of inflammation. For example, it inhibits both the production and release of histamine and other allergic/inflammatory mediators. In addition, it exerts potent antioxidant activity and vitamin C-sparing action. It has been found to be anti-cancer. Quercetin can be found in the herbal products based on Hawthorn which are used for acute symptoms of Congestive Heart Failure.
## Epicatechin
Epicatechin improves blood flow and thus seems good for cardiac health. Cocoa, the major ingredient of dark chocolate, contains relatively high amounts of epicatechin and has been found to have nearly twice the antioxidant content of red wine and up to three times that of green tea in in-vitro tests. But in the test outlined above it now appears the beneficial antioxidant effects are minimal as the antioxidants are rapidly excreted from the body.
## Oligomeric proanthocyanidins
Proanthocyanidins extracts demonstrate a wide range of pharmacological activity. Their effects include increasing intracellular vitamin C levels, decreasing capillary permeability and fragility, scavenging oxidants and free radicals, and inhibiting destruction of collagen, the most abundant protein in the body.
# Important dietary sources
Good sources of flavonoids include all citrus fruits, berries, onions, parsley, legumes, green tea, red wine, seabuckthorn, and dark chocolate (that with a cocoa content of seventy percent or greater).
## Citrus
The citrus bioflavonoids include hesperidin, quercetin, rutin (a glycoside of quercetin), and tangeritin. In addition to possessing antioxidant activity and an ability to increase intracellular levels of vitamin C, rutin and hesperidin exert beneficial effects on capillary permeability and blood flow. They also exhibit some of the anti-allergy and anti-inflammatory benefits of quercetin. Quercetin can also inhibit reverse transcriptase, part of the replication process of retroviruses. The therapeutical relevance of this inhibition has not been established. Hydroxyethylrutosides (HER) have been used in the treatment of capillary permeability, easy bruising, hemorrhoids, and varicose veins.
## Tea
Green tea flavonoids are potent antioxidant compounds, thought to reduce incidence of cancer and heart disease. The major flavonoids in green tea are the catechins (catechin, epicatechin, epicatechin gallate, and epigallocatechin gallate (EGCG)).
In producing teas such as oolong tea and black tea, the leaves are allowed to oxidize, during which enzymes present in the tea convert some or all of the catechins to larger molecules. White tea is the least processed of teas and is shown to present the highest amount of catechins known to occur in camellia sinensis.However, green tea is produced by steaming the fresh-cut leaf, which inactivates these enzymes, and oxidation does not significantly occur.
## Wine
Grape skins contain significant amounts of flavonoids as well as other polyphenols. Both red and white wine contain flavonoids; however, since red wine is produced by fermentation in the presence of the grape skins, red wine has been observed to contain higher levels of flavonoids, and other polyphenolics such as resveratrol.
# Subgroups
Over 5000 naturally occurring flavonoids have been characterized from various plants. They have been classified according to their chemical structure, and are usually subdivided into the following subgroups:
## Flavones
Flavones are divided into four groups:
- Flavones
Flavones use the 2-phenylchromen-4-one skeleton.
Examples: Luteolin, Apigenin, Tangeritin
- Flavonols
Flavonols or 3-hydroxyflavones use the 3-hydroxy-2-phenylchromen-4-one skeleton.
Examples: Quercetin, Kaempferol, Myricetin, Fisetin, Isorhamnetin, Pachypodol, Rhamnazin
- Flavanones
Flavanones use the 2,3-dihydro-2-phenylchromen-4-one skeleton.
Examples: Hesperetin, Naringenin, Eriodictyol
- 3-Hydroxyflavanones or 2,3-dihydroflavonols
3-Hydroxyflavanones use the 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one skeleton.
Examples: Dihydroquercetin, Dihydrokaempferol
## Isoflavones
- Isoflavones
Isoflavones use the 3-phenylchromen-4-one skeleton.
Examples: Genistein, Daidzein, Glycitein
## Flavan-3-ols and Anthocyanidins
- Flavan-3-ols
Flavan-3-ols use the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton.
Examples: Catechins (Catechin (C), Gallocatechin (GC), Catechin 3-gallate (Cg), Gallocatechin 3-gallate (GCg)), Epicatechins (Epicatechin (EC), Epigallocatechin (EGC), Epicatechin 3-gallate (ECg), Epigallocatechin 3-gallate (EGCg))
- Anthocyanidins
Anthocyanidins are the aglycones of anthocyanins. Anthocyanidins use the flavylium (2-phenylchromenylium) ion skeleton
Examples: Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin
# Availability through microorganisms
A number of recent research articles have demonstrated the efficient production of flavonoid molecules from genetically-engineered microorganisms. | Flavonoid
# Overview
The term flavonoid refers to a class of plant secondary metabolites. According to the IUPAC nomenclature,[1] they can be classified into:
- flavonoids, derived from 2-phenylchromen-4-one (2-phenyl-1,4-benzopyrone) structure
- isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure
- neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) structure.
Flavonoids are most commonly known for their antioxidant activity. However, it is now known that the health benefits they provide against cancer and heart disease are the result of other mechanisms.[2] Flavonoids are also commonly referred to as bioflavonoids in the media – the terms are equivalent and interchangeable, for flavonoids are biological in origin.
# Biosynthesis
Flavonoids are synthesized by the phenylpropanoid metabolic pathway in which the amino acid phenylalanine is used to produce 4-coumaroyl-CoA. This can be combined with malonyl-CoA to yield the true backbone of flavonoids, a group of compounds called chalcones which contain two phenyl rings (see polyphenols). Conjugate ring-closure of chalcones results in the familiar form of flavonoids, the three-ringed structure of a flavone. The metabolic pathway continues through a series of enzymatic modifications to yield flavanones → dihydroflavonols → anthocyanins. Along this pathway many products can be formed, including the flavonols, flavan-3-ols, proanthocyanidins (tannins) and a host of other polyphenolics.
# Biological effects
Flavonoids are widely distributed in plants fulfilling many functions including producing yellow or red/blue pigmentation in flowers and protection from attack by microbes and insects. The widespread distribution of flavonoids, their variety and their relatively low toxicity compared to other active plant compounds (for instance alkaloids) mean that many animals, including humans, ingest significant quantities in their diet. Flavonoids have been referred to as "nature's biological response modifiers" because of strong experimental evidence of their inherent ability to modify the body's reaction to allergens, viruses, and carcinogens. They show anti-allergic, anti-inflammatory[3]
, anti-microbial and anti-cancer activity.
Consumers and food manufacturers have become interested in flavonoids for their medicinal properties, especially their potential role in the prevention of cancers and cardiovascular disease. The beneficial effects of fruit, vegetables, and tea or even red wine have been attributed to flavonoid compounds rather than to known nutrients and vitamins.
## Health benefit not due to direct antioxidant value
In 2007, research conducted at the Linus Pauling Institute and published in Free Radical Biology and Medicine indicates that inside the human body, flavonoids themselves are of little or no direct antioxidant value. Unlike in the controlled conditions of a test tube, flavonoids are poorly absorbed by the human body (less than 5%), and most of what is absorbed is quickly metabolized and excreted from the body.
The huge increase in antioxidant capacity of blood seen after the consumption of flavonoid-rich foods is not caused directly by the flavonoids themselves, but most likely is due to increased uric acid levels that result from expelling flavonoids from the body.[2] According to Frei, "we can now follow the activity of flavonoids in the body, and one thing that is clear is that the body sees them as foreign compounds and is trying to get rid of them. But this process of gearing up to get rid of unwanted compounds is inducing so-called Phase II enzymes that also help eliminate mutagens and carcinogens, and therefore may be of value in cancer prevention... Flavonoids could also induce mechanisms that help kill cancer cells and inhibit tumor invasion."[2]
Their research also indicated that only small amounts of flavonoids are necessary to see these medical benefits. Taking large dietary supplements provides no extra benefit and may pose some risks.[2]
### Diarrhea
A study done at Children's Hospital & Research Center Oakland, in collaboration with scientists at Heinrich Heine University in Germany, has shown that epicatechin, quercetin and luteolin can inhibit the development of fluids that result in diarrhea by targeting the intestinal cystic fibrosis transmembrane conductance regulator Cl– transport inhibiting cAMP-stimulated Cl– secretion in the intestine.[4]
# Important flavonoids
## Quercetin
Quercetin is a flavonoid and more specifically a flavonol (see below), that constitutes the aglycone of the glycoside rutin. In studies, quercetin is found to be the most active of the flavonoids, and many medicinal plants owe much of their activity to their high quercetin content. Quercetin has demonstrated significant anti-inflammatory activity because of direct inhibition of several initial processes of inflammation. For example, it inhibits both the production and release of histamine and other allergic/inflammatory mediators. In addition, it exerts potent antioxidant activity and vitamin C-sparing action. It has been found to be anti-cancer. Quercetin can be found in the herbal products based on Hawthorn which are used for acute symptoms of Congestive Heart Failure.
## Epicatechin
Epicatechin improves blood flow and thus seems good for cardiac health. Cocoa, the major ingredient of dark chocolate, contains relatively high amounts of epicatechin and has been found to have nearly twice the antioxidant content of red wine and up to three times that of green tea in in-vitro tests.[5] [6] But in the test outlined above it now appears the beneficial antioxidant effects are minimal as the antioxidants are rapidly excreted from the body.
## Oligomeric proanthocyanidins
Proanthocyanidins extracts demonstrate a wide range of pharmacological activity. Their effects include increasing intracellular vitamin C levels, decreasing capillary permeability and fragility, scavenging oxidants and free radicals, and inhibiting destruction of collagen, the most abundant protein in the body.
# Important dietary sources
Good sources of flavonoids include all citrus fruits, berries, onions, parsley, legumes, green tea, red wine, seabuckthorn, and dark chocolate (that with a cocoa content of seventy percent or greater).
## Citrus
The citrus bioflavonoids include hesperidin, quercetin, rutin (a glycoside of quercetin), and tangeritin. In addition to possessing antioxidant activity and an ability to increase intracellular levels of vitamin C, rutin and hesperidin exert beneficial effects on capillary permeability and blood flow. They also exhibit some of the anti-allergy and anti-inflammatory benefits of quercetin. Quercetin can also inhibit reverse transcriptase, part of the replication process of retroviruses.[7] The therapeutical relevance of this inhibition has not been established. Hydroxyethylrutosides (HER) have been used in the treatment of capillary permeability, easy bruising, hemorrhoids, and varicose veins.
## Tea
Green tea flavonoids are potent antioxidant compounds, thought to reduce incidence of cancer and heart disease. The major flavonoids in green tea are the catechins (catechin, epicatechin, epicatechin gallate, and epigallocatechin gallate (EGCG)).
In producing teas such as oolong tea and black tea, the leaves are allowed to oxidize, during which enzymes present in the tea convert some or all of the catechins to larger molecules. White tea is the least processed of teas and is shown to present the highest amount of catechins known to occur in camellia sinensis.However, green tea is produced by steaming the fresh-cut leaf, which inactivates these enzymes, and oxidation does not significantly occur.
## Wine
Grape skins contain significant amounts of flavonoids as well as other polyphenols[8]. Both red and white wine contain flavonoids; however, since red wine is produced by fermentation in the presence of the grape skins, red wine has been observed to contain higher levels of flavonoids, and other polyphenolics such as resveratrol.
# Subgroups
Over 5000 naturally occurring flavonoids have been characterized from various plants. They have been classified according to their chemical structure, and are usually subdivided into the following subgroups:
## Flavones
Flavones are divided into four groups:[9]
- Flavones
Flavones use the 2-phenylchromen-4-one skeleton.
Examples: Luteolin, Apigenin, Tangeritin
- Flavonols
Flavonols or 3-hydroxyflavones use the 3-hydroxy-2-phenylchromen-4-one skeleton.
Examples: Quercetin, Kaempferol, Myricetin, Fisetin, Isorhamnetin, Pachypodol, Rhamnazin
- Flavanones
Flavanones use the 2,3-dihydro-2-phenylchromen-4-one skeleton.
Examples: Hesperetin, Naringenin, Eriodictyol
- 3-Hydroxyflavanones or 2,3-dihydroflavonols
3-Hydroxyflavanones use the 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one skeleton.
Examples: Dihydroquercetin, Dihydrokaempferol
## Isoflavones
- Isoflavones
Isoflavones use the 3-phenylchromen-4-one skeleton.
Examples: Genistein, Daidzein, Glycitein
## Flavan-3-ols and Anthocyanidins
- Flavan-3-ols
Flavan-3-ols use the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton.
Examples: Catechins (Catechin (C), Gallocatechin (GC), Catechin 3-gallate (Cg), Gallocatechin 3-gallate (GCg)), Epicatechins (Epicatechin (EC), Epigallocatechin (EGC), Epicatechin 3-gallate (ECg), Epigallocatechin 3-gallate (EGCg))
- Anthocyanidins
Anthocyanidins are the aglycones of anthocyanins. Anthocyanidins use the flavylium (2-phenylchromenylium) ion skeleton
Examples: Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin
# Availability through microorganisms
A number of recent research articles have demonstrated the efficient production of flavonoid molecules from genetically-engineered microorganisms[10]. | https://www.wikidoc.org/index.php/Bioflavonoid | |
a86c2d8d25827974f410a2e2c6b63fa64e457dc8 | wikidoc | Biomarker | Biomarker
# Overview
A Biomarker is a substance used as an indicator of a biologic state. It is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.
Biomarkers validated by genetic and molecular biology methods can be classified into three types.
- Type 0 - Natural history markers
- Type 1 - Drug activity markers and
- Type II - Surrogate markers
It can be any kind of molecule indicating the existence (past or present) of living organisms. In particular, in the fields of geology and astrobiology biomarkers are also known as biosignatures. The term is also used to describe biological involvement in the generation of petroleum.
# Medicine
In medicine a biomarker is an indicator of a particular disease state or a particular state of an organism.
An NIH study group committed to the following definition in 1998: "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention."
In the past, biomarkers were primarily physiological indicators such as blood pressure or heart rate. More recently, biomarker is becoming a synonym for molecular biomarker, such as elevated prostate specific antigen as a molecular biomarker for prostate cancer. Biomarkers also cover the use of molecular indicators of environmental exposure in epidemiologic studies such as human papilloma virus or certain markers of tobacco exposure such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
A biomarker can be a substance whose detection indicates a particular disease state (for example, the presence of an antibody may indicate an infection). More specifically, a "biomarker" indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment. Once a proposed biomarker has been validated, it can be used to diagnose disease risk, presence of disease in an individual, or to tailor treatments for the disease in an individual (choices of drug treatment or administration regimes). In evaluating potential drug therapies, a biomarker may be used as a surrogate for a natural endpoint such as survival or irreversible morbidity. If a treatment alters the biomarker, which has a direct connection to improved health, the biomarker serves as a "surrogate endpoint" for evaluating clinical benefit.
# Cell Biology
A biomarker can be understood as a molecule that is present (or absent) from a particular cellular type. This facilitates the characterization of a cell type, their identification, and eventually their isolation. Cell sorting techniques are based on cellular biomarkers (for example, Fluorescent-activated cell sorting).
One example of cellular biomarker is the protein Oct-4 that is found in embryonic stem cells.
A biomarker can also be used to indicate exposure to various environmental substances in epidemiology and toxicology. In these cases, the biomarker may be the external substance itself (e.g. asbestos particles or NNK from tobacco), or a variant of the external substance processed by the body (a metabolite). (See also: Bioindicator.)
In genetics, a biomarker (identified as genetic marker) is a fragment of DNA sequence that causes disease or is associated with susceptibility to disease.
# Biomarker discovery
Biomarker discovery is the process by which biomarkers are discovered. It is a medical term.
Many commonly used blood tests in medicine are biomarkers. The way that these tests have been found can be seen as biomarker discovery. However, their identification has mostly been a one-at-a time approach. Many of these well-known tests have been identified based on clear biological insight, from physiology or biochemistry. This means that only a few markers at a time have been considered. One example of this way of biomarker discovery is the use of injections of inulin for measuring kidney function. From this, one discovered a naturally occurring molecule, creatinine, that enabled the same measurements to be made easily without injections. This can be seen as a serial process.
The recent interest in biomarker discovery is because new molecular biologic techniques promise to find relevant markers rapidly, without detailed insight into mechanisms of disease. By screening many possible biomolecules at a time, a parallel approach can be tried. Genomics and proteomics are some technologies that are used in this process. Significant technical difficulties remain.
There is considerable interest in biomarker discovery from the pharmaceutical industry. Blood test or other biomarkers could serve as intermediate markers of disease in clinical trials, and also be possible drug targets. | Biomarker
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A Biomarker is a substance used as an indicator of a biologic state. It is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.
Biomarkers validated by genetic and molecular biology methods can be classified into three types.
- Type 0 - Natural history markers
- Type 1 - Drug activity markers and
- Type II - Surrogate markers
It can be any kind of molecule indicating the existence (past or present) of living organisms. In particular, in the fields of geology and astrobiology biomarkers are also known as biosignatures. The term is also used to describe biological involvement in the generation of petroleum.
# Medicine
In medicine a biomarker is an indicator of a particular disease state or a particular state of an organism.
An NIH study group committed to the following definition in 1998: "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention." [1]
In the past, biomarkers were primarily physiological indicators such as blood pressure or heart rate. More recently, biomarker is becoming a synonym for molecular biomarker, such as elevated prostate specific antigen as a molecular biomarker for prostate cancer. Biomarkers also cover the use of molecular indicators of environmental exposure in epidemiologic studies such as human papilloma virus or certain markers of tobacco exposure such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).
A biomarker can be a substance whose detection indicates a particular disease state (for example, the presence of an antibody may indicate an infection). More specifically, a "biomarker" indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment. Once a proposed biomarker has been validated, it can be used to diagnose disease risk, presence of disease in an individual, or to tailor treatments for the disease in an individual (choices of drug treatment or administration regimes). In evaluating potential drug therapies, a biomarker may be used as a surrogate for a natural endpoint such as survival or irreversible morbidity. If a treatment alters the biomarker, which has a direct connection to improved health, the biomarker serves as a "surrogate endpoint" for evaluating clinical benefit.
# Cell Biology
A biomarker can be understood as a molecule that is present (or absent) from a particular cellular type. This facilitates the characterization of a cell type, their identification, and eventually their isolation. Cell sorting techniques are based on cellular biomarkers (for example, Fluorescent-activated cell sorting).
One example of cellular biomarker is the protein Oct-4 that is found in embryonic stem cells.
A biomarker can also be used to indicate exposure to various environmental substances in epidemiology and toxicology. In these cases, the biomarker may be the external substance itself (e.g. asbestos particles or NNK from tobacco), or a variant of the external substance processed by the body (a metabolite). (See also: Bioindicator.)
In genetics, a biomarker (identified as genetic marker) is a fragment of DNA sequence that causes disease or is associated with susceptibility to disease.
# Biomarker discovery
Biomarker discovery is the process by which biomarkers are discovered. It is a medical term.
Many commonly used blood tests in medicine are biomarkers. The way that these tests have been found can be seen as biomarker discovery. However, their identification has mostly been a one-at-a time approach. Many of these well-known tests have been identified based on clear biological insight, from physiology or biochemistry. This means that only a few markers at a time have been considered. One example of this way of biomarker discovery is the use of injections of inulin for measuring kidney function. From this, one discovered a naturally occurring molecule, creatinine, that enabled the same measurements to be made easily without injections. This can be seen as a serial process.
The recent interest in biomarker discovery is because new molecular biologic techniques promise to find relevant markers rapidly, without detailed insight into mechanisms of disease. By screening many possible biomolecules at a time, a parallel approach can be tried. Genomics and proteomics are some technologies that are used in this process. Significant technical difficulties remain.
There is considerable interest in biomarker discovery from the pharmaceutical industry. Blood test or other biomarkers could serve as intermediate markers of disease in clinical trials, and also be possible drug targets. | https://www.wikidoc.org/index.php/Biomarker | |
542e03c30290907108df7774a3c8b025ab7f4567 | wikidoc | Biopterin | Biopterin
Biopterin is a coenzyme that is produced within the body.
Defects in biopterin synthesis or regeneration can cause a form of hyperphenylalaninemia ("PKU") .
Biopterin is synthesized in several parts of the body, including the pineal gland and ???.
Biopterin deficiency has been associated with a variety of disorders, including dystonia and ???. | Biopterin
Template:Chembox new
Biopterin is a coenzyme that is produced within the body.
Defects in biopterin synthesis or regeneration can cause a form of hyperphenylalaninemia ("PKU") [1].
Biopterin is synthesized in several parts of the body, including the pineal gland[2] and ???.
Biopterin deficiency has been associated with a variety of disorders, including dystonia [3] and ???. | https://www.wikidoc.org/index.php/Biopterin | |
1c193a19d28f5f6544c0fdbe606eb538b9221826 | wikidoc | Biorhythm | Biorhythm
A biorhythm is a hypothetical cyclic pattern of alterations in physiology, emotions, and/or intellect. "Bio" pertains to life and "rhythm" pertains to the flow with regular movement. Critics assert that there is no conclusive evidence to back its claims, and that as such it is a form of pseudoscience.
# Basic theory
The theory of biorhythms claims that one's life is affected by rhythmic biological cycles, and seeks to make predictions regarding these cycles and the personal ease of carrying out tasks related to the cycles. These inherent rhythms are said to control or initiate various biological processes and are classically composed of three cyclic rhythms that are said to govern human behavior and demonstrate innate periodicity in natural physiological change: the physical, the emotional, and the intellectual (or mental) cycles. Others claim there are additional rhythms, some of which may be combinations of the three primary cycles. Some proponents think that biorhythms may be potentially related to bioelectricity and its interactions in the body.
- Physical cycle (23 days; Circavigintan)
coordination
strength
well-being
- coordination
- strength
- well-being
- Emotional cycle (28 days; Circatrigintan)
creativity
sensitivity
mood
perception
awareness
- creativity
- sensitivity
- mood
- perception
- awareness
- Intellectual cycle (33 days; Circatrigintan)
alertness
analytical functioning
logical analysis
memory or recall
communication
- alertness
- analytical functioning
- logical analysis
- memory or recall
- communication
Basic rhythms follow certain facets of physiological cycles, though they may include others, and the details may vary depending on the source. The three classical cycles of biorhythms are endogenous infradian rhythms. The theory's basis lies in physiological and emotional cycles. They are often represented graphically as either symmetric or asymmetric waveforms, though most theories rely on symmetric forms. The most commonly used form is the sinusoidal waveform, which is thought to be a plausible representation of a bioelectric activity cycle. Due to this sinusoidal nature, the cyclical flow of bioelectric activity undergoes periodic reverses in direction. Each cycle oscillates between a positive phase and a negative phase , during which bioelectric activity strengthens and weakens. The waveforms start, in most theories, at the neutral baseline (0%) at the time of birth of each individual. Each day that the waveform again crosses this baseline is dubbed a critical day, which means that tasks in the domain of the cycle are far more erratic than on other non-critical days. The purpose of mapping the biorhythmic cycles is to enable the calculation of critical days for performing or avoiding various activities.
The classical definition (derivatives of the original theory exist) states that one's birth is an unfavorable circumstantial event, as is the day about 58 years later when the three cycles are again synchronised at their minimum values. According to the classical definition, the theory is assumed to apply only to humans. In the classical theory, the value of each cycle can be calculated at any given time in the life of an individual, and there are web sites that do exactly that.
# Related terminology
## Biological rhythm cycles
# Application
In the workplace, railroads and airlines have experimented the most with biorhythms. A pilot describes the Japanese and American attitudes towards biorhythms. He acknowledges, researching his pilot logbook, that his greatest errors of judgment occurred during critical days, but concludes that an awareness of one's critical days and paying extra attention is sufficient to ensure safety. A former United Airlines pilot and user of the Biorhythms for Windows program confirms that United Airlines used biorhythms until the mid-1990s, while the Nippon Express air freight still used biorhythms.
Charting biorhythms for personal use was popular in the United States during the 1970s; many places (especially video arcades and amusement areas) had a biorhythm machine that provided charts upon entry of date of birth.
# History
The classical theory originated at the turn of the 19th century, between 1897 and 1902, from observational research.
Hermann Swoboda, professor of psychology at the University of Vienna, who was researching periodic variations in fevers, looked into the possibility of a rhythmic change in mood and health. He collected data on reaction to pain, outbreak of fevers, illnesses, asthma, heart attacks, and recurrent dreams. He concluded that there was a 23-day physical cycle and a 28-day emotional cycle.
Wilhelm Fliess, a nose and throat specialist and reportedly a numerologist, was independently researching the occurrences of fevers, recurrent illnesses and deaths in his patients. He too came to the conclusion that there was a 23 and a 28-day rhythm. Fliess' theories were of great interest and importance to Sigmund Freud during his early work in developing his psychoanalytic concepts.
Alfred Teltscher, professor of engineering at the University of Innsbruck, observed that his students' good days and bad days followed a rhythmic pattern of 33 days. Teltscher found that the brain's ability to absorb, mental ability, and alertness ran in 33 day cycles. In the 1920s, Dr. Rexford Hersey (psychologist; Pennsylvania, America) also reportedly made contributions to the classical theory.
These three biorhythms compose the classical theory. The classical theory has been studied, especially in Germany, Japan, and the United States, with conflicting results. Various modern derivatives exist of the classical theory.
# Plausibility
Proponents of biorhythmics call it an established interdisciplinary area of scientific endeavor which is still speculative, alternatively, a protoscience. Critics state that biorhythms are based only upon numerological associations. The plausibility of biorhythmics is contested by mathematicians, biologists and other scientists. The most basic assertion is that, even if physiological rhythms do exist, why would they begin precisely on the day of our birth?
Biorhythms have echoes of chronobiology, the study of circadian and other rhythms. Through medical research, doctors have found that there are periodicity and rhythms in a person's lifespan, although few doctors believe they correspond to those described as "biorhythms". Biochronometry has shown that rhythm and cycles such as the circadian (from Latin circa diem; literally, "about a day") exist. To proponents, these discoveries (among others) demonstrate that people are affected by physiological, emotional and intellectual rhythms (though the exact relationships to the biorhythm cycles are not precisely understood). Studies regarding the effects of biorhythm on the human condition are still conducted.
The Biorhythm theory is often treated as falsely claiming scientific validity. Biorhythm critics' responses range from opposing it as harmful to ignoring it or treating it as entertainment. Some of the criticisms of the various theories in the category of biorhythmics are:
- The choices of periodical function, frequency and phase are arbitrary.
- The assumption is made that the cycles are the same for everyone.
- The frequency is assumed to be constant.
- Evidence tends to be anecdotal.
- Arguments are made based in ignorance of number theory.
- Tests of the hypothesis have basic flaws.
- The quantitative generalizations of complex human behavior are inadequate.
- Hypotheses are not formulated precisely.
- Experimental data fail peer review.
- Experiments cannot be replicated.
- Some unscrupulous practitioners resemble professional fortune-telling fraud artists.
Some biorhythm critics say that biorhythms can be thrown off by such occurrences in the calendar as the beginning of the new year, holidays, or something as simple as the start of the week.
There have been some three dozen studies supporting biorhythm theory but all of them have suffered from methodological and statistical errors (Hines, 1998). An examination of some 134 biorhythm studies found that the theory is not valid (Hines, 1998). (Hines, Terence M. "Comprehensive Review of Biorhythm Theory," Psychological Reports, 1998, 83, 19-64.)
# Calculation
The formulae for the curves are
- physical: \sin(2\pi t/23),
- emotional: \sin(2\pi t/28) and
- intellectual: \sin(2\pi t/33),
where t indicates the number of days since birth.
# Patents
- U.S. Patent 4,960,980 - Bioclock calculating device for human body
- U.S. Patent 4,625,732 - Apparatus for measuring the actual psychophysiological condition
- U.S. Patent 4,551,620 - Biorhythms analog computer-calendar
- U.S. Patent 4,465,077 - Apparatus and method of determining fertility status
- U.S. Patent 4,184,202 - Biorhythm computer
- U.S. Patent 4,101,962 - Electronic calculator for determining biorhythm data | Biorhythm
A biorhythm is a hypothetical cyclic pattern of alterations in physiology, emotions, and/or intellect. "Bio" pertains to life and "rhythm" pertains to the flow with regular movement. Critics assert that there is no conclusive evidence to back its claims, and that as such it is a form of pseudoscience.
# Basic theory
The theory of biorhythms claims that one's life is affected by rhythmic biological cycles, and seeks to make predictions regarding these cycles and the personal ease of carrying out tasks related to the cycles. These inherent rhythms are said to control or initiate various biological processes and are classically composed of three cyclic rhythms that are said to govern human behavior and demonstrate innate periodicity in natural physiological change: the physical, the emotional, and the intellectual (or mental) cycles. Others claim there are additional rhythms, some of which may be combinations of the three primary cycles. Some proponents think that biorhythms may be potentially related to bioelectricity and its interactions in the body.
- Physical cycle (23 days; Circavigintan)
coordination
strength
well-being
- coordination
- strength
- well-being
- Emotional cycle (28 days; Circatrigintan)
creativity
sensitivity
mood
perception
awareness
- creativity
- sensitivity
- mood
- perception
- awareness
- Intellectual cycle (33 days; Circatrigintan)
alertness
analytical functioning
logical analysis
memory or recall
communication
- alertness
- analytical functioning
- logical analysis
- memory or recall
- communication
Basic rhythms follow certain facets of physiological cycles, though they may include others, and the details may vary depending on the source. The three classical cycles of biorhythms are endogenous infradian rhythms. The theory's basis lies in physiological and emotional cycles. They are often represented graphically as either symmetric or asymmetric waveforms, though most theories rely on symmetric forms. The most commonly used form is the sinusoidal waveform, which is thought to be a plausible representation of a bioelectric activity cycle. Due to this sinusoidal nature, the cyclical flow of bioelectric activity undergoes periodic reverses in direction. Each cycle oscillates between a positive phase [0%..100%] and a negative phase [-100%..0%], during which bioelectric activity strengthens and weakens. The waveforms start, in most theories, at the neutral baseline (0%) at the time of birth of each individual. Each day that the waveform again crosses this baseline is dubbed a critical day, which means that tasks in the domain of the cycle are far more erratic than on other non-critical days. The purpose of mapping the biorhythmic cycles is to enable the calculation of critical days for performing or avoiding various activities.
The classical definition (derivatives of the original theory exist) states that one's birth is an unfavorable circumstantial event, as is the day about 58 years later when the three cycles are again synchronised at their minimum values. According to the classical definition, the theory is assumed to apply only to humans. In the classical theory, the value of each cycle can be calculated at any given time in the life of an individual, and there are web sites that do exactly that.
# Related terminology
## Biological rhythm cycles
# Application
In the workplace, railroads and airlines have experimented the most with biorhythms. A pilot describes the Japanese and American attitudes towards biorhythms.[1] He acknowledges, researching his pilot logbook, that his greatest errors of judgment occurred during critical days, but concludes that an awareness of one's critical days and paying extra attention is sufficient to ensure safety. A former United Airlines pilot and user of the Biorhythms for Windows[2] program confirms that United Airlines used biorhythms until the mid-1990s, while the Nippon Express air freight still used biorhythms.[citation needed]
Charting biorhythms for personal use was popular in the United States during the 1970s; many places (especially video arcades and amusement areas) had a biorhythm machine that provided charts upon entry of date of birth.
# History
The classical theory originated at the turn of the 19th century, between 1897 and 1902, from observational research.
Hermann Swoboda, professor of psychology at the University of Vienna, who was researching periodic variations in fevers, looked into the possibility of a rhythmic change in mood and health. He collected data on reaction to pain, outbreak of fevers, illnesses, asthma, heart attacks, and recurrent dreams. He concluded that there was a 23-day physical cycle and a 28-day emotional cycle.[citation needed]
Wilhelm Fliess, a nose and throat specialist and reportedly a numerologist, was independently researching the occurrences of fevers, recurrent illnesses and deaths in his patients. He too came to the conclusion that there was a 23 and a 28-day rhythm. Fliess' theories were of great interest and importance to Sigmund Freud during his early work in developing his psychoanalytic concepts.
Alfred Teltscher, professor of engineering at the University of Innsbruck, observed that his students' good days and bad days followed a rhythmic pattern of 33 days. Teltscher found that the brain's ability to absorb, mental ability, and alertness ran in 33 day cycles. In the 1920s, Dr. Rexford Hersey (psychologist; Pennsylvania, America) also reportedly made contributions to the classical theory.[citation needed]
These three biorhythms compose the classical theory. The classical theory has been studied, especially in Germany, Japan, and the United States, with conflicting results.[citation needed] Various modern derivatives exist of the classical theory.
# Plausibility
Proponents of biorhythmics call it an established interdisciplinary area of scientific endeavor which is still speculative, alternatively, a protoscience. Critics state that biorhythms are based only upon numerological associations. The plausibility of biorhythmics is contested by mathematicians, biologists and other scientists.[citation needed] The most basic assertion is that, even if physiological rhythms do exist, why would they begin precisely on the day of our birth?
Biorhythms have echoes of chronobiology, the study of circadian and other rhythms. Through medical research, doctors have found that there are periodicity and rhythms in a person's lifespan, although few doctors believe they correspond to those described as "biorhythms". Biochronometry has shown that rhythm and cycles such as the circadian (from Latin circa diem; literally, "about a day") exist. To proponents, these discoveries (among others) demonstrate that people are affected by physiological, emotional and intellectual rhythms (though the exact relationships to the biorhythm cycles are not precisely understood). Studies regarding the effects of biorhythm on the human condition are still conducted.[citation needed]
The Biorhythm theory is often treated as falsely claiming scientific validity. Biorhythm critics' responses range from opposing it as harmful to ignoring it or treating it as entertainment. Some of the criticisms of the various theories in the category of biorhythmics are:
- The choices of periodical function, frequency and phase are arbitrary.
- The assumption is made that the cycles are the same for everyone.
- The frequency is assumed to be constant.
- Evidence tends to be anecdotal.
- Arguments are made based in ignorance of number theory.
- Tests of the hypothesis have basic flaws.
- The quantitative generalizations of complex human behavior are inadequate.
- Hypotheses are not formulated precisely.
- Experimental data fail peer review.
- Experiments cannot be replicated.
- Some unscrupulous practitioners resemble professional fortune-telling fraud artists.
Some biorhythm critics say that biorhythms can be thrown off by such occurrences in the calendar as the beginning of the new year, holidays, or something as simple as the start of the week.[citation needed]
There have been some three dozen studies supporting biorhythm theory but all of them have suffered from methodological and statistical errors (Hines, 1998). An examination of some 134 biorhythm studies found that the theory is not valid (Hines, 1998). (Hines, Terence M. "Comprehensive Review of Biorhythm Theory," Psychological Reports, 1998, 83, 19-64.)
# Calculation
The formulae for the curves are
- physical: <math>\sin(2\pi t/23)</math>,
- emotional: <math>\sin(2\pi t/28)</math> and
- intellectual: <math>\sin(2\pi t/33)</math>,
where <math>t</math> indicates the number of days since birth.
# Patents
- U.S. Patent 4,960,980 - Bioclock calculating device for human body
- U.S. Patent 4,625,732 - Apparatus for measuring the actual psychophysiological condition
- U.S. Patent 4,551,620 - Biorhythms analog computer-calendar
- U.S. Patent 4,465,077 - Apparatus and method of determining fertility status
- U.S. Patent 4,184,202 - Biorhythm computer
- U.S. Patent 4,101,962 - Electronic calculator for determining biorhythm data | https://www.wikidoc.org/index.php/Biorhythm | |
6094d910884e2a68a77bc627a32c910ba14491ea | wikidoc | Biosafety | Biosafety
Biosafety: prevention of large-scale loss of biological integrity, focusing both on ecology and human health.
Biosafety is related to several fields
- in ecology (referring to imported life forms from beyond ecoregion borders),
- in agriculture (reducing the risk of alien viral or transgenic genes, or prions such as BSE/"MadCow", reducing the risk of food bacterial contamination)
- in medicine (referring to organs or tissues from biological origin, or genetic therapy products, virus; levels of lab containment protocols measured as 1, 2, 3, 4 in rising order of danger),
- in chemistry (i.e., nitrates in water, PCB levels affecting fertility) and
- in exobiology (i.e., NASA's policy for containing alien microbes that may exist on space samples - sometimes called "biosafety level 5").
The international Biosafety Protocol deals primarily with the agricultural definition but many advocacy groups seek to expand it to include post-genetic threats: new molecules, artificial life forms, and even robots which may compete directly in the natural food chain.
Biosafety in agriculture, chemistry, medicine, exobiology and beyond will likely require application of the precautionary principle, and a new definition focused on the biological nature of the threatened organism rather than the nature of the threat.
When biological warfare or new, currently hypothetical, threats (i.e., robots, new artificial bacteria) are considered, biosafety precautions are generally not sufficient. The new field of biosecurity addresses these complex threats.
Biosafety level refers to the stringency of precautions deemed necessary by the Centers for Disease Control and Prevention (CDC) for laboratory work with infectious materials.
# Gallery
- Centers for Disease Control microbiologist, and Special Pathogens Branch (SPB) staff member, as he was in the process of counting viral plaques within fixed monolayers of cells, set atop a light box. From Public Health Image Library (PHIL). | Biosafety
Biosafety: prevention of large-scale loss of biological integrity, focusing both on ecology and human health.
Biosafety is related to several fields
- in ecology (referring to imported life forms from beyond ecoregion borders),
- in agriculture (reducing the risk of alien viral or transgenic genes, or prions such as BSE/"MadCow", reducing the risk of food bacterial contamination)
- in medicine (referring to organs or tissues from biological origin, or genetic therapy products, virus; levels of lab containment protocols measured as 1, 2, 3, 4 in rising order of danger),
- in chemistry (i.e., nitrates in water, PCB levels affecting fertility) and
- in exobiology (i.e., NASA's policy for containing alien microbes that may exist on space samples - sometimes called "biosafety level 5").
The international Biosafety Protocol deals primarily with the agricultural definition but many advocacy groups seek to expand it to include post-genetic threats: new molecules, artificial life forms, and even robots which may compete directly in the natural food chain.
Biosafety in agriculture, chemistry, medicine, exobiology and beyond will likely require application of the precautionary principle, and a new definition focused on the biological nature of the threatened organism rather than the nature of the threat.
When biological warfare or new, currently hypothetical, threats (i.e., robots, new artificial bacteria) are considered, biosafety precautions are generally not sufficient. The new field of biosecurity addresses these complex threats.
Biosafety level refers to the stringency of precautions deemed necessary by the Centers for Disease Control and Prevention (CDC) for laboratory work with infectious materials.
# Gallery
- Centers for Disease Control microbiologist, and Special Pathogens Branch (SPB) staff member, as he was in the process of counting viral plaques within fixed monolayers of cells, set atop a light box. From Public Health Image Library (PHIL). [1] | https://www.wikidoc.org/index.php/Biosafety | |
e6a92e5ffe62ce478ce59b465bf53efd30cb1086 | wikidoc | Biosphere | Biosphere
The biosphere is the part of the Earth, including air, land, surface rocks, and water, within which life occurs, and which biotic processes in turn alter or transform. From the broadest biophysiological point of view, the biosphere is the global ecological system integrating all living beings and their relationships, including their interaction with the elements of the lithosphere, hydrosphere, and atmosphere. This biosphere is postulated to have evolved, beginning through a process of biogenesis or biopoesis, at least some 3.5 billion years ago.
Biomass accounts for about 3.7 kg carbon per square meter of the earth's surface averaged over land and sea, making a total of about 1900 gigatonnes of carbon.
# Origin and use of the term
The term "biosphere" was coined by geologist Eduard Suess in 1875, which he defined as:
The place on earth's surface where life dwells.
While this concept has a geological origin, it is an indication of the impact of both Darwin and Maury on the earth sciences. The biosphere's ecological context comes from the 1920s (see Vladimir I. Vernadsky), preceding the 1935 introduction of the term "ecosystem" by Sir Arthur Tansley (see ecology history). Vernadsky defined ecology as the science of the biosphere. It is an interdisciplinary concept for integrating astronomy, geophysics, meteorology, biogeography, evolution, geology, geochemistry, hydrology and, generally speaking, all life and earth sciences.
## Narrow definition
Some life scientists and earth scientists use biosphere in a more limited sense. For example, geochemists define the biosphere as being the total sum of living organisms (the "biomass" or "biota" as referred to by biologists and ecologists). In this sense, the biosphere is but one of four separate components of the geochemical model, the other three being lithosphere, hydrosphere, and atmosphere. The narrow meaning used by geochemists is one of the consequences of specialization in modern science. Some might prefer the word ecosphere, coined in the 1960s, as all encompassing of both biological and physical components of the planet.
The Second International Conference on Closed Life Systems defined biospherics as the science and technology of analogs and models of Earth's biosphere; i.e., artificial Earth-like biospheres. Others may include the creation of artificial non-Earth biospheres — for example, human-centered biospheres or a native Martian biosphere — in the field of biospherics.
## Gaia's biosphere
The concept that the biosphere is itself a living organism, either actually or metaphorically, is known as the Gaia hypothesis.
James Lovelock, an atmospheric scientist from the United Kingdom, proposed the Gaia hypothesis to explain how biotic and abiotic factors interact in the biosphere. This hypothesis considers Earth itself a kind of living organism. Its atmosphere, geosphere, and hydrosphere are cooperating systems that yield a biosphere full of life. in the early 1970s, Lynn Margulis, a microbiologist from the United States, added to the hypothesis specifically noting the ties between the biosphere and other Earth systems. For example, when carbon dioxide levels increase in the atmosphere, plants grow more quickly. As their growth continue, they remove more and more carbon dioxide from the atmosphere.
Many scientists are now devoting their careers to organizing new fields of study, such as geobiology and geomicrobiology, to examine these intriguing relationships .
# Extent of Earth's biosphere
Nearly every part of the planet, from the polar ice caps to the Equator, supports life of some kind. Recent advances in microbiology have demonstrated that microbes live deep beneath the Earth's terrestrial surface, and that the total mass of microbial life in so-called "uninhabitable zones" may, in biomass, exceed all animal and plant life on the surface.
The actual thickness of the biosphere on earth is hard to measure. Birds typically fly at altitudes of 650 to 2000 meters, and fish that live deep underwater can be found down to -8,372 meters in the Puerto Rico Trench.
There are more extreme examples for life on the planet: Rüppell's Vulture has been found at altitudes of 11,300 meters; Bar-headed Geese migrate at altitudes of at least 8,300 meters (over Mount Everest); Yaks live at elevations between 3,200 to 5,400 meters above sea level; mountain goats live up to 3,050 meters. Herbivorous animals at these elevations depend on lichens, grasses, and herbs but the biggest tree is the Tine palm or mountain coconut found 3,400 meters above sea level.
Microscopic organisms live at such extremes that, taking them into consideration puts the thickness of the biosphere much greater, but at minimum it extends from 5,400 meters above sea level to at least 9,000 meters below sea level.
Our biosphere is divided into a number of biomes, inhabited by broadly similar flora and fauna. On land, biomes are separated primarily by latitude. Terrestrial biomes lying within the Arctic and Antarctic Circles are relatively barren of plant and animal life, while most of the more populous biomes lie near the equator. Terrestrial organisms in temperate and Arctic biomes have relatively small amounts of total biomass, smaller energy budgets, and display prominent adaptations to cold, including world-spanning migrations, social adaptations, homeothermy, estivation and multiple layers of insulation.
# Specific biospheres
When the word Biosphere is followed by a number, it is usually referring to a specific system. Thus:
- Biosphere 1 - The planet Earth
- Biosphere 2 - A laboratory in Arizona which contains 3.15 acres (13,000 m²) of closed ecosystem.
- BIOS-3 was a closed ecosystem at the Institute of Biophysics in Krasnoyarsk, Siberia, in what was then the Soviet Union.
- Biosphere J - An experiment in Japan.
# Hyperbaric biosphere
In 1999, Carl Baugh patented a small "hyperbaric biosphere" chamber, designed to emulate the conditions thought by him to exist on the early earth, providing double atmospheric pressure, enhanced oxygen, and protection from ultraviolet radiation, while magnetic coils attempt to make up for earth's reduced magnetic field; a much larger hyperbaric biosphere is currently under construction in the same location. | Biosphere
The biosphere is the part of the Earth, including air, land, surface rocks, and water, within which life occurs, and which biotic processes in turn alter or transform. From the broadest biophysiological point of view, the biosphere is the global ecological system integrating all living beings and their relationships, including their interaction with the elements of the lithosphere, hydrosphere, and atmosphere. This biosphere is postulated to have evolved, beginning through a process of biogenesis or biopoesis, at least some 3.5 billion years ago.
Biomass accounts for about 3.7 kg carbon per square meter of the earth's surface averaged over land and sea, making a total of about 1900 gigatonnes of carbon.
# Origin and use of the term
The term "biosphere" was coined by geologist Eduard Suess in 1875, which he defined as:[1]
The place on earth's surface where life dwells.
While this concept has a geological origin, it is an indication of the impact of both Darwin and Maury on the earth sciences. The biosphere's ecological context comes from the 1920s (see Vladimir I. Vernadsky), preceding the 1935 introduction of the term "ecosystem" by Sir Arthur Tansley (see ecology history). Vernadsky defined ecology as the science of the biosphere. It is an interdisciplinary concept for integrating astronomy, geophysics, meteorology, biogeography, evolution, geology, geochemistry, hydrology and, generally speaking, all life and earth sciences.
## Narrow definition
Some life scientists and earth scientists use biosphere in a more limited sense. For example, geochemists define the biosphere as being the total sum of living organisms (the "biomass" or "biota" as referred to by biologists and ecologists). In this sense, the biosphere is but one of four separate components of the geochemical model, the other three being lithosphere, hydrosphere, and atmosphere. The narrow meaning used by geochemists is one of the consequences of specialization in modern science. Some might prefer the word ecosphere, coined in the 1960s, as all encompassing of both biological and physical components of the planet.
The Second International Conference on Closed Life Systems defined biospherics as the science and technology of analogs and models of Earth's biosphere; i.e., artificial Earth-like biospheres. Others may include the creation of artificial non-Earth biospheres — for example, human-centered biospheres or a native Martian biosphere — in the field of biospherics.
## Gaia's biosphere
The concept that the biosphere is itself a living organism, either actually or metaphorically, is known as the Gaia hypothesis.
James Lovelock, an atmospheric scientist from the United Kingdom, proposed the Gaia hypothesis to explain how biotic and abiotic factors interact in the biosphere. This hypothesis considers Earth itself a kind of living organism. Its atmosphere, geosphere, and hydrosphere are cooperating systems that yield a biosphere full of life. in the early 1970s, Lynn Margulis, a microbiologist from the United States, added to the hypothesis specifically noting the ties between the biosphere and other Earth systems. For example, when carbon dioxide levels increase in the atmosphere, plants grow more quickly. As their growth continue, they remove more and more carbon dioxide from the atmosphere.
Many scientists are now devoting their careers to organizing new fields of study, such as geobiology and geomicrobiology, to examine these intriguing relationships .
# Extent of Earth's biosphere
Nearly every part of the planet, from the polar ice caps to the Equator, supports life of some kind. Recent advances in microbiology have demonstrated that microbes live deep beneath the Earth's terrestrial surface, and that the total mass of microbial life in so-called "uninhabitable zones" may, in biomass, exceed all animal and plant life on the surface.
The actual thickness of the biosphere on earth is hard to measure. Birds typically fly at altitudes of 650 to 2000 meters, and fish that live deep underwater can be found down to -8,372 meters in the Puerto Rico Trench.
There are more extreme examples for life on the planet: Rüppell's Vulture has been found at altitudes of 11,300 meters; Bar-headed Geese migrate at altitudes of at least 8,300 meters (over Mount Everest); Yaks live at elevations between 3,200 to 5,400 meters above sea level; mountain goats live up to 3,050 meters. Herbivorous animals at these elevations depend on lichens, grasses, and herbs but the biggest tree is the Tine palm or mountain coconut found 3,400 meters above sea level.
Microscopic organisms live at such extremes that, taking them into consideration puts the thickness of the biosphere much greater, but at minimum it extends from 5,400 meters above sea level to at least 9,000 meters below sea level.
Our biosphere is divided into a number of biomes, inhabited by broadly similar flora and fauna. On land, biomes are separated primarily by latitude. Terrestrial biomes lying within the Arctic and Antarctic Circles are relatively barren of plant and animal life, while most of the more populous biomes lie near the equator. Terrestrial organisms in temperate and Arctic biomes have relatively small amounts of total biomass, smaller energy budgets, and display prominent adaptations to cold, including world-spanning migrations, social adaptations, homeothermy, estivation and multiple layers of insulation.
# Specific biospheres
When the word Biosphere is followed by a number, it is usually referring to a specific system. Thus:
- Biosphere 1 - The planet Earth
- Biosphere 2 - A laboratory in Arizona which contains 3.15 acres (13,000 m²) of closed ecosystem.
- BIOS-3 was a closed ecosystem at the Institute of Biophysics in Krasnoyarsk, Siberia, in what was then the Soviet Union.
- Biosphere J - An experiment in Japan.
# Hyperbaric biosphere
In 1999, Carl Baugh patented a small "hyperbaric biosphere" chamber, designed to emulate the conditions thought by him to exist on the early earth, providing double atmospheric pressure, enhanced oxygen, and protection from ultraviolet radiation, while magnetic coils attempt to make up for earth's reduced magnetic field;[2] a much larger hyperbaric biosphere is currently under construction in the same location.[3] | https://www.wikidoc.org/index.php/Biosphere | |
6de739f94d42c476003dd1098faec92742d0604d | wikidoc | Birthmark | Birthmark
A birthmark is a blemish on the skin formed before birth. They are part of the group of skin lesions known as naevi. The cause of birthmarks is unknown, but may include cellular damage due to radiation or chemicals. Some types seem to run in families.
In Italian and Middle Eastern cultures they are called voglie in Italian or wiham in Arabic, both of which translate to "wishes" because, according to folklore, they are caused by unsatisfied wishes of the mother during pregnancy. For example, if a pregnant woman does not satisfy a sudden wish or craving for strawberries, it's said that the infant might bear a strawberry mark.
# Types
A number of different types of birthmarks are known that include, but are not limited to, stork bites, Mongolian blue spots, strawberry marks, café au lait spots, congenital melanocytic nevi, and port-wine stains. | Birthmark
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A birthmark is a blemish on the skin formed before birth. They are part of the group of skin lesions known as naevi. The cause of birthmarks is unknown, but may include cellular damage due to radiation or chemicals. Some types seem to run in families.
In Italian and Middle Eastern cultures they are called voglie in Italian or wiham in Arabic, both of which translate to "wishes" because, according to folklore, they are caused by unsatisfied wishes of the mother during pregnancy. For example, if a pregnant woman does not satisfy a sudden wish or craving for strawberries, it's said that the infant might bear a strawberry mark.
# Types
A number of different types of birthmarks are known that include, but are not limited to, stork bites, Mongolian blue spots, strawberry marks, café au lait spots, congenital melanocytic nevi, and port-wine stains. | https://www.wikidoc.org/index.php/Birthmark | |
990fea79b33c7605412e09bf4fc216d9a3d960c7 | wikidoc | Bisabolol | Bisabolol
Bisabolol, or more formally α-(-)-bisabolol or also known as levomenol, is a natural monocyclic sesquiterpene alcohol. It is a colorless viscous oil that is the primary constituent of the essential oil from German chamomile (Matricaria recutita). It is almost insoluble in water and glycerin, but well soluble in ethanol. The enantiomer, α-(+)-bisabolol, is also found naturally but is rare. Synthetic bisabolol is usually a racemic mixture of the two, α-(±)-bisabolol.
Bisabolol has a weak sweet floral aroma and is used in various fragrances. It has also been used for hundreds of years in cosmetics because of its perceived skin healing properties. Bisabolol is known to have anti-irritant, anti-inflammatory and anti-microbial properties.
A structurally related compound known as β-bisabolol (CAS# ) differs only in the position of the tertiary alcohol functional group. | Bisabolol
Bisabolol, or more formally α-(-)-bisabolol or also known as levomenol, is a natural monocyclic sesquiterpene alcohol. It is a colorless viscous oil that is the primary constituent of the essential oil from German chamomile (Matricaria recutita). It is almost insoluble in water and glycerin, but well soluble in ethanol. The enantiomer, α-(+)-bisabolol, is also found naturally but is rare. Synthetic bisabolol is usually a racemic mixture of the two, α-(±)-bisabolol.
Bisabolol has a weak sweet floral aroma and is used in various fragrances. It has also been used for hundreds of years in cosmetics because of its perceived skin healing properties. Bisabolol is known to have anti-irritant, anti-inflammatory and anti-microbial properties.
A structurally related compound known as β-bisabolol (CAS# [15352-77-9]) differs only in the position of the tertiary alcohol functional group.
# External links
de:Bisabolol | https://www.wikidoc.org/index.php/Bisabolol | |
b632e6341210902f741d36c7d1fcf6eea8e6ae8a | wikidoc | Bisulfide | Bisulfide
Bisulfide(or Bisulphide in UK Enlgish spelling), also called hydrosulfide, refers the anion with the formula HS−, commonly written SH−. This species is the conjugate base of hydrogen sulfide:
In aqueous solutions, at pH less than 7, hydrogen sulfide is the dominant species; at pH > 7, bisulfide dominates.
A variety of salts are known, including sodium hydrosulfide, potassium hydrosulfide, and ammonium hydrosulfide. Some compounds described as salts of the sulfide dianion contain primarily hydrosulfide. For example, the hydrated form of sodium sulfide, nominally with the formula Na2S·(H2O)9, is better described as NaSH·NaOH·(H2O)8.
Aqueous bisulfide absorbs light at around 230nm in the UV/VIS spectrum. Groups have used field spectrometers to measure the absorption due to bisulfide (and hence its concentration) continuously in the ocean and in sewage.
Bisulfide is sometimes confused with the disulfide dianion, S22−.
ms:Bisulfida | Bisulfide
Bisulfide(or Bisulphide in UK Enlgish spelling), also called hydrosulfide, refers the anion with the formula HS−, commonly written SH−. This species is the conjugate base of hydrogen sulfide:
In aqueous solutions, at pH less than 7, hydrogen sulfide is the dominant species; at pH > 7, bisulfide dominates.
A variety of salts are known, including sodium hydrosulfide, potassium hydrosulfide, and ammonium hydrosulfide. Some compounds described as salts of the sulfide dianion contain primarily hydrosulfide. For example, the hydrated form of sodium sulfide, nominally with the formula Na2S·(H2O)9, is better described as NaSH·NaOH·(H2O)8.
Aqueous bisulfide absorbs light at around 230nm in the UV/VIS spectrum[1]. Groups have used field spectrometers to measure the absorption due to bisulfide (and hence its concentration) continuously in the ocean[2][3] and in sewage[4].
Bisulfide is sometimes confused with the disulfide dianion, S22−.
ms:Bisulfida
Template:Chemistry-stub | https://www.wikidoc.org/index.php/Bisulfide | |
baefdde53d9cbd455dca0942afd9a88a6aeb39e8 | wikidoc | Black eye | Black eye
# Overview
A black eye is bruising around the eye commonly due to an injury to the face rather than an eye injury. The name is given due to the color of bruising. Most black eye injuries are minor and will heal themselves in about one week. Trauma near the eyebrow or places not directly on the eye may make the eyelid go black.
# Pathophysiology
The dramatic appearance (discoloration and swelling) does not necessarily indicate a serious injury. The fatty tissue along with the lack of muscle around the eye socket allows a potential space for blood accumulation with relatively minor injury. As this blood is reabsorbed, various pigments are released similar to a bruise, lending itself to the extreme outward appearance. Unless there is actual trauma to the eye itself, medical attention is generally not needed.
# Diagnosis
## History and Symptoms
Eye injury and head trauma may also coincide with a black eye. Some common symptoms of a more serious injury may include:
- Double vision
- Loss of sight and or fuzzy vision
- Loss of consciousness
- Inability to move the eye or large swelling around the eye such as a hematoma
- Blood or clear fluid from the nose or the ears
- Blood on the surface of the eye itself or cuts on the eye itself
- Persistent headache
Putting a raw steak on a black eye (an old wives' tale) has long been known to have no medicinal value; doing this will lessen the bruise, but not the inflammation. The practice is, however, a staple of popular culture, usually in a humorous context in movies and TV shows.
# Treatment
## Medical Therapy
To treat a black eye, use an ice pack. The cold keeps the swelling down and also reduces internal bleeding by constricting the blood vessels. Use the ice pack for the first 24 hours. If the eye is swollen shut, use ice for ten minutes every 2 hours. To avoid putting too much pressure on the eye, crush ice in a plastic bag and tape it to the forehead. A homemade ice pack can be made by mixing 2 parts water with 1 part alcohol in a nylon bag and freezing it. The bag will be flexible and will mold to the face, plus it won't sweat.
Boxing trainers use the same concept to treat a boxer's black eye injuries. Essentially they use an extremely cold small metal iron. Any cold piece of metal (quarters or dollar coins also work) can be used to control the hemorrhaging. A similar remedy can be used at home by applying a cold soda can intermittently (5 to 10 minutes of every 15 minutes) until ice can be applied. Be sure the can is clean and hold it lightly against the cheek. Never apply direct pressure to the eyeball.
Aspirin should not be used for those with a black eye. Since it acts as an anticoagulant, aspirin can prevent blood from clotting and may make the bruising and discoloration worse. If pain relief is necessary, try acetaminophen.
Don't blow your nose. If it was a severe blow that caused your black eye (something more than just bumping into a door), blowing your nose could cause the face to blow up like a balloon. Sometimes the injury fractures the bone of the eye socket, and blowing your nose can force air out of the sinus adjacent to the socket. The air gets injected under the skin and makes the eyelids swell even more. It also can increase the chance of infection. Keep the head elevated (sleep with a few extra pillows, for example) to help limit swelling and pooling.
On the second day following the injury, applying warm washcloths or compresses can help increase circulation to the injured tissue. This aids in the re-absorption of any leftover blood that has collected at the injury site, promoting healing.
In most other European languages, a black eye is referred to as a "blue" eye (e.g. Danish: Blåt øje, Dutch: Blauw oog, German: Blaues Auge, Swedish Blåtira, Norwegian Blåøye/blekkøye) or a "purple eye" (e.g. Spanish: Ojo morado). In French, the expression "oeil au beurre noir" is used, which literally translates as "black butter eye". In many eastern Asian languages a black eye is referred to as a "panda eye". | Black eye
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A black eye is bruising around the eye commonly due to an injury to the face rather than an eye injury. The name is given due to the color of bruising. Most black eye injuries are minor and will heal themselves in about one week. Trauma near the eyebrow or places not directly on the eye may make the eyelid go black.
# Pathophysiology
The dramatic appearance (discoloration and swelling) does not necessarily indicate a serious injury. The fatty tissue along with the lack of muscle around the eye socket allows a potential space for blood accumulation with relatively minor injury. As this blood is reabsorbed, various pigments are released similar to a bruise, lending itself to the extreme outward appearance. Unless there is actual trauma to the eye itself, medical attention is generally not needed.
# Diagnosis
## History and Symptoms
Eye injury and head trauma may also coincide with a black eye. Some common symptoms of a more serious injury may include:
- Double vision
- Loss of sight and or fuzzy vision
- Loss of consciousness
- Inability to move the eye or large swelling around the eye such as a hematoma
- Blood or clear fluid from the nose or the ears
- Blood on the surface of the eye itself or cuts on the eye itself
- Persistent headache
Putting a raw steak on a black eye (an old wives' tale) has long been known to have no medicinal value; doing this will lessen the bruise, but not the inflammation.[1] The practice is, however, a staple of popular culture, usually in a humorous context in movies and TV shows.
# Treatment
## Medical Therapy
To treat a black eye, use an ice pack. The cold keeps the swelling down and also reduces internal bleeding by constricting the blood vessels. Use the ice pack for the first 24 hours. If the eye is swollen shut, use ice for ten minutes every 2 hours. To avoid putting too much pressure on the eye, crush ice in a plastic bag and tape it to the forehead. A homemade ice pack can be made by mixing 2 parts water with 1 part alcohol in a nylon bag and freezing it. The bag will be flexible and will mold to the face, plus it won't sweat.
Boxing trainers use the same concept to treat a boxer's black eye injuries. Essentially they use an extremely cold small metal iron. Any cold piece of metal (quarters or dollar coins also work) can be used to control the hemorrhaging. A similar remedy can be used at home by applying a cold soda can intermittently (5 to 10 minutes of every 15 minutes) until ice can be applied. Be sure the can is clean and hold it lightly against the cheek. Never apply direct pressure to the eyeball.
Aspirin should not be used for those with a black eye. Since it acts as an anticoagulant, aspirin can prevent blood from clotting and may make the bruising and discoloration worse. If pain relief is necessary, try acetaminophen.
Don't blow your nose. If it was a severe blow that caused your black eye (something more than just bumping into a door), blowing your nose could cause the face to blow up like a balloon. Sometimes the injury fractures the bone of the eye socket, and blowing your nose can force air out of the sinus adjacent to the socket. The air gets injected under the skin and makes the eyelids swell even more. It also can increase the chance of infection. [2]Keep the head elevated (sleep with a few extra pillows, for example) to help limit swelling and pooling.
On the second day following the injury, applying warm washcloths or compresses can help increase circulation to the injured tissue. This aids in the re-absorption of any leftover blood that has collected at the injury site, promoting healing. [3]
In most other European languages, a black eye is referred to as a "blue" eye (e.g. Danish: Blåt øje, Dutch: Blauw oog, German: Blaues Auge, Swedish Blåtira, Norwegian Blåøye/blekkøye) or a "purple eye" (e.g. Spanish: Ojo morado). In French, the expression "oeil au beurre noir" is used, which literally translates as "black butter eye". In many eastern Asian languages a black eye is referred to as a "panda eye". | https://www.wikidoc.org/index.php/Black_eye | |
e21cfac592e178b0bf8832fcd372a7bbf6abf9a3 | wikidoc | Black tea | Black tea
Black tea is a variety of tea that is more oxidized than the green, oolong and white varieties.
All four varieties are made from leaves of Camellia sinensis. Black tea is generally stronger in flavor and contains more caffeine than the less oxidized teas.
In Chinese and culturally influenced languages, black tea is known as "crimson tea" (紅茶, Mandarin Chinese hóngchá; Japanese kōcha; Korean hongcha), perhaps a more accurate description of the colour of the liquid. The name black tea, however, could alternatively refer to the colour of the oxidized leaves. In Chinese, "black tea" is a commonly used classification for post-fermented teas, such as Pu-erh tea. However, in the Western world, "red tea" more commonly refers to rooibos, a South African tisane.
While green tea usually loses its flavor within a year, black tea retains its flavor for several years. For this reason, it has long been an article of trade, and compressed bricks of black tea even served as a form of de facto currency in Mongolia, Tibet, and Siberia into the 19th century. It was known since the Tang Dynasty that black tea steeped in hot water could also serve as a passable cloth dye for the lower classes that could not afford the better quality clothing colours of the time. However, far from being a mark of shame, the "brown star" mark of the dyeing process was seen as much better than plain cloth and held some importance as a mark of the lower merchant classes through the Ming Dynasty. The tea originally imported to Europe was either green or semi-oxidized. Only in the 19th century did black tea surpass green in popularity. Although green tea has recently seen a revival due to its purported health benefits, black tea still accounts for over ninety percent of all tea sold in the West.
The expression "black tea" is also used to describe a cup of tea without milk ("served black"), similar to coffee served without milk or cream.
# Varieties of black tea
Generally, unblended black teas are named after the region in which they are produced. Often, different regions are known for producing teas with characteristic flavors.
## Chinese black teas
- Lapsang Souchong (正山小种 or 烟小种): originally from Mount Wuyi, Fujian Province, China. It is a black tea which is dried over burning pine, thereby developing a strong smoky flavour.
- Keemun (祁門) : from Qimen, Anhui Province, China, a Chinese Famous Tea.
- Dian Hong (滇紅): from Yunnan Province, China. Well known for dark malty teas and golden bud teas.
- Ying De Hong (英徳紅): from Guangdong Province, China.
- Ju Qiu Mei Hong: from Hu Fou district, Hangzhou City, Zhejiang Province, China.
## Indian and Sri Lankan black teas
- Assam: from Assam, India. Full bodied, strong and distinctively malty.
- Darjeeling: from West Bengal, India.
- Kangra: from Himachal Pradesh, India.
- Nilgiri: from Nilgiri, Tamil Nadu, India.
- Ceylon: from Sri Lanka.
## Other black teas
- Kenyan: from Africa, similar to Assam.
- Vietnamese: from Vietnam, similar to some cheaper Yunnan teas, with a pleasant and sweet aroma but a more bodied and darker brew; unlike teas from Nepal or Darjeeling.
- Nepalese: from uplands of Nepal. Somewhat similar to lower grades of Darjeeling.
- Rize Tea (Çay): from Rize Province on the eastern Black Sea coast of Turkey, that is crystal clear and mahogany in colour. Prepared in a samovar or a caydanlik, it can be served strong ("koyu" dark) or weak ("açik" light), in small glasses with cubed sugar.
- Thai tea: from Thailand
- Azerbaijani tea: from Caucasus in Azerbaijan
- Georgian tea: from Caucasus in Georgia
- Krasnodar tea: from Caucasus in Russia
- Java tea: from Indonesia, has got nutty aroma, very different from both Chinese and Indian teas.
- Sumatra tea: from Indonesia, similar to Java tea.
# Blends of black tea
Black tea is often blended and mixed with various other plants in order to obtain a beverage.
- Earl Grey: black tea with bergamot oil.
- English Breakfast: described as full-bodied, robust, and/or rich, and blended to go well with milk and sugar.
- Irish Breakfast: it is a blend of several black teas: most often Assam teas and, less often, other types of black tea.
- In the United States, citrus fruits such as orange or lemon, or their respective rinds, are often used to create flavored black teas, sometimes in conjunction with spices (such as cinnamon). These products can be easily confused with citrus-based herbal teas, but the herbal products will generally be labelled as having no caffeine; whereas, the tea-based products do contain caffeine.
# Processing of black tea
- After the harvest, the leaves are first withered by blowing air on them.
- Then black teas are processed in either of two ways, CTC (Crush, Tear, Curl) or orthodox. The CTC method is used for lower quality leaves that end up in tea bags and are processed by machines. This method is efficient and effective for producing a better quality product from medium and lower quality leaves. Orthodox processing is done either by machines or by hand. Hand processing is used for high quality teas. While the methods employed in orthodox processing differ by tea type, this style of processing results in the high quality loose tea sought by many connoisseurs.
- Next, the leaves are oxidized under controlled temperature and humidity. (This process is also called "fermentation", which is a misnomer since no actual fermentation takes place.) The level of oxidation determines the quality of the tea. Since oxidation begins at the rolling stage itself, the time between these stages is also a crucial factor in the quality of the tea.
- Then the leaves are dried to arrest the oxidation process.
- Finally, the leaves are sorted into grades according their sizes (whole leaf, brokens, fannings and dust), usually with the use of sieves. The tea could be further sub-graded according to other criteria.
The tea is then ready for packaging.
# Tea grading
Black tea is usually graded on one of four scales of quality. Whole leaf teas are highest quality followed by broken leaves, fannings, and dusts. Whole leaf teas are produced with little or no alteration to the tea leaf, this results in a finished product with a coarser texture than that of bagged teas, whole leaf teas are widely considered the most valuable, especially if they contain leaf tips. Broken leaves are commonly sold as medium grade loose teas. Smaller broken varieties may be included in tea bags. Fannings are usually small particles of tea leftover from the production of larger tea varieties, but are occasionally manufactured specifically for use in bagged teas. Dusts are the finest particles of tea leftover from production of the above varieties, and are often used for tea bags with very fast, very harsh brews. Fannings and dust are useful in bagged teas because the greater surface area of the many particles allows for a fast, complete diffusion of the tea into the water. Fannings and dusts usually have a darker colour, lack of sweetness, and stronger flavor when brewed.
# Brewing
Generally, 2.25 grams of tea per 180 ml of water, or about a teaspoon of black tea per 6 oz. cup, should be used. Unlike green teas, which turn bitter when brewed at higher temperatures, black tea should be steeped in freshly boiled water. The more delicate black teas, such as Darjeeling, should be steeped for 3 to 4 minutes. The same holds for broken leaf teas, which have more surface area and need less brewing time than whole leaves. Whole leaf black teas, and black teas that will be served with milk or lemon, should be steeped 4 to 5 minutes.
# Major producers of black tea
The biggest producers of black tea in the world (with % value) are:
- Unilever - Lipton, PG Tips (17.6%)
- Associated British Foods - Twinings (4.4%)
- Tata Tea - Tetley (4.0%)
- Teekanne
# Nutritional information
Plain black tea without sweeteners or additives contains negligible quantities of calories, protein, sodium, and fat. Some flavored tea with different herbs added may have less than 1 gram of carbohydrates. All teas from the camellia tea plant are rich in polyphenols, which are a type of antioxidant.
# Potential health benefits
A 2001 Boston University study has concluded that short and long-term black tea consumption reverses endothelial vasomotor dysfunction in patients with coronary artery disease. This finding may partly explain the association between tea intake and decreased cardiovascular disease events.
In 2006, a German study concluded that the addition of milk prevents vascular protective effects of tea. | Black tea
Black tea is a variety of tea that is more oxidized than the green, oolong and white varieties.
All four varieties are made from leaves of Camellia sinensis. Black tea is generally stronger in flavor and contains more caffeine than the less oxidized teas.
In Chinese and culturally influenced languages, black tea is known as "crimson tea" (紅茶, Mandarin Chinese hóngchá; Japanese kōcha; Korean hongcha), perhaps a more accurate description of the colour of the liquid. The name black tea, however, could alternatively refer to the colour of the oxidized leaves. In Chinese, "black tea" is a commonly used classification for post-fermented teas, such as Pu-erh tea. However, in the Western world, "red tea" more commonly refers to rooibos, a South African tisane.
While green tea usually loses its flavor within a year, black tea retains its flavor for several years. For this reason, it has long been an article of trade, and compressed bricks of black tea even served as a form of de facto currency in Mongolia, Tibet, and Siberia into the 19th century[1]. It was known since the Tang Dynasty that black tea steeped in hot water could also serve as a passable cloth dye for the lower classes that could not afford the better quality clothing colours of the time.[citation needed] However, far from being a mark of shame, the "brown star" mark of the dyeing process was seen as much better than plain cloth and held some importance as a mark of the lower merchant classes through the Ming Dynasty[citation needed]. The tea originally imported to Europe was either green or semi-oxidized. Only in the 19th century did black tea surpass green in popularity[citation needed]. Although green tea has recently seen a revival due to its purported health benefits, black tea still accounts for over ninety percent of all tea sold in the West.
The expression "black tea" is also used to describe a cup of tea without milk ("served black"), similar to coffee served without milk or cream.
# Varieties of black tea
Generally, unblended black teas are named after the region in which they are produced. Often, different regions are known for producing teas with characteristic flavors.
## Chinese black teas
- Lapsang Souchong (正山小种 or 烟小种): originally from Mount Wuyi, Fujian Province, China. It is a black tea which is dried over burning pine, thereby developing a strong smoky flavour.
- Keemun (祁門) : from Qimen, Anhui Province, China, a Chinese Famous Tea.
- Dian Hong (滇紅): from Yunnan Province, China. Well known for dark malty teas and golden bud teas.
- Ying De Hong (英徳紅): from Guangdong Province, China.
- Ju Qiu Mei Hong: from Hu Fou district, Hangzhou City, Zhejiang Province, China.
## Indian and Sri Lankan black teas
- Assam: from Assam, India. Full bodied, strong and distinctively malty.
- Darjeeling: from West Bengal, India.
- Kangra: from Himachal Pradesh, India.
- Nilgiri: from Nilgiri, Tamil Nadu, India.
- Ceylon: from Sri Lanka.
## Other black teas
- Kenyan: from Africa, similar to Assam.
- Vietnamese: from Vietnam, similar to some cheaper Yunnan teas, with a pleasant and sweet aroma but a more bodied and darker brew; unlike teas from Nepal or Darjeeling.
- Nepalese: from uplands of Nepal. Somewhat similar to lower grades of Darjeeling.
- Rize Tea (Çay): from Rize Province on the eastern Black Sea coast of Turkey, that is crystal clear and mahogany in colour. Prepared in a samovar or a caydanlik, it can be served strong ("koyu" dark) or weak ("açik" light), in small glasses with cubed sugar.
- Thai tea: from Thailand
- Azerbaijani tea: from Caucasus in Azerbaijan
- Georgian tea: from Caucasus in Georgia
- Krasnodar tea: from Caucasus in Russia
- Java tea: from Indonesia, has got nutty aroma, very different from both Chinese and Indian teas.
- Sumatra tea: from Indonesia, similar to Java tea.
# Blends of black tea
Black tea is often blended and mixed with various other plants in order to obtain a beverage.
- Earl Grey: black tea with bergamot oil.
- English Breakfast: described as full-bodied, robust, and/or rich, and blended to go well with milk and sugar.
- Irish Breakfast: it is a blend of several black teas: most often Assam teas and, less often, other types of black tea.
- In the United States, citrus fruits such as orange or lemon, or their respective rinds, are often used to create flavored black teas, sometimes in conjunction with spices (such as cinnamon). These products can be easily confused with citrus-based herbal teas, but the herbal products will generally be labelled as having no caffeine; whereas, the tea-based products do contain caffeine.
# Processing of black tea
- After the harvest, the leaves are first withered by blowing air on them.
- Then black teas are processed in either of two ways, CTC (Crush, Tear, Curl) or orthodox. The CTC method is used for lower quality leaves that end up in tea bags and are processed by machines. This method is efficient and effective for producing a better quality product from medium and lower quality leaves. Orthodox processing is done either by machines or by hand. Hand processing is used for high quality teas. While the methods employed in orthodox processing differ by tea type, this style of processing results in the high quality loose tea sought by many connoisseurs.
- Next, the leaves are oxidized under controlled temperature and humidity. (This process is also called "fermentation", which is a misnomer since no actual fermentation takes place.) The level of oxidation determines the quality of the tea. Since oxidation begins at the rolling stage itself, the time between these stages is also a crucial factor in the quality of the tea.
- Then the leaves are dried to arrest the oxidation process.
- Finally, the leaves are sorted into grades according their sizes (whole leaf, brokens, fannings and dust), usually with the use of sieves. The tea could be further sub-graded according to other criteria.
The tea is then ready for packaging.
# Tea grading
Black tea is usually graded on one of four scales of quality. Whole leaf teas are highest quality followed by broken leaves, fannings, and dusts. Whole leaf teas are produced with little or no alteration to the tea leaf, this results in a finished product with a coarser texture than that of bagged teas, whole leaf teas are widely considered the most valuable, especially if they contain leaf tips. Broken leaves are commonly sold as medium grade loose teas. Smaller broken varieties may be included in tea bags. Fannings are usually small particles of tea leftover from the production of larger tea varieties, but are occasionally manufactured specifically for use in bagged teas. Dusts are the finest particles of tea leftover from production of the above varieties, and are often used for tea bags with very fast, very harsh brews. Fannings and dust are useful in bagged teas because the greater surface area of the many particles allows for a fast, complete diffusion of the tea into the water. Fannings and dusts usually have a darker colour, lack of sweetness, and stronger flavor when brewed.
# Brewing
Generally, 2.25 grams of tea per 180 ml of water, or about a teaspoon of black tea per 6 oz. cup, should be used. Unlike green teas, which turn bitter when brewed at higher temperatures, black tea should be steeped in freshly boiled water. The more delicate black teas, such as Darjeeling, should be steeped for 3 to 4 minutes. The same holds for broken leaf teas, which have more surface area and need less brewing time than whole leaves. Whole leaf black teas, and black teas that will be served with milk or lemon, should be steeped 4 to 5 minutes.
[2]
# Major producers of black tea
The biggest producers of black tea in the world (with % value) are:
- Unilever - Lipton, PG Tips (17.6%)
- Associated British Foods - Twinings (4.4%)
- Tata Tea - Tetley (4.0%)
- Teekanne
# Nutritional information
Plain black tea without sweeteners or additives contains negligible quantities of calories, protein, sodium, and fat. Some flavored tea with different herbs added may have less than 1 gram of carbohydrates. All teas from the camellia tea plant are rich in polyphenols, which are a type of antioxidant.
# Potential health benefits
Template:Seealso
A 2001 Boston University study has concluded that short and long-term black tea consumption reverses endothelial vasomotor dysfunction in patients with coronary artery disease. This finding may partly explain the association between tea intake and decreased cardiovascular disease events.
[3]
In 2006, a German study concluded that the addition of milk prevents vascular protective effects of tea.
[4]
Template:Teas | https://www.wikidoc.org/index.php/Black_tea | |
a489e931788ed6409cd0892d673de3b3b2401da0 | wikidoc | Blackhead | Blackhead
A blackhead (medically known as an open comedo , plural comedones ) is a yellowish or blackish bump or plug on the skin. A blackhead is a type of acne vulgaris. It is caused by excess oils that have accumulated in the sebaceous gland's duct. Blackheads are typically caused by excessive oil and makeup, which can facilitate the multiplication of the bacterium Propionibacterium acnes, the predominant anaerobe of the normal skin flora. The substance found in these bumps mostly consists of keratin and modified sebum (an oily secretion of the sebaceous gland), which darkens (resembling dirt) as it oxidizes.
Blackheads may be extracted by a professional such as a doctor, and should not be picked at without sterilized instruments designed for blackhead removal.
For information on the causes and treatment of blackheads, see the above linked acne vulgaris. | Blackhead
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A blackhead (medically known as an open comedo[1] , plural comedones [2]) is a yellowish or blackish bump or plug on the skin. A blackhead is a type of acne vulgaris. It is caused by excess oils that have accumulated in the sebaceous gland's duct. Blackheads are typically caused by excessive oil and makeup, which can facilitate the multiplication of the bacterium Propionibacterium acnes, the predominant anaerobe of the normal skin flora. The substance found in these bumps mostly consists of keratin and modified sebum (an oily secretion of the sebaceous gland), which darkens (resembling dirt) as it oxidizes. [3]
Blackheads may be extracted by a professional such as a doctor, and should not be picked at without sterilized instruments designed for blackhead removal.
For information on the causes and treatment of blackheads, see the above linked acne vulgaris. | https://www.wikidoc.org/index.php/Blackhead | |
2b72a8ffde7952a2cb413fbb624d9ae2d9de1095 | wikidoc | Blanching | Blanching
Blanching is a cooking term that describes a process of food preparation wherein the food substance, usually a vegetable or fruit, is plunged into boiling water, removed after a brief, timed interval and finally plunged into iced water or placed under cold running water (shocked) to halt the cooking process.
Uses of blanching
- Peeling Blanching loosens the skin on some fruits or nuts, such as onions, tomatoes, plums, peaches, or almonds.
- Flavor Blanching enhances the flavor of some vegetables, such as broccoli, by releasing bitter acids stored in the cellular structure of the food.
- Appearance Blanching enhances the color of some (particularly green) vegetables by releasing gases trapped in the cellular material that obscure the greenness of the chlorophyll. Since blanching is done - and halted - quickly, the heat does not have time to break down chlorophyll as well.
- Shelf life Blanching neutralizes bacteria and enzymes present in foods, thus delaying spoilage. This is often done as a preparatory step for freezing and refrigerating vegetables.
Blanching can also describe deep frying in oil at a lower temperature as with the initial cooking of chips.
Blanching also weakens the structure of vegetables rendering them softer than fresh, this is beneficial for canning vegetables where the air in vegetables needs to be minimal. | Blanching
Template:Cookbook
Blanching is a cooking term that describes a process of food preparation wherein the food substance, usually a vegetable or fruit, is plunged into boiling water, removed after a brief, timed interval and finally plunged into iced water or placed under cold running water (shocked) to halt the cooking process.
Uses of blanching
- Peeling Blanching loosens the skin on some fruits or nuts, such as onions, tomatoes, plums, peaches, or almonds.
- Flavor Blanching enhances the flavor of some vegetables, such as broccoli, by releasing bitter acids stored in the cellular structure of the food.
- Appearance Blanching enhances the color of some (particularly green) vegetables by releasing gases trapped in the cellular material that obscure the greenness of the chlorophyll. Since blanching is done - and halted - quickly, the heat does not have time to break down chlorophyll as well.
- Shelf life Blanching neutralizes bacteria and enzymes present in foods, thus delaying spoilage. This is often done as a preparatory step for freezing and refrigerating vegetables.
Blanching can also describe deep frying in oil at a lower temperature as with the initial cooking of chips.
Blanching also weakens the structure of vegetables rendering them softer than fresh, this is beneficial for canning vegetables where the air in vegetables needs to be minimal. | https://www.wikidoc.org/index.php/Blanching | |
f5f6f45bfc384fe9e99de850a4c9aa0a5d7b0e46 | wikidoc | Bleomycin | Bleomycin
- Pulmonary fibrosis is the most severe toxicity associated with bleomycin. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses.
- A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin.
- Bleomycin for Injection, USP should be considered a palliative treatment. It has been shown to be useful in the management of the following neoplasms either as a single agent or in proven combinations with other approved chemotherapeutic agents:
- Head and neck (including mouth, tongue, tonsil, nasopharynx, oropharynx, sinus, palate, lip, buccal mucosa, gingivae, epiglottis, skin, larynx), penis, cervix, and vulva. The response to Bleomycin for injection is poorer in patients with previously irradiated head and neck cancer.
- Lymphomas: Hodgkin’s disease, non-Hodgkin’s lymphoma.
- Embryonal cell, choriocarcinoma, and teratocarcinoma
- Bleomycin for Injection, USP has also been shown to be useful in the management of:
- Bleomycin for Injection is effective as a sclerosing agent for the treatment of malignant pleural effusion and prevention of recurrent pleural effusions.
# Dosage
- Because of the possibility of an anaphylactoid reaction, lymphoma patients should be treated with 2 units or less for the first 2 doses. If no acute reaction occurs, then the regular dosage schedule may be followed.
- The following dose schedule is recommended:
- 0.25 to 0.5 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.
- 0.25 to 0.5 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly. After a 50% response, a maintenance dose of 1 unit daily or 5 units weekly intravenously or intramuscularly should be given.
- Pulmonary toxicity of Bleomycin for Injection, USP appears to be dose-related with a striking increase when the total dose is over 400 units. Total doses over 400 units should be given with great caution.
- When Bleomycin for Injection, USP is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.
- Improvement of Hodgkin’s disease and testicular tumors is prompt and noted within 2 weeks. If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as 3 weeks before any improvement is noted.
- 60 units administered as a single dose bolus intrapleural injection
- The following dosing reductions are proposed for patients with creatinine clearance (CrCL) values of less than 50 mL/min:
- CrCL can be estimated from the individual patient’s measured serum creatinine (Scr) values using the Cockcroft and Gault formula:
- Carcinoma of esophagus
- Cystic craniopharyngioma
- Germ cell tumor of ovary
- Gestational trophoblastic neoplasia
- Malignant effusion - Peritoneal effusion
- Malignant melanoma
- Malignant pericardial effusion
- Malignant tumor of thyroid gland
- Mycosis fungoides, Advanced stage, in combination with other agents
- Pulmonary toxicities occur in 10% of treated patients. In approximately 1%, the nonspecific pneumonitis induced by bleomycin progresses to pulmonary fibrosis and death. Although this is age and dose related, the toxicity is unpredictable. Frequent roentgenograms are recommended.
- A severe idiosyncratic reaction (similar to anaphylaxis) consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin. Since these reactions usually occur after the first or second dose, careful monitoring is essential after these doses.
- Renal or hepatic toxicity, beginning as a deterioration in renal or liver function tests, have been reported. These toxicities may occur at any time after initiation of therapy.
# Precautions
- Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Lower doses of bleomycin may be required in these patients than those with normal renal function
- The most serious side effects are pulmonary adverse reactions, occurring in approximately 10% of treated patients. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Approximately 1% of patients treated have died of pulmonary fibrosis. Pulmonary toxicity is both dose and age related, being more common in patients over 70 years of age and in those receiving over 400 units total dose. This toxicity, however, is unpredictable and has been seen in young patients receiving low doses. Some published reports have suggested that the risk of pulmonary toxicity may be increased when bleomycin is used in combination with G-CSF (filgrastim) or other cytokines. However, randomized clinical studies completed to date have not demonstrated an increased risk of pulmonary complications in patients treated with bleomycin and G-CSF.
- Because of lack of specificity of the clinical syndrome, the identification of patients with pulmonary toxicity due to bleomycin has been extremely difficult. The earliest symptom associated with bleomycin pulmonary toxicity is dyspnea. The earliest sign is fine rales.
- Radiographically, bleomycin-induced pneumonitis produces nonspecific patchy opacities, usually of the lower lung fields. The most common changes in pulmonary function tests are a decrease in total lung volume and a decrease in vital capacity. However, these changes are not predictive of the development of pulmonary fibrosis.
- The microscopic tissue changes due to bleomycin toxicity include bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous edema, and interstitial fibrosis. The acute stage may involve capillary changes and subsequent fibrinous exudation into alveoli producing a change similar to hyaline membrane formation and progressing to a diffuse interstitial fibrosis resembling the Hamman-Rich syndrome. These microscopic findings are nonspecific; e.g., similar changes are seen in radiation pneumonitis and pneumocystic pneumonitis.
- To monitor the onset of pulmonary toxicity, roentgenograms of the chest should be taken every 1 to 2 weeks. If pulmonary changes are noted, treatment should be discontinued until it can be determined if they are drug related. Recent studies have suggested that sequential measurement of the pulmonary diffusion capacity for carbon monoxide (DLco) during treatment with bleomycin may be an indicator of subclinical pulmonary toxicity. It is recommended that the DLco be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DLco falls below 30% to 35% of the pretreatment value.
- Because of bleomycin’s sensitization of lung tissue, patients who have received bleomycin are at greater risk of developing pulmonary toxicity when oxygen is administered in surgery. While long exposure to very high oxygen concentrations is a known cause of lung damage, after bleomycin administration, lung damage can occur at lower concentrations that are usually considered safe. Suggested preventive measures are:
- Maintain FiO2 at concentrations approximating that of room air (25%) during surgery and the postoperative period.
- Monitor carefully fluid replacement, focusing more on colloid administration rather than crystalloid.
- Sudden onset of an acute chest pain syndrome suggestive of pleuropericarditis has been reported during bleomycin infusions. Although each patient must be individually evaluated, further courses of bleomycin do not appear to be contraindicated.
- Pulmonary adverse events which may be related to the intrapleural administration of bleomycin have been reported.
- In approximately 1% of the lymphoma patients treated with bleomycin, an idiosyncratic reaction, similar to anaphylaxis clinically, has been reported. The reaction may be immediate or delayed for several hours, and usually occurs after the first or second dose. It consists of hypotension, mental confusion, fever, chills, and wheezing. Treatment is symptomatic including volume expansion, pressor agents, antihistamines, and corticosteroids.
- These adverse reactions have been reported in approximately 50% of treated patients. They consist of erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of the skin. Hyperkeratosis, nail changes, alopecia, pruritus, and stomatitis have also been reported. It was necessary to discontinue bleomycin therapy in 2% of treated patients because of these toxicities.
- Scleroderma-like skin changes have been reported.
- Skin toxicity is a relatively late manifestation usually developing in the second and third week of treatment after 150 to 200 units of bleomycin have been administered and appears to be related to the cumulative dose.
- Intrapleural administration of bleomycin has been associated with local pain. Hypotension possibly requiring symptomatic treatment has been reported. Death has been reported in association with bleomycin pleurodesis in seriously ill patients.
- Vascular toxicities coincident with the use of bleomycin in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (HUS), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud’s phenomenon occurring in patients treated with bleomycin in combination with vinblastine with or without cisplatin or, in a few cases, with bleomycin as a single agent. It is currently unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.
- Fever, chills, and vomiting have been reported. Anorexia and weight loss have been reported and may persist long after termination of this medication. Pain at tumor site, phlebitis, and other local reactions have been reported.
- Malaise has been reported.
- Because bleomycin is eliminated predominantly through renal excretion, the administration of nephrotoxic drugs with bleomycin may affect its renal clearance. Specifically, in one report of 2 children receiving concomitant cisplatin with bleomycin, total body clearance of bleomycin decreased from 39 to 18 mL/min/m2 as the cumulative dose of cisplatin exceeded 300 mg/m2. Terminal half-life of bleomycin also increased from 4.4 to 6 hours. Fatal bleomycin pulmonary toxicity has been reported in a patient with unrecognized cisplatin-induced oliguric renal failure.
- There have been no studies in pregnant women. If bleomycin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with bleomycin.
- Children of less than 3 years of age have higher total body clearance than in adults, 71 mL/min/m2 versus 51 mL/min/m2, respectively, following intravenous bolus administration. Children of more than 8 years of age have comparable clearance as in adults.
- In children with normal renal function, plasma concentrations of bleomycin decline biexponentially as in adults. The volume of distribution and terminal half-life of bleomycin in children appears comparable to that in adults.
- Bleomycin 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.
- Caution should be exercised when handling Bleomycin for Injection. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Bleomycin for Injection. If Bleomycin for Injection contacts the skin, immediately wash the skin thoroughly with soap and water. If contact with mucous membranes occurs, the membranes should be flushed immediately and thoroughly with water.
- The Bleomycin for Injection 15 units vial should be reconstituted with 1 to 5 mL of Sterile Water for Injection, USP, Sodium Chloride for Injection, 0.9%, USP, or Sterile Bacteriostatic Water for Injection, USP. The Bleomycin for Injection 30 units vial should be reconstituted with 2 to 10 mL of the above diluents.
- The contents of the 15 units or 30 units vial should be dissolved in 5 mL or 10 mL, respectively, of Sodium Chloride for Injection, 0.9%, USP, and administered slowly over a period of 10 minutes.
- Sixty units of Bleomycin for Injection are dissolved in 50 to 100 mL Sodium Chloride for Injection, 0.9%, USP, and administered through a thoracostomy tube following drainage of excess pleural fluid and confirmation of complete lung expansion. The literature suggests that successful pleurodesis is, in part, dependent upon complete drainage of the pleural fluid and re-establishment of negative intrapleural pressure prior to instillation of a sclerosing agent. Therefore, the amount of drainage from the chest tube should be as minimal as possible prior to instillation of Bleomycin for Injection. Although there is no conclusive evidence to support this contention, it is generally accepted that chest tube drainage should be less than 100 mL in a 24-hour period prior to sclerosis. However, Bleomycin for Injection instillation may be appropriate when drainage is between 100 to 300 mL under clinical conditions that necessitate sclerosis therapy. The thoracostomy tube is clamped after Bleomycin for Injection instillation. The patient is moved from the supine to the left and right lateral positions several times during the next four hours. The clamp is then removed and suction re-established. The amount of time the chest tube remains in place following sclerosis is dictated by the clinical situation.
- The intrapleural injection of topical anesthetics or systemic narcotic analgesia is generally not required.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin.
- 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.
- Bleomycin is known to cause single, and to a lesser extent, double-stranded breaks in DNA. In in vitro and in vivo experiments, bleomycin has been shown to cause cell cycle arrest in G2 and in mitosis.
- When administered into the pleural cavity in the treatment of malignant pleural effusion, bleomycin acts as a sclerosing agent.
- Bleomycin for Injection, USP is provided as a sterile lyophilized powder for reconstitution containing 15 units per vial and 30 units per vial, which are intended for intramuscular, intravenous, subcutaneous or intrapleural administration.
- Its chemical name is N’-bleomycin-amide (bleomycin A2) and N’-bleomycin-amide (bleomycin B2).
- Bleomycin is rapidly absorbed following either intramuscular, subcutaneous, intraperitoneal, or intrapleural administration reaching peak plasma concentrations in 30 to 60 minutes. Systemic bioavailability of bleomycin is 100% and 70% following intramuscular and subcutaneous administrations, respectively, and 45% following both intraperitoneal and intrapleural administrations, compared to intravenous and bolus administration.
- Following intramuscular doses of 1 to 10 units/m2, both peak plasma concentration and AUC increased in proportion with the increase of dose.
- Following intravenous bolus administration of 30 units of bleomycin to one patient with a primary germ cell tumor of the brain, a peak CSF level was 40% of the simultaneously-obtained plasma level and was attained in 2 hours after drug administration. The area under the bleomycin CSF concentration x time curve was 25% of the area of the bleomycin plasma concentration x time curve.
- Bleomycin is widely distributed throughout the body with a mean volume of distribution of 17.5 L/m2 in patients following a 15 units/m2 intravenous bolus dose. Protein binding of bleomycin has not been studied.
- Bleomycin is inactivated by a cytosolic cysteine proteinase enzyme, bleomycin hydrolase. The enzyme is widely distributed in normal tissues with the exception of the skin and lungs, both targets of bleomycin toxicity. Systemic elimination of the drug by enzymatic degradation is probably only important in patients with severely compromised renal function.
- The primary route of elimination is via the kidneys. About 65% of the administered intravenous dose is excreted in urine within 24 hours. In patients with normal renal function, plasma concentrations of bleomycin decline biexponentially with a mean terminal half-life of 2 hours following intravenous bolus administration. Total body clearance and renal clearance averaged 51 mL/min/m2 and 23 mL/min/m2, respectively.
- Following intrapleural administration to patients with normal renal function, a lower percentage of drug (40%) is recovered in the urine, as compared to that found in the urine after intravenous administration.
- The carcinogenic potential of bleomycin in humans is unknown. A study in F344-type male rats demonstrated an increased incidence of nodular hyperplasia after induced lung carcinogenesis by nitrosamines, followed by treatment with bleomycin. In another study where the drug was administered to rats by subcutaneous injection at 0.35 mg/kg weekly (3.82 units/m2 weekly or about 30% at the recommended human dose), necropsy findings included dose-related injection site fibrosarcomas as well as various renal tumors. Bleomycin has been shown to be mutagenic both in vitro and in vivo. The effects of bleomycin on fertility have not been studied.
- The safety and efficacy of bleomycin 60 units and tetracycline (1 g) as treatment for malignant pleural effusion were evaluated in a multicenter, randomized trial. Patients were required to have cytologically positive pleural effusion, good performance status (0,1,2), lung re-expansion following tube thoracostomy with drainage rates of 100 mL/24 hours or less, no prior intrapleural therapy, no prior systemic bleomycin therapy, no chest irradiation, and no recent change in systemic therapy. Overall survival did not differ between the bleomycin (n=44) and tetracycline treatment (n=41) groups. Of patients evaluated within 30 days of instillation, the recurrence rate was 36% (10/28) with bleomycin and 67% (18/27) with tetracycline (p=0.023). Toxicity was similar between groups.
- The sterile powder is stable under refrigeration 2°C to 8°C (36°F to 46°F) and should not be used after the expiration date is reached.
- Bleomycin for Injection should not be reconstituted or diluted with D5W or other dextrose containing diluents. When reconstituted in D5W and analyzed by HPLC, Bleomycin for Injection demonstrates a loss of A2 and B2 potency that does not occur when Bleomycin for Injection is reconstituted in Sodium Chloride for Injection, 0.9%, USP.
- Bleomycin for Injection is stable for 24 hours at room temperature in Sodium Chloride.
- This container closure is not made with natural rubber latex.
- ↑ Poignonec S, Lachiver LD, Lamas G, Coutellier A, Caumes E, Soudant J (1995). "Intralesional bleomycin for acquired immunodeficiency syndrome-associated cutaneous Kaposi's sarcoma". Arch Dermatol. 131 (2): 228. PMID 7531965.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}
- ↑ Brambilla L, Boneschi V, Beretta G, Finzi AF (1984). "Intralesional chemotherapy for Kaposi's sarcoma". Dermatologica. 169 (3): 150–5. PMID 6207059.CS1 maint: Multiple names: authors list (link)
- ↑ Coonley CJ, Bains M, Hilaris B, Chapman R, Kelsen DP (1984). "Cisplatin and bleomycin in the treatment of esophageal carcinoma. A final report". Cancer. 54 (11): 2351–5. PMID 6208990.CS1 maint: Multiple names: authors list (link)
- ↑ Dinwoodie WR, Bartolucci AA, Lyman GH, Velez-Garcia E, Martelo OJ, Sarma PR (1986). "Phase II evaluation of cisplatin, bleomycin, and vindesine in advanced squamous cell carcinoma of the esophagus: a Southeastern Cancer Study Group Trial". Cancer Treat Rep. 70 (2): 267–70. PMID 2418969.CS1 maint: Multiple names: authors list (link)
- ↑ Hukin J, Steinbok P, Lafay-Cousin L, Hendson G, Strother D, Mercier C; et al. (2007). "Intracystic bleomycin therapy for craniopharyngioma in children: the Canadian experience". Cancer. 109 (10): 2124–31. doi:10.1002/cncr.22633. PMID 17407137.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Mottolese C, Stan H, Hermier M, Berlier P, Convert J, Frappaz D; et al. (2001). "Intracystic chemotherapy with bleomycin in the treatment of craniopharyngiomas". Childs Nerv Syst. 17 (12): 724–30. doi:10.1007/s00381-001-0524-5. PMID 11862438.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Hader WJ, Steinbok P, Hukin J, Fryer C (2000). "Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children". Pediatr Neurosurg. 33 (4): 211–8. doi:55955 Check |doi= value (help). PMID 11124639.CS1 maint: Multiple names: authors list (link)
- ↑ Gershenson DM, Morris M, Burke TW, Levenback C, Matthews CM, Wharton JT (1996). "Treatment of poor-prognosis sex cord-stromal tumors of the ovary with the combination of bleomycin, etoposide, and cisplatin". Obstet Gynecol. 87 (4): 527–31. doi:10.1016/0029-7844(95)00491-2. PMID 8602303.CS1 maint: Multiple names: authors list (link)
- ↑ Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ (1987). "Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide". N Engl J Med. 316 (23): 1435–40. doi:10.1056/NEJM198706043162302. PMID 2437455.CS1 maint: Multiple names: authors list (link)
- ↑ Chen LP, Cai SM, Fan JX, Li ZT (1995). "PEBA regimen (cisplatin, etoposide, bleomycin, and adriamycin) in the treatment of drug-resistant choriocarcinoma". Gynecol Oncol. 56 (2): 231–4. PMID 7534740.CS1 maint: Multiple names: authors list (link)
- ↑ Maiche AG (1994). "Management of peritoneal effusions with intracavitary mitoxantrone or bleomycin". Anticancer Drugs. 5 (3): 305–8. PMID 7522646.
- ↑ Luikart SD, Kennealey GT, Kirkwood JM (1984). "Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma". J Clin Oncol. 2 (3): 164–8. PMID 6199481.CS1 maint: Multiple names: authors list (link)
- ↑ Punt CJ, van Herpen CM, Jansen RL, Vreugdenhil G, Muller EW, de Mulder PH (1997). "Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD) plus interferon alpha for metastatic melanoma: a multicentre phase II study". Br J Cancer. 76 (2): 266–9. PMC 2223935. PMID 9231931.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Liu G, Crump M, Goss PE, Dancey J, Shepherd FA (1996). "Prospective comparison of the sclerosing agents doxycycline and bleomycin for the primary management of malignant pericardial effusion and cardiac tamponade". J Clin Oncol. 14 (12): 3141–7. PMID 8955660.CS1 maint: Multiple names: authors list (link)
- ↑ De Besi P, Busnardo B, Toso S, Girelli ME, Nacamulli D, Simioni N; et al. (1991). "Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer". J Endocrinol Invest. 14 (6): 475–80. PMID 1723086.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Fierro MT, Doveil GC, Quaglino P, Savoia P, Verrone A, Bernengo MG (1997). "Combination of etoposide, idarubicin, cyclophosphamide, vincristine, prednisone and bleomycin (VICOP-B) in the treatment of advanced cutaneous T-cell lymphoma". Dermatology. 194 (3): 268–72. PMID 9187846.CS1 maint: Multiple names: authors list (link)
- ↑ "Bleomycin". | Bleomycin
- Pulmonary fibrosis is the most severe toxicity associated with bleomycin. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses.
- A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin.
- Bleomycin for Injection, USP should be considered a palliative treatment. It has been shown to be useful in the management of the following neoplasms either as a single agent or in proven combinations with other approved chemotherapeutic agents:
- Head and neck (including mouth, tongue, tonsil, nasopharynx, oropharynx, sinus, palate, lip, buccal mucosa, gingivae, epiglottis, skin, larynx), penis, cervix, and vulva. The response to Bleomycin for injection is poorer in patients with previously irradiated head and neck cancer.
- Lymphomas: Hodgkin’s disease, non-Hodgkin’s lymphoma.
- Embryonal cell, choriocarcinoma, and teratocarcinoma
- Bleomycin for Injection, USP has also been shown to be useful in the management of:
- Bleomycin for Injection is effective as a sclerosing agent for the treatment of malignant pleural effusion and prevention of recurrent pleural effusions.
### Dosage
- Because of the possibility of an anaphylactoid reaction, lymphoma patients should be treated with 2 units or less for the first 2 doses. If no acute reaction occurs, then the regular dosage schedule may be followed.
- The following dose schedule is recommended:
- 0.25 to 0.5 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.
- 0.25 to 0.5 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly. After a 50% response, a maintenance dose of 1 unit daily or 5 units weekly intravenously or intramuscularly should be given.
- Pulmonary toxicity of Bleomycin for Injection, USP appears to be dose-related with a striking increase when the total dose is over 400 units. Total doses over 400 units should be given with great caution.
- When Bleomycin for Injection, USP is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.
- Improvement of Hodgkin’s disease and testicular tumors is prompt and noted within 2 weeks. If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as 3 weeks before any improvement is noted.
- 60 units administered as a single dose bolus intrapleural injection
- The following dosing reductions are proposed for patients with creatinine clearance (CrCL) values of less than 50 mL/min:
- CrCL can be estimated from the individual patient’s measured serum creatinine (Scr) values using the Cockcroft and Gault formula:
- Carcinoma of esophagus[3][4]
- Cystic craniopharyngioma[5][6][7]
- Germ cell tumor of ovary[8][9]
- Gestational trophoblastic neoplasia[10]
- Malignant effusion - Peritoneal effusion[11]
- Malignant melanoma[12][13]
- Malignant pericardial effusion[14]
- Malignant tumor of thyroid gland[15]
- Mycosis fungoides, Advanced stage, in combination with other agents[16]
- Pulmonary toxicities occur in 10% of treated patients. In approximately 1%, the nonspecific pneumonitis induced by bleomycin progresses to pulmonary fibrosis and death. Although this is age and dose related, the toxicity is unpredictable. Frequent roentgenograms are recommended.
- A severe idiosyncratic reaction (similar to anaphylaxis) consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with bleomycin. Since these reactions usually occur after the first or second dose, careful monitoring is essential after these doses.
- Renal or hepatic toxicity, beginning as a deterioration in renal or liver function tests, have been reported. These toxicities may occur at any time after initiation of therapy.
### Precautions
- Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Lower doses of bleomycin may be required in these patients than those with normal renal function
- The most serious side effects are pulmonary adverse reactions, occurring in approximately 10% of treated patients. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Approximately 1% of patients treated have died of pulmonary fibrosis. Pulmonary toxicity is both dose and age related, being more common in patients over 70 years of age and in those receiving over 400 units total dose. This toxicity, however, is unpredictable and has been seen in young patients receiving low doses. Some published reports have suggested that the risk of pulmonary toxicity may be increased when bleomycin is used in combination with G-CSF (filgrastim) or other cytokines. However, randomized clinical studies completed to date have not demonstrated an increased risk of pulmonary complications in patients treated with bleomycin and G-CSF.
- Because of lack of specificity of the clinical syndrome, the identification of patients with pulmonary toxicity due to bleomycin has been extremely difficult. The earliest symptom associated with bleomycin pulmonary toxicity is dyspnea. The earliest sign is fine rales.
- Radiographically, bleomycin-induced pneumonitis produces nonspecific patchy opacities, usually of the lower lung fields. The most common changes in pulmonary function tests are a decrease in total lung volume and a decrease in vital capacity. However, these changes are not predictive of the development of pulmonary fibrosis.
- The microscopic tissue changes due to bleomycin toxicity include bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous edema, and interstitial fibrosis. The acute stage may involve capillary changes and subsequent fibrinous exudation into alveoli producing a change similar to hyaline membrane formation and progressing to a diffuse interstitial fibrosis resembling the Hamman-Rich syndrome. These microscopic findings are nonspecific; e.g., similar changes are seen in radiation pneumonitis and pneumocystic pneumonitis.
- To monitor the onset of pulmonary toxicity, roentgenograms of the chest should be taken every 1 to 2 weeks. If pulmonary changes are noted, treatment should be discontinued until it can be determined if they are drug related. Recent studies have suggested that sequential measurement of the pulmonary diffusion capacity for carbon monoxide (DLco) during treatment with bleomycin may be an indicator of subclinical pulmonary toxicity. It is recommended that the DLco be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DLco falls below 30% to 35% of the pretreatment value.
- Because of bleomycin’s sensitization of lung tissue, patients who have received bleomycin are at greater risk of developing pulmonary toxicity when oxygen is administered in surgery. While long exposure to very high oxygen concentrations is a known cause of lung damage, after bleomycin administration, lung damage can occur at lower concentrations that are usually considered safe. Suggested preventive measures are:
- Maintain FiO2 at concentrations approximating that of room air (25%) during surgery and the postoperative period.
- Monitor carefully fluid replacement, focusing more on colloid administration rather than crystalloid.
- Sudden onset of an acute chest pain syndrome suggestive of pleuropericarditis has been reported during bleomycin infusions. Although each patient must be individually evaluated, further courses of bleomycin do not appear to be contraindicated.
- Pulmonary adverse events which may be related to the intrapleural administration of bleomycin have been reported.
- In approximately 1% of the lymphoma patients treated with bleomycin, an idiosyncratic reaction, similar to anaphylaxis clinically, has been reported. The reaction may be immediate or delayed for several hours, and usually occurs after the first or second dose. It consists of hypotension, mental confusion, fever, chills, and wheezing. Treatment is symptomatic including volume expansion, pressor agents, antihistamines, and corticosteroids.
- These adverse reactions have been reported in approximately 50% of treated patients. They consist of erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of the skin. Hyperkeratosis, nail changes, alopecia, pruritus, and stomatitis have also been reported. It was necessary to discontinue bleomycin therapy in 2% of treated patients because of these toxicities.
- Scleroderma-like skin changes have been reported.
- Skin toxicity is a relatively late manifestation usually developing in the second and third week of treatment after 150 to 200 units of bleomycin have been administered and appears to be related to the cumulative dose.
- Intrapleural administration of bleomycin has been associated with local pain. Hypotension possibly requiring symptomatic treatment has been reported. Death has been reported in association with bleomycin pleurodesis in seriously ill patients.
- Vascular toxicities coincident with the use of bleomycin in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (HUS), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud’s phenomenon occurring in patients treated with bleomycin in combination with vinblastine with or without cisplatin or, in a few cases, with bleomycin as a single agent. It is currently unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.
- Fever, chills, and vomiting have been reported. Anorexia and weight loss have been reported and may persist long after termination of this medication. Pain at tumor site, phlebitis, and other local reactions have been reported.
- Malaise has been reported.
- Because bleomycin is eliminated predominantly through renal excretion, the administration of nephrotoxic drugs with bleomycin may affect its renal clearance. Specifically, in one report of 2 children receiving concomitant cisplatin with bleomycin, total body clearance of bleomycin decreased from 39 to 18 mL/min/m2 as the cumulative dose of cisplatin exceeded 300 mg/m2. Terminal half-life of bleomycin also increased from 4.4 to 6 hours. Fatal bleomycin pulmonary toxicity has been reported in a patient with unrecognized cisplatin-induced oliguric renal failure.
- There have been no studies in pregnant women. If bleomycin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with bleomycin.
- Children of less than 3 years of age have higher total body clearance than in adults, 71 mL/min/m2 versus 51 mL/min/m2, respectively, following intravenous bolus administration. Children of more than 8 years of age have comparable clearance as in adults.
- In children with normal renal function, plasma concentrations of bleomycin decline biexponentially as in adults. The volume of distribution and terminal half-life of bleomycin in children appears comparable to that in adults.
- Bleomycin 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.
- Caution should be exercised when handling Bleomycin for Injection. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Bleomycin for Injection. If Bleomycin for Injection contacts the skin, immediately wash the skin thoroughly with soap and water. If contact with mucous membranes occurs, the membranes should be flushed immediately and thoroughly with water.
- The Bleomycin for Injection 15 units vial should be reconstituted with 1 to 5 mL of Sterile Water for Injection, USP, Sodium Chloride for Injection, 0.9%, USP, or Sterile Bacteriostatic Water for Injection, USP. The Bleomycin for Injection 30 units vial should be reconstituted with 2 to 10 mL of the above diluents.
- The contents of the 15 units or 30 units vial should be dissolved in 5 mL or 10 mL, respectively, of Sodium Chloride for Injection, 0.9%, USP, and administered slowly over a period of 10 minutes.
- Sixty units of Bleomycin for Injection are dissolved in 50 to 100 mL Sodium Chloride for Injection, 0.9%, USP, and administered through a thoracostomy tube following drainage of excess pleural fluid and confirmation of complete lung expansion. The literature suggests that successful pleurodesis is, in part, dependent upon complete drainage of the pleural fluid and re-establishment of negative intrapleural pressure prior to instillation of a sclerosing agent. Therefore, the amount of drainage from the chest tube should be as minimal as possible prior to instillation of Bleomycin for Injection. Although there is no conclusive evidence to support this contention, it is generally accepted that chest tube drainage should be less than 100 mL in a 24-hour period prior to sclerosis. However, Bleomycin for Injection instillation may be appropriate when drainage is between 100 to 300 mL under clinical conditions that necessitate sclerosis therapy. The thoracostomy tube is clamped after Bleomycin for Injection instillation. The patient is moved from the supine to the left and right lateral positions several times during the next four hours. The clamp is then removed and suction re-established. The amount of time the chest tube remains in place following sclerosis is dictated by the clinical situation.
- The intrapleural injection of topical anesthetics or systemic narcotic analgesia is generally not required.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin.
- 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.
- Bleomycin is known to cause single, and to a lesser extent, double-stranded breaks in DNA. In in vitro and in vivo experiments, bleomycin has been shown to cause cell cycle arrest in G2 and in mitosis.
- When administered into the pleural cavity in the treatment of malignant pleural effusion, bleomycin acts as a sclerosing agent.
- Bleomycin for Injection, USP is provided as a sterile lyophilized powder for reconstitution containing 15 units per vial and 30 units per vial, which are intended for intramuscular, intravenous, subcutaneous or intrapleural administration.
- Its chemical name is N’-[3-(dimethylsulphonio)propyl]bleomycin-amide (bleomycin A2) and N’-[4-(guaniodobutyl)]bleomycin-amide (bleomycin B2).
- Bleomycin is rapidly absorbed following either intramuscular, subcutaneous, intraperitoneal, or intrapleural administration reaching peak plasma concentrations in 30 to 60 minutes. Systemic bioavailability of bleomycin is 100% and 70% following intramuscular and subcutaneous administrations, respectively, and 45% following both intraperitoneal and intrapleural administrations, compared to intravenous and bolus administration.
- Following intramuscular doses of 1 to 10 units/m2, both peak plasma concentration and AUC increased in proportion with the increase of dose.
- Following intravenous bolus administration of 30 units of bleomycin to one patient with a primary germ cell tumor of the brain, a peak CSF level was 40% of the simultaneously-obtained plasma level and was attained in 2 hours after drug administration. The area under the bleomycin CSF concentration x time curve was 25% of the area of the bleomycin plasma concentration x time curve.
- Bleomycin is widely distributed throughout the body with a mean volume of distribution of 17.5 L/m2 in patients following a 15 units/m2 intravenous bolus dose. Protein binding of bleomycin has not been studied.
- Bleomycin is inactivated by a cytosolic cysteine proteinase enzyme, bleomycin hydrolase. The enzyme is widely distributed in normal tissues with the exception of the skin and lungs, both targets of bleomycin toxicity. Systemic elimination of the drug by enzymatic degradation is probably only important in patients with severely compromised renal function.
- The primary route of elimination is via the kidneys. About 65% of the administered intravenous dose is excreted in urine within 24 hours. In patients with normal renal function, plasma concentrations of bleomycin decline biexponentially with a mean terminal half-life of 2 hours following intravenous bolus administration. Total body clearance and renal clearance averaged 51 mL/min/m2 and 23 mL/min/m2, respectively.
- Following intrapleural administration to patients with normal renal function, a lower percentage of drug (40%) is recovered in the urine, as compared to that found in the urine after intravenous administration.
- The carcinogenic potential of bleomycin in humans is unknown. A study in F344-type male rats demonstrated an increased incidence of nodular hyperplasia after induced lung carcinogenesis by nitrosamines, followed by treatment with bleomycin. In another study where the drug was administered to rats by subcutaneous injection at 0.35 mg/kg weekly (3.82 units/m2 weekly or about 30% at the recommended human dose), necropsy findings included dose-related injection site fibrosarcomas as well as various renal tumors. Bleomycin has been shown to be mutagenic both in vitro and in vivo. The effects of bleomycin on fertility have not been studied.
- The safety and efficacy of bleomycin 60 units and tetracycline (1 g) as treatment for malignant pleural effusion were evaluated in a multicenter, randomized trial. Patients were required to have cytologically positive pleural effusion, good performance status (0,1,2), lung re-expansion following tube thoracostomy with drainage rates of 100 mL/24 hours or less, no prior intrapleural therapy, no prior systemic bleomycin therapy, no chest irradiation, and no recent change in systemic therapy. Overall survival did not differ between the bleomycin (n=44) and tetracycline treatment (n=41) groups. Of patients evaluated within 30 days of instillation, the recurrence rate was 36% (10/28) with bleomycin and 67% (18/27) with tetracycline (p=0.023). Toxicity was similar between groups.
- The sterile powder is stable under refrigeration 2°C to 8°C (36°F to 46°F) and should not be used after the expiration date is reached.
- Bleomycin for Injection should not be reconstituted or diluted with D5W or other dextrose containing diluents. When reconstituted in D5W and analyzed by HPLC, Bleomycin for Injection demonstrates a loss of A2 and B2 potency that does not occur when Bleomycin for Injection is reconstituted in Sodium Chloride for Injection, 0.9%, USP.
- Bleomycin for Injection is stable for 24 hours at room temperature in Sodium Chloride.
- This container closure is not made with natural rubber latex.
- ↑ Poignonec S, Lachiver LD, Lamas G, Coutellier A, Caumes E, Soudant J (1995). "Intralesional bleomycin for acquired immunodeficiency syndrome-associated cutaneous Kaposi's sarcoma". Arch Dermatol. 131 (2): 228. PMID 7531965.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}
- ↑ Brambilla L, Boneschi V, Beretta G, Finzi AF (1984). "Intralesional chemotherapy for Kaposi's sarcoma". Dermatologica. 169 (3): 150–5. PMID 6207059.CS1 maint: Multiple names: authors list (link)
- ↑ Coonley CJ, Bains M, Hilaris B, Chapman R, Kelsen DP (1984). "Cisplatin and bleomycin in the treatment of esophageal carcinoma. A final report". Cancer. 54 (11): 2351–5. PMID 6208990.CS1 maint: Multiple names: authors list (link)
- ↑ Dinwoodie WR, Bartolucci AA, Lyman GH, Velez-Garcia E, Martelo OJ, Sarma PR (1986). "Phase II evaluation of cisplatin, bleomycin, and vindesine in advanced squamous cell carcinoma of the esophagus: a Southeastern Cancer Study Group Trial". Cancer Treat Rep. 70 (2): 267–70. PMID 2418969.CS1 maint: Multiple names: authors list (link)
- ↑ Hukin J, Steinbok P, Lafay-Cousin L, Hendson G, Strother D, Mercier C; et al. (2007). "Intracystic bleomycin therapy for craniopharyngioma in children: the Canadian experience". Cancer. 109 (10): 2124–31. doi:10.1002/cncr.22633. PMID 17407137.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Mottolese C, Stan H, Hermier M, Berlier P, Convert J, Frappaz D; et al. (2001). "Intracystic chemotherapy with bleomycin in the treatment of craniopharyngiomas". Childs Nerv Syst. 17 (12): 724–30. doi:10.1007/s00381-001-0524-5. PMID 11862438.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Hader WJ, Steinbok P, Hukin J, Fryer C (2000). "Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children". Pediatr Neurosurg. 33 (4): 211–8. doi:55955 Check |doi= value (help). PMID 11124639.CS1 maint: Multiple names: authors list (link)
- ↑ Gershenson DM, Morris M, Burke TW, Levenback C, Matthews CM, Wharton JT (1996). "Treatment of poor-prognosis sex cord-stromal tumors of the ovary with the combination of bleomycin, etoposide, and cisplatin". Obstet Gynecol. 87 (4): 527–31. doi:10.1016/0029-7844(95)00491-2. PMID 8602303.CS1 maint: Multiple names: authors list (link)
- ↑ Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ (1987). "Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide". N Engl J Med. 316 (23): 1435–40. doi:10.1056/NEJM198706043162302. PMID 2437455.CS1 maint: Multiple names: authors list (link)
- ↑ Chen LP, Cai SM, Fan JX, Li ZT (1995). "PEBA regimen (cisplatin, etoposide, bleomycin, and adriamycin) in the treatment of drug-resistant choriocarcinoma". Gynecol Oncol. 56 (2): 231–4. PMID 7534740.CS1 maint: Multiple names: authors list (link)
- ↑ Maiche AG (1994). "Management of peritoneal effusions with intracavitary mitoxantrone or bleomycin". Anticancer Drugs. 5 (3): 305–8. PMID 7522646.
- ↑ Luikart SD, Kennealey GT, Kirkwood JM (1984). "Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma". J Clin Oncol. 2 (3): 164–8. PMID 6199481.CS1 maint: Multiple names: authors list (link)
- ↑ Punt CJ, van Herpen CM, Jansen RL, Vreugdenhil G, Muller EW, de Mulder PH (1997). "Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD) plus interferon alpha for metastatic melanoma: a multicentre phase II study". Br J Cancer. 76 (2): 266–9. PMC 2223935. PMID 9231931.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Liu G, Crump M, Goss PE, Dancey J, Shepherd FA (1996). "Prospective comparison of the sclerosing agents doxycycline and bleomycin for the primary management of malignant pericardial effusion and cardiac tamponade". J Clin Oncol. 14 (12): 3141–7. PMID 8955660.CS1 maint: Multiple names: authors list (link)
- ↑ De Besi P, Busnardo B, Toso S, Girelli ME, Nacamulli D, Simioni N; et al. (1991). "Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer". J Endocrinol Invest. 14 (6): 475–80. PMID 1723086.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Fierro MT, Doveil GC, Quaglino P, Savoia P, Verrone A, Bernengo MG (1997). "Combination of etoposide, idarubicin, cyclophosphamide, vincristine, prednisone and bleomycin (VICOP-B) in the treatment of advanced cutaneous T-cell lymphoma". Dermatology. 194 (3): 268–72. PMID 9187846.CS1 maint: Multiple names: authors list (link)
- ↑ "Bleomycin". | https://www.wikidoc.org/index.php/Blenoxane | |
7180f140b86a0c8dbfa2604fe12b96d37c3f3e69 | wikidoc | Blindfold | Blindfold
A blindfold (from Middle English blindfellen) is a garment, usually of cloth, tied to one's head to cover the eyes to disable the wearer's sight. It can be worn when the eyes are in a closed state and thus prevents the wearer from opening them. Even with the eyes open (as permitted by many blindfolds, especially those made of cloth), the user cannot see.
# Applications
Blindfolds can be used in various applications.
- As a Sleep mask: They block out light when sleeping, especially during air travel, or for those who sleep during the day. It is believed that shutting out light allows the user to achieve a deeper level of sleep. They can also provide relief from claustrophobia for Magnetic resonance imaging (MRI) patients.
- In children's games, such as Pin the Tail on the Donkey and when hitting a piñata.
- During both martial arts and weight lifting to encourage reliance on other senses, such as touch or hearing.
- As a sensory deprivation tool in meditation (to focus attention on oneself rather than outside imagery).
- A kidnapping victim, hostage, prisoner, etc. may be blindfolded to avoid identification of location(s) or people. (A common alternative to this usage is the use of a hood instead.)
- Sometimes by guests who are not captured are still blindfolded or may consent to be blindfolded for the same reasons, as occurs in fiction when being led/driven to their respective hidouts.
- By the recipient of an execution by firing squad.
- Before sunglasses, they were worn as the primary facial cover for those who could not see. This usage, though uncommon, is still practised in modern times.
## Sexology
Sexual blindfold use is common in and outside of the bondage community, one of the initial things recommended for sexual variety. Blindfolds (along with feathers and handcuffs) are commonly sold in novelty "bondage kits" marketed toward non-BDSM practitioners. Many impromptu items already found in the bedroom lend themselves to such use without preparation or prior purchase of specialized equipment.
### BDSM
Blindfolds can be worn during BDSM situations by the submissive. Types can range, though they are typically leather, with a buckle in the back, sometimes locking.
Use of a blindfold is said to enhance the remaining senses of the wearer, focusing attention on sound, smells and physical contact. This increased awareness is said to allow for greater excitement and anticipation by eliminating visual cues, as one cannot see what to expect. It also requires trust of the submissive, with all the emotional ramifications that entails.
The dominant conversely enjoys extra control, focusing the attention of the submissive where they desire. For the submissive it takes the focus of attention off the visual and physical, moving it to the cerebral. Eliminating that primary "distraction" is said to allow for a more perceptive experience.
# In popular culture
- In the anime Ragnarok: the animation the character Takius wears a blindfold (an item from the mmorpg called a "dark blinder").
- The video game Kingdom hearts 2 as well as accompanying videos deep dive and feature one of the main characters riku wearing a blindfold to hide his eyes.
- The character "Blank" from the video game Final fantasy 9 wears an elaborate blindfold, thought the reason for this is never given. | Blindfold
A blindfold (from Middle English blindfellen) is a garment, usually of cloth, tied to one's head to cover the eyes to disable the wearer's sight. It can be worn when the eyes are in a closed state and thus prevents the wearer from opening them. Even with the eyes open (as permitted by many blindfolds, especially those made of cloth), the user cannot see.
# Applications
Blindfolds can be used in various applications.
- As a Sleep mask: They block out light when sleeping, especially during air travel, or for those who sleep during the day. It is believed that shutting out light allows the user to achieve a deeper level of sleep. They can also provide relief from claustrophobia for Magnetic resonance imaging (MRI) patients.
- In children's games, such as Pin the Tail on the Donkey and when hitting a piñata.
- During both martial arts and weight lifting to encourage reliance on other senses, such as touch or hearing.
- As a sensory deprivation tool in meditation (to focus attention on oneself rather than outside imagery).
- A kidnapping victim, hostage, prisoner, etc. may be blindfolded to avoid identification of location(s) or people. (A common alternative to this usage is the use of a hood instead.)
- Sometimes by guests who are not captured are still blindfolded or may consent to be blindfolded for the same reasons, as occurs in fiction when being led/driven to their respective hidouts.
- By the recipient of an execution by firing squad.
- Before sunglasses, they were worn as the primary facial cover for those who could not see. This usage, though uncommon, is still practised in modern times.
## Sexology
Sexual blindfold use is common in and outside of the bondage community, one of the initial things recommended for sexual variety. Blindfolds (along with feathers and handcuffs) are commonly sold in novelty "bondage kits" marketed toward non-BDSM practitioners.[1] Many impromptu items already found in the bedroom lend themselves to such use without preparation or prior purchase of specialized equipment.
### BDSM
Blindfolds can be worn during BDSM situations by the submissive. Types can range, though they are typically leather, with a buckle in the back, sometimes locking.
Use of a blindfold is said to enhance the remaining senses of the wearer, focusing attention on sound, smells and physical contact. This increased awareness is said to allow for greater excitement and anticipation by eliminating visual cues, as one cannot see what to expect. It also requires trust of the submissive, with all the emotional ramifications that entails.[2]
The dominant conversely enjoys extra control, focusing the attention of the submissive where they desire. For the submissive it takes the focus of attention off the visual and physical, moving it to the cerebral. Eliminating that primary "distraction" is said to allow for a more perceptive experience.
# In popular culture
- In the anime Ragnarok: the animation the character Takius wears a blindfold (an item from the mmorpg called a "dark blinder").
- The video game Kingdom hearts 2 as well as accompanying videos deep dive and feature one of the main characters riku wearing a blindfold to hide his eyes.
- The character "Blank" from the video game Final fantasy 9 wears an elaborate blindfold, thought the reason for this is never given. | https://www.wikidoc.org/index.php/Blindfold | |
54ab86dfb3faf594757a3391540b62192e82b7fd | wikidoc | Capillary | Capillary
Capillaries are the smallest of a body's blood vessels, measuring 5-10 μm, which connect arterioles and venules, and are important for the interchange of oxygen, carbon dioxide, and other substances between blood and tissue cells.
# Structure
The walls of capillaries are composed of only a single layer of cells, the endothelium. This layer is so thin that molecules such as oxygen, water and lipids can pass through them by diffusion and enter the tissues. Waste products such as carbon dioxide and urea can diffuse back into the blood to be carried away for removal from the body.
Capillary permeability can be increased by the release of certain cytokines.
# Transport across endothelium
The endothelium also actively transports nutrients, messengers and other substances.
Large molecules may be too big to diffuse across endothelial cells. In some cases, vesicles contained in the capillary membrane use endocytosis and exocytosis to transport material between blood and the tissues. Blood hydrostatic pressure varies along the length of the capillar, and is roughly 40 mm Hg at the atreiolar end and 15 mm Hg at the venus end. The opposing force from outside the capillary is osmotic pressure and is 25 mm Hg. The result is an outward movement of fluid and ions at the atreiolar end, and an influx of fluid at the venus end of the capillary.
# Immune response
In an immune response, the endothelial cells of the capillary will upregulate receptor molecules, thus "catching" immune cells as they pass by the site of infection and aiding extravasation of these cells into the tissue.
# Capillary bed
The "capillary bed" is the network of capillaries supplying an organ. The more metabolically active the cells, the more capillaries it will require to supply nutrients.
The capillary bed usually carries no more than 25% of the amount of blood it could contain, although this amount can be increased through autoregulation by inducing relaxation of smooth muscle.
The capillaries do not possess this smooth muscle in their own walls, and so any change in their diameter is passive. Any signalling molecules they release (such as endothelin for constriction and nitric oxide for dilation) act on the smooth muscle cells in the walls of nearby, larger vessels, e.g. arterioles.
# Types
Capillaries come in three types:
- Continuous - Continuous capillaries have a sealed endothelium and only allow small molecules, water and ions to diffuse.
- Fenestrated - Fenestrated capillaries (derived from "fenestra," the Latin word for "window") have openings that allow larger molecules to diffuse.
- Sinusoidal - Sinusoidal capillaries are special forms of fenestrated capillaries that have larger openings in the epithelium allowing red blood cells and serum proteins to enter. | Capillary
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Capillaries are the smallest of a body's blood vessels, measuring 5-10 μm, which connect arterioles and venules, and are important for the interchange of oxygen, carbon dioxide, and other substances between blood and tissue cells.[1]
# Structure
The walls of capillaries are composed of only a single layer of cells, the endothelium. This layer is so thin that molecules such as oxygen, water and lipids can pass through them by diffusion and enter the tissues. Waste products such as carbon dioxide and urea can diffuse back into the blood to be carried away for removal from the body.
Capillary permeability can be increased by the release of certain cytokines.
# Transport across endothelium
The endothelium also actively transports nutrients, messengers and other substances.
Large molecules may be too big to diffuse across endothelial cells. In some cases, vesicles contained in the capillary membrane use endocytosis and exocytosis to transport material between blood and the tissues. Blood hydrostatic pressure varies along the length of the capillar, and is roughly 40 mm Hg at the atreiolar end and 15 mm Hg at the venus end. The opposing force from outside the capillary is osmotic pressure and is 25 mm Hg. The result is an outward movement of fluid and ions at the atreiolar end, and an influx of fluid at the venus end of the capillary.
# Immune response
In an immune response, the endothelial cells of the capillary will upregulate receptor molecules, thus "catching" immune cells as they pass by the site of infection and aiding extravasation of these cells into the tissue.
# Capillary bed
The "capillary bed" is the network of capillaries supplying an organ. The more metabolically active the cells, the more capillaries it will require to supply nutrients.
The capillary bed usually carries no more than 25% of the amount of blood it could contain, although this amount can be increased through autoregulation by inducing relaxation of smooth muscle.
The capillaries do not possess this smooth muscle in their own walls, and so any change in their diameter is passive. Any signalling molecules they release (such as endothelin for constriction and nitric oxide for dilation) act on the smooth muscle cells in the walls of nearby, larger vessels, e.g. arterioles.
# Types
Capillaries come in three types:
- Continuous - Continuous capillaries have a sealed endothelium and only allow small molecules, water and ions to diffuse.
- Fenestrated - Fenestrated capillaries (derived from "fenestra," the Latin word for "window") have openings that allow larger molecules to diffuse.[2]
- Sinusoidal - Sinusoidal capillaries are special forms of fenestrated capillaries that have larger openings in the epithelium allowing red blood cells and serum proteins to enter. | https://www.wikidoc.org/index.php/Blood_capillary | |
22d7de6511e387a9e85aba712d2c0c4591d4fb0b | wikidoc | Dyscrasia | Dyscrasia
Dyscrasia (from Greek "Dyskrasia", meaning bad mixture), in Ancient Greek medicine,(This word is given in Aphorism 79 or Organon of Medicine by Dr. Samuel Hahnemann.)
is the imbalance of the four humours (blood, black bile, yellow bile, and water(phlegm)) which were believed to exist in the body, and were believed to be the direct cause of all disease. This is similar to the Asian concept of Yin and Yang; it was believed that imbalance of the two polarities caused ailment.
It is still occasionally used in medical context for an unspecified disorder of the blood. Specifically it is defined in current medicine as a morbid general state resulting from the presence of abnormal material in the blood, usually applied to diseases affecting blood cells or platelets. 1
Antimetabolitic Agents such as Leucovorin, Methotrexate, etc. may cause blood dyscrasias. | Dyscrasia
Dyscrasia (from Greek "Dyskrasia", meaning bad mixture), in Ancient Greek medicine,(This word is given in Aphorism 79 or Organon of Medicine by Dr. Samuel Hahnemann.)
is the imbalance of the four humours (blood, black bile, yellow bile, and water(phlegm)) which were believed to exist in the body, and were believed to be the direct cause of all disease. This is similar to the Asian concept of Yin and Yang; it was believed that imbalance of the two polarities caused ailment.
It is still occasionally used in medical context for an unspecified disorder of the blood. Specifically it is defined in current medicine as a morbid general state resulting from the presence of abnormal material in the blood, usually applied to diseases affecting blood cells or platelets. 1
Antimetabolitic Agents such as Leucovorin, Methotrexate, etc. may cause blood dyscrasias.
Template:Disease-stub | https://www.wikidoc.org/index.php/Blood_dyscrasia | |
26349273d1760b83b33dea91ef4f8ddb64b2b18a | wikidoc | Bloodroot | Bloodroot
Bloodroot (Sanguinaria canadensis) is a perennial, herbaceous flowering plant native to eastern North America from Nova Scotia, Canada southward to Florida, United States. It is the only species in the genus Sanguinaria, and is included in the family Papaveraceae and most closely related to Eomecon of eastern Asia.
Bloodroot is also known as bloodwort, red puccoon root, and sometimes pauson. Bloodroot has also been known as tetterwort in America, although that name is used in Britain to refer to Greater Celandine.
Bloodroot is a variable species growing from 20 to 50 cm tall, normally with one large, sheath-like basal multi-lobed leaf up to 12 cm across. The flowers are produced from March to May, with 8-12 delicate white petals and yellow reproductive parts. The flowers appear over clasping leaves while blooming. Plants are variable in leaf and flower shape and have in the past been separated out as different subspecies do to these variable shapes; currently most taxonomic treatments lump these different forms into one highly variable species. Bloodroot stores sap in an orange colored rhizome, that grows shallowly under or at the soil surface. Over many years of growth, the branching rhizome can grow into a large colony. Plants start to bloom before the foliage unfolds in early spring and after blooming the leaves expand to their full size and go summer dormant in mid to late summer. Plants are found growing in moist to dry woods and thickets, often on flood plains and near shores or streams on slopes, they grow less frequently in clearings and meadows or on dunes, and are rarely found in disturbed sites. The flowers are pollinated by small bees and flies, seeds develop in elongated green pods 40 to 60 mm in length and ripen before the foliage goes dormant. The seeds are round in shape and when ripe are black to orange-red in color. Deer will feed on the plants in early spring.
Caution: the sap is toxic; see below for further details.
# Reproduction and genetics
Bloodroot is one of many plants whose seeds are spread by ants, a process called myrmecochory. The seeds have a fleshy organ called an elaiosome that attracts ants. The ants take the seeds to their nest, where they eat the elaiosomes, and put the seeds in their nest debris, where they are protected until they germinate. They also get the added bonus of growing in a medium made richer by the ant nest debris.
The double flowering forms are prized by gardeners for their large showy white flowers, which are produced very early in the gardening season. Bloodroot flower petals are shed with in a day or two of pollination so the flower display is short lived. The double forms bloom much longer than the normal forms, the double flowers are made up of stamens that have been changed into petal looking like parts, making pollination more difficult.
# Bloodroot produces morphine-like alkaloids
Bloodroot produces benzylisoquinoline alkaloids, primarily the toxin sanguinarine. The alkaloids are transported to, and stored in, the rhizome.
In comparing the biosynthesis of morphine and sanguinarine, the final intermediate in common is (S)-reticuline. A number of plants in Papaveraceae and Ranunculaceae, as well as plants in the genus Colchicum (family Colchicaceae) and genus Chondodendron (family Menispermaceae), also produce such benzylisoquinoline alkaloids.
Plant geneticists have identified and sequenced genes which produce the enzymes required for this production. One enzyme involved is CYP80B1, which produces (S)-3'-hydroxy-N-methylcoclaurine from (S)-N-methylcoclaurine.
## Bloodroot extracts are toxic to animal cells
Sanguinarine kills animal cells by blocking the action of Na+/K+-ATPase transmembrane proteins. As a result, applying bloodroot to the skin may destroy tissue and lead to the formation of a large scab, called an eschar. Bloodroot and its extracts are thus considered escharotic.
In spite of supposed curative properties, and historical use by Native Americans as an emetic, internal use is inadvisable. Although applying escharotic agents, including bloodroot, to the skin is sometimes suggested as a home treatment to remove skin cancers, these attempts can be severely disfiguring . Salves derived from bloodroot cannot be relied on to remove an entire malignant tumor. Microscopic tumor deposits may remain after visible tumor tissue is burned away, and case reports have shown that in such instances tumor has recurred and/or metastasized.
On 13 Aug 2005, U.S. news media reported that Dan Raber (of Georgia, United States) came under felony investigation for dispensing bloodroot paste to women with various ailments including breast cancer. It was reported that nine women developed disfiguring destruction of skin and underlying tissue. Reports also indicated that Lois March, M.D., who is a practicing physician in Cordele, Georgia, has also come under U.S. FDA investigation for her role in prescribing pain medication to Raber's disfigured customers while their use of bloodroot was ongoing.
## Commercial uses of sanguinarine extracted from bloodroot
The United States FDA has approved the inclusion of sanguinarine in toothpastes as an antibacterial or anti-plaque agent. Currently, it is believed that this use may cause leukoplakia, a premalignant oral lesion. On 24 Nov 2003, the Colgate-Palmolive Company of Piscataway, New Jersey, United States commented by memorandum (see: PDF file) to the United States Food and Drug Administration that then-proposed rules for levels of sanguinarine in mouthwash and dental wash products were lower than necessary. Professor George T. Gallagher also commented from his post at Boston University Goldman School of Dental Medicine, see his memorandum of 23 June 2003.
Sangrovit® is an animal food additive sold and distributed in Europe. Sangrovit is manufactured by Germany-based Phytobiotics. Sangrovit contains sanguinarine and chelerythrine. On 14 May 2003, Cat Holmes reported in the Georgia Faces that Jim Affolter and Selima Campbell, horticulturists at the University of Georgia College of Agricultural and Environmental Sciences, were meeting with Phytobiotics to relate their research into commercial cultivation of bloodroot. It is also used in the mole remover Dermatend.
# Historical use of Bloodroot and derivatives
The plant was used as a dye and for an herbal remedy by the native population. A break in the surface of the plant, especially the roots, reveals a reddish sap.
In physician William Cook's 1869 work The Physiomedical Dispensatory is recorded a chapter on the uses and preparations of bloodroot. described tinctures and extractions, and also included at least the following cautionary report:
The U. S. Dispensatory says four persons lost their lives at Bellevue Hospital, New York, by drinking largely of blood root tincture in mistake for ardent spirits
Greater Celandine (Chelidonium majus), a member of the Poppy family (Papaveraceae) was used in Colonial America as a wart remedy. Bloodroot has been similarly applied in the past. This may explain the multiple American and British definitions of "Tetterwort" in 1913. | Bloodroot
Bloodroot (Sanguinaria canadensis) is a perennial, herbaceous flowering plant native to eastern North America from Nova Scotia, Canada southward to Florida, United States. It is the only species in the genus Sanguinaria, and is included in the family Papaveraceae and most closely related to Eomecon of eastern Asia.
Bloodroot is also known as bloodwort, red puccoon root, and sometimes pauson. Bloodroot has also been known as tetterwort in America, although that name is used in Britain to refer to Greater Celandine.
Bloodroot is a variable species growing from 20 to 50 cm tall, normally with one large, sheath-like basal multi-lobed leaf up to 12 cm across. The flowers are produced from March to May, with 8-12 delicate white petals and yellow reproductive parts. The flowers appear over clasping leaves while blooming. Plants are variable in leaf and flower shape and have in the past been separated out as different subspecies do to these variable shapes; currently most taxonomic treatments lump these different forms into one highly variable species. Bloodroot stores sap in an orange colored rhizome, that grows shallowly under or at the soil surface. Over many years of growth, the branching rhizome can grow into a large colony. Plants start to bloom before the foliage unfolds in early spring and after blooming the leaves expand to their full size and go summer dormant in mid to late summer. Plants are found growing in moist to dry woods and thickets, often on flood plains and near shores or streams on slopes, they grow less frequently in clearings and meadows or on dunes, and are rarely found in disturbed sites. The flowers are pollinated by small bees and flies, seeds develop in elongated green pods 40 to 60 mm in length and ripen before the foliage goes dormant. The seeds are round in shape and when ripe are black to orange-red in color. Deer will feed on the plants in early spring.
Caution: the sap is toxic; see below for further details.
# Reproduction and genetics
Bloodroot is one of many plants whose seeds are spread by ants, a process called myrmecochory. The seeds have a fleshy organ called an elaiosome that attracts ants. The ants take the seeds to their nest, where they eat the elaiosomes, and put the seeds in their nest debris, where they are protected until they germinate. They also get the added bonus of growing in a medium made richer by the ant nest debris.
The double flowering forms are prized by gardeners for their large showy white flowers, which are produced very early in the gardening season. Bloodroot flower petals are shed with in a day or two of pollination so the flower display is short lived. The double forms bloom much longer than the normal forms, the double flowers are made up of stamens that have been changed into petal looking like parts, making pollination more difficult.
# Bloodroot produces morphine-like alkaloids
Bloodroot produces benzylisoquinoline alkaloids, primarily the toxin sanguinarine. The alkaloids are transported to, and stored in, the rhizome.
In comparing the biosynthesis of morphine and sanguinarine, the final intermediate in common is (S)-reticuline.[1][2][3] A number of plants in Papaveraceae and Ranunculaceae, as well as plants in the genus Colchicum (family Colchicaceae) and genus Chondodendron (family Menispermaceae), also produce such benzylisoquinoline alkaloids.
Plant geneticists have identified and sequenced genes which produce the enzymes required for this production. One enzyme involved is CYP80B1,[4] which produces (S)-3'-hydroxy-N-methylcoclaurine from (S)-N-methylcoclaurine.[5]
## Bloodroot extracts are toxic to animal cells
Sanguinarine kills animal cells by blocking the action of Na+/K+-ATPase transmembrane proteins. As a result, applying bloodroot to the skin may destroy tissue and lead to the formation of a large scab, called an eschar. Bloodroot and its extracts are thus considered escharotic.
In spite of supposed curative properties, and historical use by Native Americans as an emetic, internal use is inadvisable. Although applying escharotic agents, including bloodroot, to the skin is sometimes suggested as a home treatment to remove skin cancers, these attempts can be severely disfiguring [6]. Salves derived from bloodroot cannot be relied on to remove an entire malignant tumor. Microscopic tumor deposits may remain after visible tumor tissue is burned away, and case reports have shown that in such instances tumor has recurred and/or metastasized. [7]
On 13 Aug 2005, U.S. news media reported that Dan Raber (of Georgia, United States) came under felony investigation for dispensing bloodroot paste to women with various ailments including breast cancer. It was reported that nine women developed disfiguring destruction of skin and underlying tissue. Reports also indicated that Lois March, M.D., who is a practicing physician in Cordele, Georgia, has also come under U.S. FDA investigation for her role in prescribing pain medication to Raber's disfigured customers while their use of bloodroot was ongoing.[8][9][10]
## Commercial uses of sanguinarine extracted from bloodroot
The United States FDA has approved the inclusion of sanguinarine in toothpastes as an antibacterial or anti-plaque agent.[11][12][13][14] Currently, it is believed that this use may cause leukoplakia, a premalignant oral lesion.[15] On 24 Nov 2003, the Colgate-Palmolive Company of Piscataway, New Jersey, United States commented by memorandum (see: PDF file) to the United States Food and Drug Administration that then-proposed rules for levels of sanguinarine in mouthwash and dental wash products were lower than necessary. Professor George T. Gallagher also commented from his post at Boston University Goldman School of Dental Medicine, see his memorandum[1] of 23 June 2003.
Sangrovit® is an animal food additive sold and distributed in Europe. Sangrovit is manufactured by Germany-based Phytobiotics. Sangrovit contains sanguinarine and chelerythrine. On 14 May 2003, Cat Holmes reported in the Georgia Faces[16] that Jim Affolter and Selima Campbell, horticulturists at the University of Georgia College of Agricultural and Environmental Sciences, were meeting with Phytobiotics to relate their research into commercial cultivation of bloodroot. It is also used in the mole remover Dermatend.
# Historical use of Bloodroot and derivatives
The plant was used as a dye and for an herbal remedy by the native population. A break in the surface of the plant, especially the roots, reveals a reddish sap.
In physician William Cook's 1869 work The Physiomedical Dispensatory is recorded a chapter on the uses and preparations of bloodroot.[17] described tinctures and extractions, and also included at least the following cautionary report:
The U. S. Dispensatory says four persons lost their lives at Bellevue Hospital, New York, by drinking largely of blood root tincture in mistake for ardent spirits [...]
Greater Celandine (Chelidonium majus), a member of the Poppy family (Papaveraceae) was used in Colonial America as a wart remedy. Bloodroot has been similarly applied in the past. This may explain the multiple American and British definitions of "Tetterwort" in 1913. | https://www.wikidoc.org/index.php/Bloodroot | |
1473c62655ca706b0fc8d32776eb402d7090431e | wikidoc | Body odor | Body odor
Bromhidrosis or body odor (also called bromidrosis, osmidrosis and ozochrotia) is the smell of bacteria growing on the body. These bacteria multiply considerably in the presence of sweat, but sweat itself is almost totally odorless. Body odor is associated with the hair, feet, groin (upper medial thigh), anus, skin in general, armpits, genitals, pubic hair, and mouth.
# Specificity
Body odor is specific to the individual, and can be used to identify people, though this is more often done by dogs than by humans. An individual's body odor is also influenced by diet, gender, genetics, health, medication, and mood.
# Genetics
Body odor is largely influenced by the major histocompatibility complex (MHC) molecules. These are genetically determined and play an important role in immunity of the organism. The vomeronasal organ contains cells sensitive to MHC molecules in a genotype-specific way. Experiments on animals and volunteers shown the potential sexual partners tend to be perceived more attractive if their MHC composition is substantially different. This behavior pattern promotes variability of the immune system of individuals in the population, thus making the population more robust against new diseases.
A recent study suggests that body odor is genetically determined by a gene that also codes the type of earwax one has. East Asians evidently have a greater chance of having the 'dry' earwax type and reduced axial sweating and odor. This may be due to adaptation to colder climates.
# Treatment
Although body odor is commonly associated with hygiene, its presentation can be affected by changes in diet. The use of anti-bacterial soap while bathing is recommended. | Body odor
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Bromhidrosis or body odor (also called bromidrosis, osmidrosis and ozochrotia) is the smell of bacteria growing on the body. These bacteria multiply considerably in the presence of sweat, but sweat itself is almost totally odorless. Body odor is associated with the hair, feet, groin (upper medial thigh), anus, skin in general, armpits, genitals, pubic hair, and mouth.
# Specificity
Body odor is specific to the individual, and can be used to identify people, though this is more often done by dogs than by humans. An individual's body odor is also influenced by diet, gender, genetics, health, medication, and mood.
# Genetics
Body odor is largely influenced by the major histocompatibility complex (MHC) molecules. These are genetically determined and play an important role in immunity of the organism. The vomeronasal organ contains cells sensitive to MHC molecules in a genotype-specific way. Experiments on animals and volunteers shown the potential sexual partners tend to be perceived more attractive if their MHC composition is substantially different. This behavior pattern promotes variability of the immune system of individuals in the population, thus making the population more robust against new diseases.
A recent study suggests that body odor is genetically determined by a gene that also codes the type of earwax one has.[1][2] East Asians evidently have a greater chance of having the 'dry' earwax type and reduced axial sweating and odor. This may be due to adaptation to colder climates.
# Treatment
Although body odor is commonly associated with hygiene, its presentation can be affected by changes in diet.[3] The use of anti-bacterial soap while bathing is recommended. | https://www.wikidoc.org/index.php/Body_odor | |
2093fec8816df70e7a91ba7ce30d912643b04acc | wikidoc | Boldenone | Boldenone
# Overview
Boldenone (1,4-androstadiene-3-one-17β-ol, available as the undecylenate ester), also known under the trade names Equipoise, Ganabol, Equigan and Ultragan, is an anabolic steroid developed for veterinary use, mostly for treatment of horses. It is not indicated for use in humans in the US and is only available through veterinary clinics.
The activity of boldenone is mainly anabolic, with a low androgenic potency. It has a very long half-life, and can show up on a steroid test for up to 5 months.
Boldenone will increase nitrogen retention, protein synthesis, increases appetite and stimulates the release of erythropoietin in the kidneys.
Because it has similar properties to methandienone (methylated boldenone), it is a favorite for adding strength and size. Boldenone is popular for bulking because it increases the appetite. Boldenone is well known for increasing vascularity.
Boldenone has a low rate of aromatization (about 50% of Testosterone), which means it does not convert to estrogen easily and does not cause very much water retention.
It is easily detectable in blood tests due to its long metabolic half-life. Trace amounts of the drug can easily be detected for months after discontinued use.
# Side effects
Although commonly compared to nandrolone, boldenone lacks progesterone receptor interaction and all the associated progestinic side effects. Boldenone can, however, produce mild androgenic side effects. Oily skin, acne, increased aggression and hair loss are all possible with this compound but rare. Boldenone does reduce to a more potent androgen dihydroboldenone via the 5alpha-reductase enzyme (analogous to the conversion of testosterone to dihydrotestosterone (DHT), however its affinity for this interaction in the human body is low to nonexistent. Suppression of the HPTA, water retention, possible increase in acne and possible conversion to estrogen, high blood pressure are all side effects associated with Boldenone. Boldenone is also known to cause anxiety and flu like symptoms which manifest themselves most acutely in short ester versions like: acetate, and propionate (almost unusable), but which are also present in the enanthate, cypionate, and undecyclenate forms. | Boldenone
# Overview
Boldenone (1,4-androstadiene-3-one-17β-ol, available as the undecylenate ester), also known under the trade names Equipoise, Ganabol, Equigan and Ultragan, is an anabolic steroid developed for veterinary use, mostly for treatment of horses. It is not indicated for use in humans in the US and is only available through veterinary clinics.
The activity of boldenone is mainly anabolic, with a low androgenic potency. It has a very long half-life, and can show up on a steroid test for up to 5 months.
Boldenone will increase nitrogen retention, protein synthesis, increases appetite and stimulates the release of erythropoietin in the kidneys.
Because it has similar properties to methandienone (methylated boldenone), it is a favorite for adding strength and size. Boldenone is popular for bulking because it increases the appetite. Boldenone is well known for increasing vascularity.
Boldenone has a low rate of aromatization (about 50% of Testosterone), which means it does not convert to estrogen easily and does not cause very much water retention.
It is easily detectable in blood tests due to its long metabolic half-life. Trace amounts of the drug can easily be detected for months after discontinued use.
# Side effects
Although commonly compared to nandrolone, boldenone lacks progesterone receptor interaction and all the associated progestinic side effects. Boldenone can, however, produce mild androgenic side effects. Oily skin, acne, increased aggression and hair loss are all possible with this compound but rare. Boldenone does reduce to a more potent androgen dihydroboldenone via the 5alpha-reductase enzyme (analogous to the conversion of testosterone to dihydrotestosterone (DHT), however its affinity for this interaction in the human body is low to nonexistent. Suppression of the HPTA, water retention, possible increase in acne and possible conversion to estrogen, high blood pressure are all side effects associated with Boldenone. Boldenone is also known to cause anxiety and flu like symptoms which manifest themselves most acutely in short ester versions like: acetate, and propionate (almost unusable), but which are also present in the enanthate, cypionate, and undecyclenate forms. | https://www.wikidoc.org/index.php/Boldenone | |
5e8a818698170279a2b23b255d2958b58c07ec60 | wikidoc | Bolometer | Bolometer
A bolometer is a device for measuring the energy of incident electromagnetic radiation. It was invented in 1878 by the American astronomer Samuel Pierpont Langley.
It consists of an "absorber" connected to a heat sink (area of constant temperature) through an insulating link. The result is that any radiation absorbed by the absorber raises its temperature above that of the heat sink—the higher the energy absorbed, the higher the temperature will be. Temperature change can be measured directly or via an attached thermometer (composite design).
While bolometers can be used to measure radiation energy of any frequency, for most wavelength ranges there are other methods of detection that are more sensitive. However, for sub-millimetre wavelengths (from around 200 µm to 1 mm wavelength), the bolometer is the most sensitive detector for any measurement over more than a very narrow wavelength range.
Bolometers are therefore used for astronomy at these wavelengths. However, to achieve the best sensitivity, they must be cooled down to a fraction of a degree above absolute zero (typically from 50 millikelvins to 300 mK).
Bolometers are directly sensitive to the energy left inside the absorber. For this reason they can be used not only for ionizing particles and photons, but also for non-ionizing particles, for any sort of radiation and even to search for unknown forms of mass or energy (like dark matter); this lack of discrimination can also be a shortcoming. They are very slow to respond and slow to reset (i.e., return to thermal equilibrium with the environment). On the other hand, compared to more conventional particle detectors, they are extremely efficient in energy resolution and in sensitivity. They can be used to test very high radio-purity. They are also known as thermal detectors.
The term bolometer is also used in particle physics to designate an unconventional particle detector. They use the same principle described above. The bolometers are sensitive not only to light but to every form of energy.
The operating principle is similar to that of a calorimeter in thermodynamics. However, the approximations, ultra low temperature, and the different purpose of the device make the operational use rather different. In the jargon of high energy physics, these devices are not called calorimeters since this term is already used for a different type of detector (see Calorimeter (particle physics)).
Their use as particle detectors is still at the developmental stage. Their use as particle detectors was proposed from the beginning of the 20th century, but the first regular, though pioneering, use was only in the 1980s because of the difficulty associated with having a system at cryogenic temperature.
# Langley's bolometer
The first bolometer used for infrared observations by Langley had a very basic design: It consisted of two platinum strips, covered with lampblack, one strip was shielded from the radiation and one exposed to it. The strips formed two branches of a wheatstone bridge which was fitted with a sensitive galvanometer and connected to a battery.
Electromagnetic radiation falling on the exposed strip would heat it, and change its resistance, the circuit thus effectively operating as a resistance temperature detector.
This instrument enabled him to feel his way thermally over the whole spectrum, noting all the chief Fraunhofer lines and bands, which were shown by sharp serrations, or more prolonged depressions of the curve which gave the emissions, and discovered the lines and bands of the invisible infra-red portion.
# Microbolometers
A microbolometer is a specific type of bolometer used as a detector in a thermal camera. It is a grid of vanadium oxide or amorphous silicon heat sensors atop a corresponding grid of silicon. Infrared radiation from a specific range of wavelengths strikes the vanadium oxide and changes its electrical resistance. This resistance change is measured and processed into temperatures which can be represented graphically. The microbolometer grid is commonly found in three sizes, a 640x480 array, a 320×240 array or less expensive 160×120 array. Both arrays provide the same resolution with the larger array providing a wider field of view. Larger, 1024x768 arrays were announced in 2008.
# Cold-electron Bolometer
A cold-electron bolometer uses a SIN (superconducting, insulator, normal metal) junction. The incoming photon is received from a waveguide into the normal metal. It gives its energy to an electron that becomes excited. The significantly increased energy of that electron causes it to tunnel through the narrow insulator layer into the superconductor where it gives rise to a current, that in turn can be measured. The advantage with this is that the absorber is at the same time cooled due to the energy loss. | Bolometer
A bolometer is a device for measuring the energy of incident electromagnetic radiation. It was invented in 1878 by the American astronomer Samuel Pierpont Langley.
It consists of an "absorber" connected to a heat sink (area of constant temperature) through an insulating link. The result is that any radiation absorbed by the absorber raises its temperature above that of the heat sink—the higher the energy absorbed, the higher the temperature will be. Temperature change can be measured directly or via an attached thermometer (composite design).
While bolometers can be used to measure radiation energy of any frequency, for most wavelength ranges there are other methods of detection that are more sensitive. However, for sub-millimetre wavelengths (from around 200 µm to 1 mm wavelength), the bolometer is the most sensitive detector for any measurement over more than a very narrow wavelength range.
Bolometers are therefore used for astronomy at these wavelengths. However, to achieve the best sensitivity, they must be cooled down to a fraction of a degree above absolute zero (typically from 50 millikelvins to 300 mK).
Bolometers are directly sensitive to the energy left inside the absorber. For this reason they can be used not only for ionizing particles and photons, but also for non-ionizing particles, for any sort of radiation and even to search for unknown forms of mass or energy (like dark matter); this lack of discrimination can also be a shortcoming. They are very slow to respond and slow to reset (i.e., return to thermal equilibrium with the environment). On the other hand, compared to more conventional particle detectors, they are extremely efficient in energy resolution and in sensitivity. They can be used to test very high radio-purity. They are also known as thermal detectors.
The term bolometer is also used in particle physics to designate an unconventional particle detector. They use the same principle described above. The bolometers are sensitive not only to light but to every form of energy.
The operating principle is similar to that of a calorimeter in thermodynamics. However, the approximations, ultra low temperature, and the different purpose of the device make the operational use rather different. In the jargon of high energy physics, these devices are not called calorimeters since this term is already used for a different type of detector (see Calorimeter (particle physics)).
Their use as particle detectors is still at the developmental stage. Their use as particle detectors was proposed from the beginning of the 20th century, but the first regular, though pioneering, use was only in the 1980s because of the difficulty associated with having a system at cryogenic temperature.
# Langley's bolometer
The first bolometer used for infrared observations by Langley had a very basic design: It consisted of two platinum strips, covered with lampblack, one strip was shielded from the radiation and one exposed to it. The strips formed two branches of a wheatstone bridge which was fitted with a sensitive galvanometer and connected to a battery.
Electromagnetic radiation falling on the exposed strip would heat it, and change its resistance, the circuit thus effectively operating as a resistance temperature detector.
This instrument enabled him to feel his way thermally over the whole spectrum, noting all the chief Fraunhofer lines and bands, which were shown by sharp serrations, or more prolonged depressions of the curve which gave the emissions, and discovered the lines and bands of the invisible infra-red portion.
# Microbolometers
A microbolometer is a specific type of bolometer used as a detector in a thermal camera. It is a grid of vanadium oxide or amorphous silicon heat sensors atop a corresponding grid of silicon. Infrared radiation from a specific range of wavelengths strikes the vanadium oxide and changes its electrical resistance. This resistance change is measured and processed into temperatures which can be represented graphically. The microbolometer grid is commonly found in three sizes, a 640x480 array, a 320×240 array or less expensive 160×120 array. Both arrays provide the same resolution with the larger array providing a wider field of view. Larger, 1024x768 arrays were announced in 2008.
# Cold-electron Bolometer
A cold-electron bolometer uses a SIN (superconducting, insulator, normal metal) junction. The incoming photon is received from a waveguide into the normal metal. It gives its energy to an electron that becomes excited. The significantly increased energy of that electron causes it to tunnel through the narrow insulator layer into the superconductor where it gives rise to a current, that in turn can be measured. The advantage with this is that the absorber is at the same time cooled due to the energy loss. | https://www.wikidoc.org/index.php/Bolometer | |
f975d5945f0a2b1092cc7ffdac5405e515051a7e | wikidoc | Bone pain | Bone pain
Synonyms and keywords: Ostealgia; Osteodynia.
# Overview
Bone pain is a debilitating form of pain emanating from the bone tissue. It occurs as a result of a wide range of diseases and/or physical conditions and may severely impair the quality of life for patients who suffer from it. Bone pain has multiple causes, such as extensive physical stress and diseases such as cancer.
For many years it has been known that bones are innervated with sensory neurons. Yet their exact anatomy remained obscure due to the contrasting physical properties of bone and neural tissue. However, until recently, it was not determined what types of nerves innervated which sections of bone. The periosteal layer of bone tissue is highly pain-sensitive and an important cause of pain in several disease conditions causing bone pain, like fractures, osteoarthritis, etc. However, in certain diseases the endosteal and haversian nerve supply seems to play an important role, e.g. osteomalacia, osteonecrosis, and so on. Thus there are several types of bone pain, each with many potential sources or origins of cause.
# Pathophysiology
Stimulation of specialized pain-sensitive nerve fibers (nociceptors) that innervate bone tissue leads to the sensation of bone pain. Bone pain originates from both the periosteum and the bone marrow which relay nociceptive signals to the brain creating the sensation of pain. Bone tissue is innervated by both myelinated (A beta and A delta fiber) and unmyelinated (C fiber) sensory neurons. In combination, they can provide an initial burst of pain, initiated by the faster myelinated fibers, followed by a slower and longer lasting dull pain initiated by unmyelinated fibers.
Nociceptors responsible for bone pain can be activated via several mechanisms including deterioration of surrounding tissue, bone destruction, and physical stress which shears the bone, vascular, muscle, and nervous tissue.
# Bone Cancer
Bone cancer is one of the most serious forms of pain. Because of its severity and uniqueness with respect to other forms of pain, it is extensively researched. According to studies of bone cancer in mouse femur models, it has been determined that bone pain related to cancer occurs as a result of destruction of bone tissue. Chemical changes that occur within the spinal cord as a result of bone destruction give further insight into the mechanism of bone pain.
Metastatic cancer cells often aim to establish themselves within the skeleton. When the cancer cells have metastasized, the mechanical dynamics of the bone matrix become weaker as skeletal strength decreases. This leads to several other complications throughout the body including pain, thus decreasing the patient’s quality of life.
Bone tumors are composed of a conglomeration of cell types including cancer and immune system cells. Oftentimes tumor cells secrete growth factors which activate receptors close to primary afferent neurons. Activation of these neural receptors is a contributing factor to pain sensation. Additionally, inflammatory lipids called prostaglandins, which are produced at high rates by cancer cells within tumors, activate nociceptors when they bind together.
# Diseases affecting bones
- Viral illness (such as a cold that has spread to the bones/joints)
- Leukemia (blasts that have surfaced to the top of the bone, often with tenderness)less common)
- Blood infection (anemia/other)
- Trauma to the bone (such as a fall)
- Arthritis pain
- Weather changes
- Fibromyalgia (widespread body pain with tenderness)
- Cancer - can be primary bone tumor or spread from another cancer known as a Bony metastasis.
- Paget's disease
- Osteoporosis
# Causes
## Common Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Treatment
The use of anesthetics within the actual bone has been a common treatment for several years. This method provides a direct approach using analgesics to relieve pain sensations.
Another commonly used method for treating bone pain is radiotherapy, which can be safely administered in low doses. Radiotherapy utilizes radioactive isotopes and other atomic particles to damage the DNA in cells, thus leading to cell death. By targeting cancer tumors, radiotherapy can lead to decrease in tumor size and even tumor destruction. A form of radiotherapy that is often used in cases of bone cancer is systemic radioisotope therapy, where the radioisotopes target sections of the bone specifically undergoing metastasis.
In the case of bone fractures, surgical treatment is generally the most effective. Analgesics can be used in conjunction with surgery to help ease pain of damaged bone.
# Scientific Research and Future Treatments
Mouse and other animal models are being heavily used to determine the neuron tissue densities in bone and mechanisms for maintenance of bone pain. This information is pertinent to determining the biological and physiological components of pain in the bone. By creating a detailed map relating the types of nerves going through the different sections of bone, it is possible to pin-point locations in the bone that are at a higher risk of being susceptible to bone pain.
Treatments focusing on biological components such as cannabinoid receptors are being tested for effectiveness. Through testing in mouse models, it has been shown that activation of the CB-1 receptor helps reduce reactions associated with acute pain, indicating that it alleviates bone pain. Thus, a new target for potential treatments is activation of the CB-1 receptor.
Modern research and techniques are attempting to provide longer lasting and more effective methods of treating bone pain by developing and applying new physiological knowledge of nervous tissue within the bone. If thorough understanding of the intra-neuronal mechanisms relating to pain can be developed, then new and more effective treatment options can be created and tested. Thus, it is critical to fully understand the mechanism which dictates bone pain. | Bone pain
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Ostealgia; Osteodynia.
# Overview
Bone pain is a debilitating form of pain emanating from the bone tissue. It occurs as a result of a wide range of diseases and/or physical conditions and may severely impair the quality of life for patients who suffer from it.[1] Bone pain has multiple causes, such as extensive physical stress and diseases such as cancer.[2][3]
For many years it has been known that bones are innervated with sensory neurons. Yet their exact anatomy remained obscure due to the contrasting physical properties of bone and neural tissue.[4] However, until recently, it was not determined what types of nerves innervated which sections of bone.[5] The periosteal layer of bone tissue is highly pain-sensitive and an important cause of pain in several disease conditions causing bone pain, like fractures, osteoarthritis, etc. However, in certain diseases the endosteal and haversian nerve supply seems to play an important role, e.g. osteomalacia, osteonecrosis, and so on.[6] Thus there are several types of bone pain, each with many potential sources or origins of cause.
# Pathophysiology
Stimulation of specialized pain-sensitive nerve fibers (nociceptors) that innervate bone tissue leads to the sensation of bone pain. Bone pain originates from both the periosteum and the bone marrow which relay nociceptive signals to the brain creating the sensation of pain. Bone tissue is innervated by both myelinated (A beta and A delta fiber) and unmyelinated (C fiber) sensory neurons. In combination, they can provide an initial burst of pain, initiated by the faster myelinated fibers, followed by a slower and longer lasting dull pain initiated by unmyelinated fibers.[3][5]
Nociceptors responsible for bone pain can be activated via several mechanisms including deterioration of surrounding tissue, bone destruction,[1] and physical stress which shears the bone, vascular, muscle, and nervous tissue.
# Bone Cancer
Bone cancer is one of the most serious forms of pain. Because of its severity and uniqueness with respect to other forms of pain, it is extensively researched. According to studies of bone cancer in mouse femur models, it has been determined that bone pain related to cancer occurs as a result of destruction of bone tissue. Chemical changes that occur within the spinal cord as a result of bone destruction give further insight into the mechanism of bone pain.[1]
Metastatic cancer cells often aim to establish themselves within the skeleton. When the cancer cells have metastasized, the mechanical dynamics of the bone matrix become weaker as skeletal strength decreases. This leads to several other complications throughout the body including pain, thus decreasing the patient’s quality of life.[7]
Bone tumors are composed of a conglomeration of cell types including cancer and immune system cells. Oftentimes tumor cells secrete growth factors which activate receptors close to primary afferent neurons. Activation of these neural receptors is a contributing factor to pain sensation. Additionally, inflammatory lipids called prostaglandins, which are produced at high rates by cancer cells within tumors, activate nociceptors when they bind together.[3]
# Diseases affecting bones
- Viral illness (such as a cold that has spread to the bones/joints)
- Leukemia (blasts that have surfaced to the top of the bone, often with tenderness)less common)
- Blood infection (anemia/other)
- Trauma to the bone (such as a fall)
- Arthritis pain
- Weather changes
- Fibromyalgia (widespread body pain with tenderness)
- Cancer - can be primary bone tumor or spread from another cancer known as a Bony metastasis.
- Paget's disease
- Osteoporosis
# Causes
## Common Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Treatment
The use of anesthetics within the actual bone has been a common treatment for several years. This method provides a direct approach using analgesics to relieve pain sensations.[4]
Another commonly used method for treating bone pain is radiotherapy, which can be safely administered in low doses. Radiotherapy utilizes radioactive isotopes and other atomic particles to damage the DNA in cells, thus leading to cell death. By targeting cancer tumors, radiotherapy can lead to decrease in tumor size and even tumor destruction.[8] A form of radiotherapy that is often used in cases of bone cancer is systemic radioisotope therapy, where the radioisotopes target sections of the bone specifically undergoing metastasis.
In the case of bone fractures, surgical treatment is generally the most effective. Analgesics can be used in conjunction with surgery to help ease pain of damaged bone.[8]
# Scientific Research and Future Treatments
Mouse and other animal models are being heavily used to determine the neuron tissue densities in bone[5] and mechanisms for maintenance of bone pain.[1] This information is pertinent to determining the biological and physiological components of pain in the bone. By creating a detailed map relating the types of nerves going through the different sections of bone, it is possible to pin-point locations in the bone that are at a higher risk of being susceptible to bone pain.
Treatments focusing on biological components such as cannabinoid receptors are being tested for effectiveness. Through testing in mouse models, it has been shown that activation of the CB-1 receptor helps reduce reactions associated with acute pain, indicating that it alleviates bone pain. Thus, a new target for potential treatments is activation of the CB-1 receptor.[9]
Modern research and techniques are attempting to provide longer lasting and more effective methods of treating bone pain by developing and applying new physiological knowledge of nervous tissue within the bone. If thorough understanding of the intra-neuronal mechanisms relating to pain can be developed, then new and more effective treatment options can be created and tested. Thus, it is critical to fully understand the mechanism which dictates bone pain. | https://www.wikidoc.org/index.php/Bone_pain | |
369064917220077c5d96203b16255995e25f9cc6 | wikidoc | Bone spur | Bone spur
# Overview
Bone spurs, also known as osteophytes, are bony projections that form along joints. Bone spurs form due to the body's increase of a damaged joint's surface area; most commonly from the onset of arthritis. Bone spurs usually limit joint movement and typically cause pain.
Bone spurs form naturally on the back of spine as a person ages and are a sign of degeneration in the spine. In this case the spurs are not the source of back pains, but instead are the common symptom of a deeper problem. However, bone spurs on the spine can impinge on nerves, which leave the spine for other parts of the body. This impingement can cause pain in both upper and lower limbs and a numbness or tingling sensations in the hands and feet due to the nerves supplying sensation to their dermatomes.
Spurs can also appear on the feet, either along toes or the heel, and can also occur on the hands. In extreme cases it has been known for these spurs to grow along a person's entire skeletal structure, along the knees, hips, shoulders, ribs, arms and ankles. Such cases are only exhibited with multiple exostosis.
Osteophytes on the fingers or toes are known as Heberden's nodes (if on the DIP joint) or Bouchard's nodes (if on the PIP joints).
Bone spurs may also be the end result of certain disease processes. Osteomyelitis, a bone infection, may leave the adjacent bone with a spur formation. Charcot foot, the neuropathic breakdown of the feet seen primarily in diabetics, will also leave bone spurs which may then become symptomatic.
# Cause
Osteophyte formation has been classically related to any sequential and consequential changes in bone formation due to aging, degeneration, mechanical instability, and disease. Often osteophytes form in osteoarthritic joints due to damage and wear from inflammation. Calcification and new bone formation can also occur in response to mechanical damage in joints, or at the attachment points for ligaments and tendons.
nl:Osteofyt
- ↑ MayoClinic.com
- ↑ Laser Spine Institute | Bone spur
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Bone spurs, also known as osteophytes, are bony projections that form along joints. Bone spurs form due to the body's increase of a damaged joint's surface area; most commonly from the onset of arthritis. Bone spurs usually limit joint movement and typically cause pain. [1]
Bone spurs form naturally on the back of spine as a person ages and are a sign of degeneration in the spine. In this case the spurs are not the source of back pains, but instead are the common symptom of a deeper problem. However, bone spurs on the spine can impinge on nerves, which leave the spine for other parts of the body. This impingement can cause pain in both upper and lower limbs and a numbness or tingling sensations in the hands and feet due to the nerves supplying sensation to their dermatomes[2]. [2]
Spurs can also appear on the feet, either along toes or the heel, and can also occur on the hands. In extreme cases it has been known for these spurs to grow along a person's entire skeletal structure, along the knees, hips, shoulders, ribs, arms and ankles. Such cases are only exhibited with multiple exostosis.
Osteophytes on the fingers or toes are known as Heberden's nodes (if on the DIP joint) or Bouchard's nodes (if on the PIP joints).
Bone spurs may also be the end result of certain disease processes. Osteomyelitis, a bone infection, may leave the adjacent bone with a spur formation. Charcot foot, the neuropathic breakdown of the feet seen primarily in diabetics, will also leave bone spurs which may then become symptomatic.
# Cause
Osteophyte formation has been classically related to any sequential and consequential changes in bone formation due to aging, degeneration, mechanical instability, and disease. Often osteophytes form in osteoarthritic joints due to damage and wear from inflammation. Calcification and new bone formation can also occur in response to mechanical damage in joints, or at the attachment points for ligaments and tendons.[3]
Template:Diseases of the musculoskeletal system and connective tissue
nl:Osteofyt
Template:WikiDoc Sources
- ↑ MayoClinic.com
- ↑ Laser Spine Institute
- ↑ [Osteophyte formation in the vertebral column: a review of etiologic factors- part 1. Contemporary Orthopaedics, 29(1): 31-37, 1994] | https://www.wikidoc.org/index.php/Bone_spur | |
dff116206445bbede9d0446e8b71b5eefaf0c4ff | wikidoc | Cyclizine | Cyclizine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Cyclizine is an antihistamine that is FDA approved for the treatment of and prevention of nausea, vomiting, or dizziness associated with motion sickness. For the treatment of vertigo of motion sickness. Common adverse reactions include drowsiness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Adults and children 12 years of age and over: 2 tablets every 4-6 hours, not to exceed 8 tablets in 24 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cyclizine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cyclizine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Adults and children 12 years of age and over: 2 tablets every 4-6 hours, not to exceed 8 tablets in 24 hours.
- Children 6 to under 12 years of age: 1 tablet every 6-8 hours, not to exceed 3 tablets in 24 hours.
- Children under 6 years of age: Consult a physician.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cyclizine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cyclizine in pediatric patients.
# Contraindications
There is limited information regarding Cyclizine Contraindications in the drug label.
# Warnings
- Do not exceed recommended dosage.
- Ask a doctor or pharmacist before use if you have a breathing problem such as emphysema or chronic bronchitis glaucoma difficulty in urination due to enlargement of the prostate gland
- Ask a doctor before use if you are taking sedatives, or tranquilizers.
- Do not give this product to children who have a breathing problem such as chronic bronchitis or who have glaucoma, without first consulting the child's doctor.
- Do not give to children under 6 years of age unless directed by a doctor.
- When using this product you may get drowsy avoid alcohol drinks alcohol, sedatives, and tranquilizers may increase the drowsiness effect be careful when driving a motor vehicle or operating machinery
- In case of overdose, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Cyclizine Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Cyclizine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Cyclizine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
If pregnant or breast-feeding, ask a health professional before use.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cyclizine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cyclizine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Cyclizine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Cyclizine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Cyclizine in geriatric settings.
### Gender
There is no FDA guidance on the use of Cyclizine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cyclizine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cyclizine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cyclizine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cyclizine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cyclizine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Cyclizine Administration in the drug label.
### Monitoring
There is limited information regarding Cyclizine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Cyclizine and IV administrations.
# Overdosage
There is limited information regarding Cyclizine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Cyclizine Mechanism of Action in the drug label.
## Structure
## Pharmacodynamics
There is limited information regarding Cyclizine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Cyclizine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Cyclizine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Cyclizine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Cyclizine How Supplied in the drug label.
## Storage
There is limited information regarding Cyclizine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cyclizine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Cyclizine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Marezine
- Bonine for Kids
- Cyclivert
# Look-Alike Drug Names
There is limited information regarding Cyclizine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cyclizine
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.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Cyclizine is an antihistamine that is FDA approved for the treatment of and prevention of nausea, vomiting, or dizziness associated with motion sickness. For the treatment of vertigo of motion sickness. Common adverse reactions include drowsiness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Adults and children 12 years of age and over: 2 tablets every 4-6 hours, not to exceed 8 tablets in 24 hours.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cyclizine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cyclizine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Adults and children 12 years of age and over: 2 tablets every 4-6 hours, not to exceed 8 tablets in 24 hours.
- Children 6 to under 12 years of age: 1 tablet every 6-8 hours, not to exceed 3 tablets in 24 hours.
- Children under 6 years of age: Consult a physician.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cyclizine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cyclizine in pediatric patients.
# Contraindications
There is limited information regarding Cyclizine Contraindications in the drug label.
# Warnings
- Do not exceed recommended dosage.
- Ask a doctor or pharmacist before use if you have a breathing problem such as emphysema or chronic bronchitis glaucoma difficulty in urination due to enlargement of the prostate gland
- Ask a doctor before use if you are taking sedatives, or tranquilizers.
- Do not give this product to children who have a breathing problem such as chronic bronchitis or who have glaucoma, without first consulting the child's doctor.
- Do not give to children under 6 years of age unless directed by a doctor.
- When using this product you may get drowsy avoid alcohol drinks alcohol, sedatives, and tranquilizers may increase the drowsiness effect be careful when driving a motor vehicle or operating machinery
- In case of overdose, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Cyclizine Clinical Trials Experience in the drug label.
## Postmarketing Experience
There is limited information regarding Cyclizine Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Cyclizine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
If pregnant or breast-feeding, ask a health professional before use.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cyclizine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cyclizine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Cyclizine in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Cyclizine in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Cyclizine in geriatric settings.
### Gender
There is no FDA guidance on the use of Cyclizine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cyclizine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cyclizine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cyclizine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cyclizine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cyclizine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Cyclizine Administration in the drug label.
### Monitoring
There is limited information regarding Cyclizine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Cyclizine and IV administrations.
# Overdosage
There is limited information regarding Cyclizine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Cyclizine Mechanism of Action in the drug label.
## Structure
## Pharmacodynamics
There is limited information regarding Cyclizine Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Cyclizine Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Cyclizine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Cyclizine Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Cyclizine How Supplied in the drug label.
## Storage
There is limited information regarding Cyclizine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cyclizine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Cyclizine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Marezine
- Bonine for Kids
- Cyclivert
# Look-Alike Drug Names
There is limited information regarding Cyclizine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Bonine_for_Kids |
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